Tolerance of an enteral diet is one of the fundamental components of postoperative wellness, along with the ability to mobilize freely without supplemental oxygen and a readiness to be discharged home as soon as possible. Accordingly, post­operative gastrointestinal (GI) tract dysfunction is best defined as intolerance of an enteral diet after having been tolerant of one preoperatively. I prefer the term postoperative GI tract dysfunction over postoperative ileus, as ileus is ill defined, covering a wide spectrum of clinical signs and having a range of published incidences so broad (5%–100%) that it defies useful discussion.

Table 1 presents a schema for classifying postoperative GI tract dysfunction.¹ This review focuses on the causes and management of early-onset GI dysfunction—ie, developing within 6 to 48 hours of surgery—which can develop into persistent dysfunction (> 72 hours) and thereby prolong the hospital stay and potentially manifest systemically. This review will not address immediate and transient postoperative nausea and vomiting, which is distinct from intolerance of an enteral diet and has been reviewed extensively elsewhere.²

GI DYSFUNCTION: A COMMON POSTOPERATIVE MORBIDITY

Postoperative GI tract dysfunction is common, as illustrated by a large prospective cohort study at Duke University Medical Center³ that used the Postoperative Morbidity Survey (which has since been validated⁴) to document complications following major noncardiac surgery (ie, anticipated duration > 2 hours and anticipated blood loss > 500 mL). Hospital discharge was delayed in 27% of the study’s 438 patients as a result of a postoperative complication, and GI dysfunction was the most common type of complication overall and on postoperative days 5, 8, and 15. Episodes of GI dysfunction ranged from intolerance of an enteral diet to ischemic gut resulting in multiple organ failure.³

Adapted from a PowerPoint slide developed by Dr. M.P.W. Grocott.

A similar prospective cohort study conducted in the United Kingdom yielded comparable findings, with GI dysfunction being the most common type of postoperative complication reported.⁴ This study served to validate the Postoperative Morbidity Survey, which is now used worldwide to describe morbidity after major surgery. Figure 1 presents rates of postoperative GI dysfunction relative to other common types of postoperative complications in both the Duke study and the UK study.^3,4

A MULTIFACTORIAL PATHOGENESIS

The pathophysiology of postoperative GI tract dysfunction can be ischemic, metabolic, toxic, neurogenic, myogenic, pharmacologic, or mechanical.

It is important to recognize that in many cases no single factor explains the whole story behind postsurgical GI tract dysfunction, and none of these factors is an ipso facto cause of such dysfunction. For instance, a “mechanical” pathogenesis refers to any manipulation of the gut that causes an inflammatory response in the gut’s various layers, resulting in injury.^5,6 However, GI tract dysfunction commonly occurs after operations (including laparoscopic procedures) in which the gut was not handled at all. Similarly, in terms of a pharmacologic pathophysiology, while opioids can affect GI propulsion and cause constipation,^7,8 avoidance of opioid use does not ensure prevention of GI tract dysfunction. Moreover, opioid abusers do not generally exhibit intolerance of enteral nutrition.

A common mechanism that is often ignored is peri­operative gut ischemia resulting in low-grade injury. Low-grade hypovolemia can cause loss of perfusion to the tip of the microvillus, triggering apoptosis and potentially necrosis, which typically requires about 3 days for recovery. An experiment among 6 healthy volunteers who underwent elective hemorrhage (25% of blood volume removed) over 1 hour demonstrated that gastric tonometry was an earlier indicator of hypovolemia than were commonly measured hemodynamic variables such as invasive blood pressure, stroke volume, heart rate, and lactate and arterial blood gas measurements.⁹

FLUID LOADING AIDS GI RECOVERY

A targeted increase of intravascular volume and global blood flow perioperatively has been shown repeatedly to improve surgical outcome.^10–24 In clinical trials, the most common intervention to achieve the predetermined hemo­dynamic goal has been fluid loading. Overall, targeted increases in perioperative global blood flow have been associated with reduced mortality,²⁵ with the presumed mechanism being maintenance of end-organ perfusion.

The role of end-organ perfusion maintenance was confirmed in a controlled study of 60 patients under­going cardiac surgery in which perioperative fluid loading (with colloid) maintained gut perfusion as measured by gastric tonometry, whereas a control group had a reproducible reduction in gut perfusion.¹⁵ Fluid loading was associated with a significant reduction in the incidence of gut mucosal hypoperfusion—from 56% to 7%—and significant reductions in the incidence of minor and major complications, mean days in the hospital, and mean days in the intensive care unit.

Fluid type matters

The type of intraoperative fluid loading is a factor in postoperative recovery.

Colloid vs crystalloid. Moretti et al found that colloid (6% hetastarch in saline or 6% hetastarch in balanced salt) was superior to crystalloid (lactated Ringer’s solution) in preventing nausea, severe pain, vomiting, periorbital edema, and double vision postoperatively (P < .05 for all) despite comparable hemodynamic profiles.²⁶

Ringer’s vs normal saline. Williams et al compared intravenous lactated Ringer’s solution with normal saline (0.9% sodium chloride) in a randomized study of healthy volunteers.²⁷ The group that received normal saline demonstrated central nervous system changes and a much higher incidence of abdominal discomfort, a finding consistent with the toxic properties of chlorine to the gut.

Balanced electrolyte solutions vs saline-based fluids. Wilkes et al compared crystalloid and colloid solutions with physiologically balanced electrolyte formulations (Hextend) against saline-based fluids (Hespan) in elderly surgical patients.²⁸ They found that balanced electrolyte solutions were superior in improving gastric mucosal perfusion and preventing hyperchloremic metabolic acidosis. As a result of a reduction in GI tract perfusion, postoperative vomiting was more frequent in the group receiving saline-based fluids.

Evidence for Doppler-guided fluid management

Use of esophageal Doppler ultrasonography to guide fluid administration intraoperatively is fairly common in the United Kingdom and is based on randomized controlled trials showing that Doppler-guided colloid administration to maximize stroke volume reduces morbidity and length of hospital stay in surgical patients. In one government-supported study of 128 colorectal resection patients, Doppler-guided small boluses of colloid increased stroke volume, cardiac output, and oxygen delivery compared with conventional (central venous pressure–based) fluid management.²⁹ Gut function improved significantly faster with Doppler-guided fluid management as evidenced by a more rapid return of flatus, opening of bowels, and achievement of a full diet, and by faster discharge from the hospital. The incidence of GI complications was reduced from 45.3% in the conventional management group to 14.1% in the Doppler group. The relative risk of GI tract dysfunction was 5.3 times higher with conventional management.

 

 

OTHER STRATEGIES TO REDUCE POSTOPERATIVE GI DYSFUNCTION

In addition to fluid loading, a number of other methods have been studied in an attempt to reduce the incidence of postoperative GI tract dysfunction.

Epidural neostigmine: Improvement in some measures

Epidural neostigmine was compared with saline control in a randomized study of 45 patients scheduled for abdominal aortic surgery.³⁰ Time to first bowel sounds and time to first flatus were significantly shorter in the neostigmine group, but time to first defecation and the incidence of post­operative complications were similar between the groups.

Laxatives speed return of GI function

In a study of 53 women undergoing fast-track hysterectomy, recovery of GI tract function was faster in those randomized to receive laxatives (magnesium oxide and disodium phosphate) starting 6 hours postoperatively compared with those receiving placebo.³¹ Median time to first defecation was reduced from 69 hours in the placebo group to 45 hours in the laxative group (P < .0001), and postoperative hospitalization was shortened by a median of 1 day in the laxative group. There were no significant between-group differences in pain scores, postoperative nausea and vomiting, or the use of morphine or antiemetics.

Fentanyl reduces gastric myoelectrical activity

Intravenous administration of the opioid fentanyl significantly reduced gastric myoelectrical activity in an uncontrolled study of 20 patients undergoing elective surgery, but wide variation in effect was observed among patients.³² There was no correlation between the myoelectrical outcome and the presence of polymorphisms of the mu-opioid receptor gene.

Systemic lidocaine accelerates return of bowel function

Perioperative administration of systemic lidocaine, given as a 1.5-mg/kg bolus followed by continuous infusion at 2 mg/min, accelerated the return of bowel function and shortened the length of hospital stay compared with placebo in a randomized study of 60 colorectal surgery patients.³³

Early oral feeding cuts length of stay

A recent meta-analysis of randomized trials found that early oral intake of fluids and food after major abdominal gynecologic surgery was associated with an increased risk of nausea but a reduced length of hospital stay.³⁴ The authors recommended an individualized approach to early feeding, and called for cost-effectiveness and patient satisfaction studies.

Mosapride improves gastric emptying

Mosapride is a 5-HT₄ agonist that has been shown to improve gastric emptying in a randomized controlled study of 40 patients undergoing laparoscopic colectomy.³⁵ Time to first postoperative bowel movement, time to maximal gastric emptying rate, and postoperative hospital stay were all significantly shorter in patients receiving mosapride versus control. Mosapride is not currently approved for marketing in the United States.

Mu-opioid antagonists: Some show promise, others don’t

Mu-opioid receptor antagonists have been developed primarily to reverse opioid-induced bowel dysfunction. Commercially available drugs in this class include alvimopan, methylnaltrexone, nalbuphine, and naloxone. A recent meta-analysis of 23 randomized controlled studies of these agents for opioid-induced bowel dysfunction concluded that alvimopan and methylnaltrexone were superior to placebo but that evidence was insufficient for the safety or efficacy of naloxone and nalbuphine.³⁶

Nasogastric decompression: Usually more harm than benefit

Prophylactic nasogastric decompression is an intervention devoid of evidence. A meta-analysis of 33 studies encompassing 5,240 patients randomized to routine nasogastric tube placement, selective nasogastric tube use, or no nasogastric tube placement after abdominal surgery found no advantage to routine nasogastric tube use.³⁷ In fact, patients not receiving routine tube placement had a significantly earlier return of bowel function and a significant decrease in pulmonary complications. The incidence of anastomotic leak was not different among the groups. Routine tube use was associated with a lower incidence of vomiting but more patient discomfort. The clear conclusion is that, in most situations, elective placement of a nasogastric tube only causes harm.

Chewing gum: A simple intervention that works

In a recent meta-analysis of five randomized controlled trials, the simple intervention of gum chewing after colorectal surgery significantly accelerated the time to flatus and time to defecation, and was associated with a nonsignificant trend toward a shorter postoperative hospital stay.³⁸

CONCLUSIONS ON MANAGEMENT

Traditional measures intended to reduce the incidence of postoperative GI tract dysfunction—administration of prokinetic drugs, placement of nasogastric tubes, avoidance of food and fluids—are not beneficial and are often harmful. Administration of targeted amounts of fluid to optimize ventricular filling and end-organ perfusion has repeatedly been demonstrated to improve outcomes, particularly those related to GI tract perfusion and function. Administration of larger volumes of colloid, to achieve predetermined increases in stroke volume, improves gut perfusion and reduces the incidence of GI tract dysfunction.

Many simple, inexpensive, and readily available strategies for preventing or reversing postoperative GI tract dysfunction have some degree of evidence-based support and should be considered. I would recommend a multimodal approach that includes a limited surgical incision, regional local anesthesia without use of opioids, immediate postoperative mobilization, early enteral feeding, and postoperative gum chewing.¹ Such an approach promises to reduce GI tract dysfunction and other postoperative complications as well as to shorten hospital stay.

 

 

DISCUSSION

Question from the audience: You mentioned the selective use of nasogastric tubes. In which patients would you use them?

Dr. Mythen: For upper GI surgeries—esophagectomy, for example—a nasogastric tube is inevitable. Beyond that, the specific indications for tube placement are very limited. At our institution, we no longer place nasogastric tubes following the vast majority of GI tract operations, with esophagectomy being the exception.

Question from the audience: Would you comment on the selective contribution of thoracic epidural analgesia with respect to early feeding after abdominal or colon surgery?

Dr. Mythen: If you’re an enthusiast for thoracic epidurals, you can present the literature in a way that definitively demonstrates a huge advantage to thoracic epidurals. When they work well for the individual, they are fantastic, but you must have a very effective team and system to deliver success to the whole patient population. At our institution the failure rate 20 to 24 hours postoperatively is about 50%.

Question from the audience: I’m an internist and I’ve never heard of the esophageal Doppler-directed fluid bolus protocol—or of anyone using colloids at all. Is that something that is generally practiced in the United States?

Dr. Mythen: Some institutions are practicing goal-directed fluid management now. If you measure stroke volume and give small boluses of colloid, you need a lot less fluid to achieve a higher intravascular volume and goal. At our institution, we’ve repackaged it as “goal-directed fluid restriction” to gain acceptance among surgeons. Uptake has been slower in the United States, though studies here have reinforced the message and been supported by editorials. Guessing about fluids, which we’ve done historically, is not very smart. One thing that differentiates an anesthesiologist from an anesthetic technician is the ability to give goal-directed fluid therapy. The ability to act in a targeted fashion makes it possible to achieve an appropriate physiological goal, but it is more difficult.

Question from the audience: In terms of maintenance fluids and chloride toxicity, is there an alternative to D5 half-normal saline for maintenance fluid?

Dr. Mythen: We don’t have a very good postoperative maintenance fluid; D5 half-normal with some potassium is probably as good as it gets at present. I emphasize getting patients to drink as quickly as possible. If they’re not drinking (not using the GI tract), they need a very high level of physician input because fluid balance is rocket science. The GI tract is very clever. Once patients are drinking and eating, they’re fine, but if they still have an intravenous line in, close attention is required.

Question from the audience: Would you use lactated Ringer’s solution in a patient who is just not eating or drinking?

Dr. Mythen: I do, actually. I tend to mix it in with some D5 half-normal saline because lactated Ringer’s is a great solution. The body can use the lactate to make sugar if necessary. The brain is one of the few organs that will metabolize lactate.

Follow-up question: Would you use it at a lower rate to prevent volume overload?

Dr. Mythen: Yes, at 60 mL/hr. The important thing is that if intravenous fluids are still required, the patient needs to be in a fairly supervised, high-dependency environment. You must address the real issue: Why aren’t they drinking? If the patient is not drinking postoperatively, someone’s done a bad job or there is something that needs fixing.

Question from audience: In the operating room, do you have a preference between albumin and a high-molecular-weight hetastarch like Hextend?

Dr. Mythen: Europe is slightly different in its choice of colloids. We’ve pretty much abandoned the high-molecular-weight starches. We do not use albumin at our institution for cost reasons, and we can’t find any evidence to support its use. We would have to close one intensive care unit bed to be able to afford using albumin. We use low-molecular-weight hydroxyethyl starches, which I believe are now coming into the United States. They have no major coagulation effect.

Tolerance of an enteral diet is one of the fundamental components of postoperative wellness, along with the ability to mobilize freely without supplemental oxygen and a readiness to be discharged home as soon as possible. Accordingly, post­operative gastrointestinal (GI) tract dysfunction is best defined as intolerance of an enteral diet after having been tolerant of one preoperatively. I prefer the term postoperative GI tract dysfunction over postoperative ileus, as ileus is ill defined, covering a wide spectrum of clinical signs and having a range of published incidences so broad (5%–100%) that it defies useful discussion.

Table 1 presents a schema for classifying postoperative GI tract dysfunction.¹ This review focuses on the causes and management of early-onset GI dysfunction—ie, developing within 6 to 48 hours of surgery—which can develop into persistent dysfunction (> 72 hours) and thereby prolong the hospital stay and potentially manifest systemically. This review will not address immediate and transient postoperative nausea and vomiting, which is distinct from intolerance of an enteral diet and has been reviewed extensively elsewhere.²

GI DYSFUNCTION: A COMMON POSTOPERATIVE MORBIDITY

Postoperative GI tract dysfunction is common, as illustrated by a large prospective cohort study at Duke University Medical Center³ that used the Postoperative Morbidity Survey (which has since been validated⁴) to document complications following major noncardiac surgery (ie, anticipated duration > 2 hours and anticipated blood loss > 500 mL). Hospital discharge was delayed in 27% of the study’s 438 patients as a result of a postoperative complication, and GI dysfunction was the most common type of complication overall and on postoperative days 5, 8, and 15. Episodes of GI dysfunction ranged from intolerance of an enteral diet to ischemic gut resulting in multiple organ failure.³

Adapted from a PowerPoint slide developed by Dr. M.P.W. Grocott.

A similar prospective cohort study conducted in the United Kingdom yielded comparable findings, with GI dysfunction being the most common type of postoperative complication reported.⁴ This study served to validate the Postoperative Morbidity Survey, which is now used worldwide to describe morbidity after major surgery. Figure 1 presents rates of postoperative GI dysfunction relative to other common types of postoperative complications in both the Duke study and the UK study.^3,4

A MULTIFACTORIAL PATHOGENESIS

The pathophysiology of postoperative GI tract dysfunction can be ischemic, metabolic, toxic, neurogenic, myogenic, pharmacologic, or mechanical.

It is important to recognize that in many cases no single factor explains the whole story behind postsurgical GI tract dysfunction, and none of these factors is an ipso facto cause of such dysfunction. For instance, a “mechanical” pathogenesis refers to any manipulation of the gut that causes an inflammatory response in the gut’s various layers, resulting in injury.^5,6 However, GI tract dysfunction commonly occurs after operations (including laparoscopic procedures) in which the gut was not handled at all. Similarly, in terms of a pharmacologic pathophysiology, while opioids can affect GI propulsion and cause constipation,^7,8 avoidance of opioid use does not ensure prevention of GI tract dysfunction. Moreover, opioid abusers do not generally exhibit intolerance of enteral nutrition.

A common mechanism that is often ignored is peri­operative gut ischemia resulting in low-grade injury. Low-grade hypovolemia can cause loss of perfusion to the tip of the microvillus, triggering apoptosis and potentially necrosis, which typically requires about 3 days for recovery. An experiment among 6 healthy volunteers who underwent elective hemorrhage (25% of blood volume removed) over 1 hour demonstrated that gastric tonometry was an earlier indicator of hypovolemia than were commonly measured hemodynamic variables such as invasive blood pressure, stroke volume, heart rate, and lactate and arterial blood gas measurements.⁹

FLUID LOADING AIDS GI RECOVERY

A targeted increase of intravascular volume and global blood flow perioperatively has been shown repeatedly to improve surgical outcome.^10–24 In clinical trials, the most common intervention to achieve the predetermined hemo­dynamic goal has been fluid loading. Overall, targeted increases in perioperative global blood flow have been associated with reduced mortality,²⁵ with the presumed mechanism being maintenance of end-organ perfusion.

The role of end-organ perfusion maintenance was confirmed in a controlled study of 60 patients under­going cardiac surgery in which perioperative fluid loading (with colloid) maintained gut perfusion as measured by gastric tonometry, whereas a control group had a reproducible reduction in gut perfusion.¹⁵ Fluid loading was associated with a significant reduction in the incidence of gut mucosal hypoperfusion—from 56% to 7%—and significant reductions in the incidence of minor and major complications, mean days in the hospital, and mean days in the intensive care unit.

Fluid type matters

The type of intraoperative fluid loading is a factor in postoperative recovery.

Colloid vs crystalloid. Moretti et al found that colloid (6% hetastarch in saline or 6% hetastarch in balanced salt) was superior to crystalloid (lactated Ringer’s solution) in preventing nausea, severe pain, vomiting, periorbital edema, and double vision postoperatively (P < .05 for all) despite comparable hemodynamic profiles.²⁶

Ringer’s vs normal saline. Williams et al compared intravenous lactated Ringer’s solution with normal saline (0.9% sodium chloride) in a randomized study of healthy volunteers.²⁷ The group that received normal saline demonstrated central nervous system changes and a much higher incidence of abdominal discomfort, a finding consistent with the toxic properties of chlorine to the gut.

Balanced electrolyte solutions vs saline-based fluids. Wilkes et al compared crystalloid and colloid solutions with physiologically balanced electrolyte formulations (Hextend) against saline-based fluids (Hespan) in elderly surgical patients.²⁸ They found that balanced electrolyte solutions were superior in improving gastric mucosal perfusion and preventing hyperchloremic metabolic acidosis. As a result of a reduction in GI tract perfusion, postoperative vomiting was more frequent in the group receiving saline-based fluids.

Evidence for Doppler-guided fluid management

Use of esophageal Doppler ultrasonography to guide fluid administration intraoperatively is fairly common in the United Kingdom and is based on randomized controlled trials showing that Doppler-guided colloid administration to maximize stroke volume reduces morbidity and length of hospital stay in surgical patients. In one government-supported study of 128 colorectal resection patients, Doppler-guided small boluses of colloid increased stroke volume, cardiac output, and oxygen delivery compared with conventional (central venous pressure–based) fluid management.²⁹ Gut function improved significantly faster with Doppler-guided fluid management as evidenced by a more rapid return of flatus, opening of bowels, and achievement of a full diet, and by faster discharge from the hospital. The incidence of GI complications was reduced from 45.3% in the conventional management group to 14.1% in the Doppler group. The relative risk of GI tract dysfunction was 5.3 times higher with conventional management.

 

 

OTHER STRATEGIES TO REDUCE POSTOPERATIVE GI DYSFUNCTION

In addition to fluid loading, a number of other methods have been studied in an attempt to reduce the incidence of postoperative GI tract dysfunction.

Epidural neostigmine: Improvement in some measures

Epidural neostigmine was compared with saline control in a randomized study of 45 patients scheduled for abdominal aortic surgery.³⁰ Time to first bowel sounds and time to first flatus were significantly shorter in the neostigmine group, but time to first defecation and the incidence of post­operative complications were similar between the groups.

Laxatives speed return of GI function

In a study of 53 women undergoing fast-track hysterectomy, recovery of GI tract function was faster in those randomized to receive laxatives (magnesium oxide and disodium phosphate) starting 6 hours postoperatively compared with those receiving placebo.³¹ Median time to first defecation was reduced from 69 hours in the placebo group to 45 hours in the laxative group (P < .0001), and postoperative hospitalization was shortened by a median of 1 day in the laxative group. There were no significant between-group differences in pain scores, postoperative nausea and vomiting, or the use of morphine or antiemetics.

Fentanyl reduces gastric myoelectrical activity

Intravenous administration of the opioid fentanyl significantly reduced gastric myoelectrical activity in an uncontrolled study of 20 patients undergoing elective surgery, but wide variation in effect was observed among patients.³² There was no correlation between the myoelectrical outcome and the presence of polymorphisms of the mu-opioid receptor gene.

Systemic lidocaine accelerates return of bowel function

Perioperative administration of systemic lidocaine, given as a 1.5-mg/kg bolus followed by continuous infusion at 2 mg/min, accelerated the return of bowel function and shortened the length of hospital stay compared with placebo in a randomized study of 60 colorectal surgery patients.³³

Early oral feeding cuts length of stay

A recent meta-analysis of randomized trials found that early oral intake of fluids and food after major abdominal gynecologic surgery was associated with an increased risk of nausea but a reduced length of hospital stay.³⁴ The authors recommended an individualized approach to early feeding, and called for cost-effectiveness and patient satisfaction studies.

Mosapride improves gastric emptying

Mosapride is a 5-HT₄ agonist that has been shown to improve gastric emptying in a randomized controlled study of 40 patients undergoing laparoscopic colectomy.³⁵ Time to first postoperative bowel movement, time to maximal gastric emptying rate, and postoperative hospital stay were all significantly shorter in patients receiving mosapride versus control. Mosapride is not currently approved for marketing in the United States.

Mu-opioid antagonists: Some show promise, others don’t

Mu-opioid receptor antagonists have been developed primarily to reverse opioid-induced bowel dysfunction. Commercially available drugs in this class include alvimopan, methylnaltrexone, nalbuphine, and naloxone. A recent meta-analysis of 23 randomized controlled studies of these agents for opioid-induced bowel dysfunction concluded that alvimopan and methylnaltrexone were superior to placebo but that evidence was insufficient for the safety or efficacy of naloxone and nalbuphine.³⁶

Nasogastric decompression: Usually more harm than benefit

Prophylactic nasogastric decompression is an intervention devoid of evidence. A meta-analysis of 33 studies encompassing 5,240 patients randomized to routine nasogastric tube placement, selective nasogastric tube use, or no nasogastric tube placement after abdominal surgery found no advantage to routine nasogastric tube use.³⁷ In fact, patients not receiving routine tube placement had a significantly earlier return of bowel function and a significant decrease in pulmonary complications. The incidence of anastomotic leak was not different among the groups. Routine tube use was associated with a lower incidence of vomiting but more patient discomfort. The clear conclusion is that, in most situations, elective placement of a nasogastric tube only causes harm.

Chewing gum: A simple intervention that works

In a recent meta-analysis of five randomized controlled trials, the simple intervention of gum chewing after colorectal surgery significantly accelerated the time to flatus and time to defecation, and was associated with a nonsignificant trend toward a shorter postoperative hospital stay.³⁸

CONCLUSIONS ON MANAGEMENT

Traditional measures intended to reduce the incidence of postoperative GI tract dysfunction—administration of prokinetic drugs, placement of nasogastric tubes, avoidance of food and fluids—are not beneficial and are often harmful. Administration of targeted amounts of fluid to optimize ventricular filling and end-organ perfusion has repeatedly been demonstrated to improve outcomes, particularly those related to GI tract perfusion and function. Administration of larger volumes of colloid, to achieve predetermined increases in stroke volume, improves gut perfusion and reduces the incidence of GI tract dysfunction.

Many simple, inexpensive, and readily available strategies for preventing or reversing postoperative GI tract dysfunction have some degree of evidence-based support and should be considered. I would recommend a multimodal approach that includes a limited surgical incision, regional local anesthesia without use of opioids, immediate postoperative mobilization, early enteral feeding, and postoperative gum chewing.¹ Such an approach promises to reduce GI tract dysfunction and other postoperative complications as well as to shorten hospital stay.

 

 

DISCUSSION

Question from the audience: You mentioned the selective use of nasogastric tubes. In which patients would you use them?

Dr. Mythen: For upper GI surgeries—esophagectomy, for example—a nasogastric tube is inevitable. Beyond that, the specific indications for tube placement are very limited. At our institution, we no longer place nasogastric tubes following the vast majority of GI tract operations, with esophagectomy being the exception.

Question from the audience: Would you comment on the selective contribution of thoracic epidural analgesia with respect to early feeding after abdominal or colon surgery?

Dr. Mythen: If you’re an enthusiast for thoracic epidurals, you can present the literature in a way that definitively demonstrates a huge advantage to thoracic epidurals. When they work well for the individual, they are fantastic, but you must have a very effective team and system to deliver success to the whole patient population. At our institution the failure rate 20 to 24 hours postoperatively is about 50%.

Question from the audience: I’m an internist and I’ve never heard of the esophageal Doppler-directed fluid bolus protocol—or of anyone using colloids at all. Is that something that is generally practiced in the United States?

Dr. Mythen: Some institutions are practicing goal-directed fluid management now. If you measure stroke volume and give small boluses of colloid, you need a lot less fluid to achieve a higher intravascular volume and goal. At our institution, we’ve repackaged it as “goal-directed fluid restriction” to gain acceptance among surgeons. Uptake has been slower in the United States, though studies here have reinforced the message and been supported by editorials. Guessing about fluids, which we’ve done historically, is not very smart. One thing that differentiates an anesthesiologist from an anesthetic technician is the ability to give goal-directed fluid therapy. The ability to act in a targeted fashion makes it possible to achieve an appropriate physiological goal, but it is more difficult.

Question from the audience: In terms of maintenance fluids and chloride toxicity, is there an alternative to D5 half-normal saline for maintenance fluid?

Dr. Mythen: We don’t have a very good postoperative maintenance fluid; D5 half-normal with some potassium is probably as good as it gets at present. I emphasize getting patients to drink as quickly as possible. If they’re not drinking (not using the GI tract), they need a very high level of physician input because fluid balance is rocket science. The GI tract is very clever. Once patients are drinking and eating, they’re fine, but if they still have an intravenous line in, close attention is required.

Question from the audience: Would you use lactated Ringer’s solution in a patient who is just not eating or drinking?

Dr. Mythen: I do, actually. I tend to mix it in with some D5 half-normal saline because lactated Ringer’s is a great solution. The body can use the lactate to make sugar if necessary. The brain is one of the few organs that will metabolize lactate.

Follow-up question: Would you use it at a lower rate to prevent volume overload?

Dr. Mythen: Yes, at 60 mL/hr. The important thing is that if intravenous fluids are still required, the patient needs to be in a fairly supervised, high-dependency environment. You must address the real issue: Why aren’t they drinking? If the patient is not drinking postoperatively, someone’s done a bad job or there is something that needs fixing.

Question from audience: In the operating room, do you have a preference between albumin and a high-molecular-weight hetastarch like Hextend?

Dr. Mythen: Europe is slightly different in its choice of colloids. We’ve pretty much abandoned the high-molecular-weight starches. We do not use albumin at our institution for cost reasons, and we can’t find any evidence to support its use. We would have to close one intensive care unit bed to be able to afford using albumin. We use low-molecular-weight hydroxyethyl starches, which I believe are now coming into the United States. They have no major coagulation effect.

Tolerance of an enteral diet is one of the fundamental components of postoperative wellness, along with the ability to mobilize freely without supplemental oxygen and a readiness to be discharged home as soon as possible. Accordingly, post­operative gastrointestinal (GI) tract dysfunction is best defined as intolerance of an enteral diet after having been tolerant of one preoperatively. I prefer the term postoperative GI tract dysfunction over postoperative ileus, as ileus is ill defined, covering a wide spectrum of clinical signs and having a range of published incidences so broad (5%–100%) that it defies useful discussion.

Table 1 presents a schema for classifying postoperative GI tract dysfunction.¹ This review focuses on the causes and management of early-onset GI dysfunction—ie, developing within 6 to 48 hours of surgery—which can develop into persistent dysfunction (> 72 hours) and thereby prolong the hospital stay and potentially manifest systemically. This review will not address immediate and transient postoperative nausea and vomiting, which is distinct from intolerance of an enteral diet and has been reviewed extensively elsewhere.²

GI DYSFUNCTION: A COMMON POSTOPERATIVE MORBIDITY

Postoperative GI tract dysfunction is common, as illustrated by a large prospective cohort study at Duke University Medical Center³ that used the Postoperative Morbidity Survey (which has since been validated⁴) to document complications following major noncardiac surgery (ie, anticipated duration > 2 hours and anticipated blood loss > 500 mL). Hospital discharge was delayed in 27% of the study’s 438 patients as a result of a postoperative complication, and GI dysfunction was the most common type of complication overall and on postoperative days 5, 8, and 15. Episodes of GI dysfunction ranged from intolerance of an enteral diet to ischemic gut resulting in multiple organ failure.³

Adapted from a PowerPoint slide developed by Dr. M.P.W. Grocott.

A similar prospective cohort study conducted in the United Kingdom yielded comparable findings, with GI dysfunction being the most common type of postoperative complication reported.⁴ This study served to validate the Postoperative Morbidity Survey, which is now used worldwide to describe morbidity after major surgery. Figure 1 presents rates of postoperative GI dysfunction relative to other common types of postoperative complications in both the Duke study and the UK study.^3,4

A MULTIFACTORIAL PATHOGENESIS

The pathophysiology of postoperative GI tract dysfunction can be ischemic, metabolic, toxic, neurogenic, myogenic, pharmacologic, or mechanical.

It is important to recognize that in many cases no single factor explains the whole story behind postsurgical GI tract dysfunction, and none of these factors is an ipso facto cause of such dysfunction. For instance, a “mechanical” pathogenesis refers to any manipulation of the gut that causes an inflammatory response in the gut’s various layers, resulting in injury.^5,6 However, GI tract dysfunction commonly occurs after operations (including laparoscopic procedures) in which the gut was not handled at all. Similarly, in terms of a pharmacologic pathophysiology, while opioids can affect GI propulsion and cause constipation,^7,8 avoidance of opioid use does not ensure prevention of GI tract dysfunction. Moreover, opioid abusers do not generally exhibit intolerance of enteral nutrition.

A common mechanism that is often ignored is peri­operative gut ischemia resulting in low-grade injury. Low-grade hypovolemia can cause loss of perfusion to the tip of the microvillus, triggering apoptosis and potentially necrosis, which typically requires about 3 days for recovery. An experiment among 6 healthy volunteers who underwent elective hemorrhage (25% of blood volume removed) over 1 hour demonstrated that gastric tonometry was an earlier indicator of hypovolemia than were commonly measured hemodynamic variables such as invasive blood pressure, stroke volume, heart rate, and lactate and arterial blood gas measurements.⁹

FLUID LOADING AIDS GI RECOVERY

A targeted increase of intravascular volume and global blood flow perioperatively has been shown repeatedly to improve surgical outcome.^10–24 In clinical trials, the most common intervention to achieve the predetermined hemo­dynamic goal has been fluid loading. Overall, targeted increases in perioperative global blood flow have been associated with reduced mortality,²⁵ with the presumed mechanism being maintenance of end-organ perfusion.

The role of end-organ perfusion maintenance was confirmed in a controlled study of 60 patients under­going cardiac surgery in which perioperative fluid loading (with colloid) maintained gut perfusion as measured by gastric tonometry, whereas a control group had a reproducible reduction in gut perfusion.¹⁵ Fluid loading was associated with a significant reduction in the incidence of gut mucosal hypoperfusion—from 56% to 7%—and significant reductions in the incidence of minor and major complications, mean days in the hospital, and mean days in the intensive care unit.

Fluid type matters

The type of intraoperative fluid loading is a factor in postoperative recovery.

Colloid vs crystalloid. Moretti et al found that colloid (6% hetastarch in saline or 6% hetastarch in balanced salt) was superior to crystalloid (lactated Ringer’s solution) in preventing nausea, severe pain, vomiting, periorbital edema, and double vision postoperatively (P < .05 for all) despite comparable hemodynamic profiles.²⁶

Ringer’s vs normal saline. Williams et al compared intravenous lactated Ringer’s solution with normal saline (0.9% sodium chloride) in a randomized study of healthy volunteers.²⁷ The group that received normal saline demonstrated central nervous system changes and a much higher incidence of abdominal discomfort, a finding consistent with the toxic properties of chlorine to the gut.

Balanced electrolyte solutions vs saline-based fluids. Wilkes et al compared crystalloid and colloid solutions with physiologically balanced electrolyte formulations (Hextend) against saline-based fluids (Hespan) in elderly surgical patients.²⁸ They found that balanced electrolyte solutions were superior in improving gastric mucosal perfusion and preventing hyperchloremic metabolic acidosis. As a result of a reduction in GI tract perfusion, postoperative vomiting was more frequent in the group receiving saline-based fluids.

Evidence for Doppler-guided fluid management

Use of esophageal Doppler ultrasonography to guide fluid administration intraoperatively is fairly common in the United Kingdom and is based on randomized controlled trials showing that Doppler-guided colloid administration to maximize stroke volume reduces morbidity and length of hospital stay in surgical patients. In one government-supported study of 128 colorectal resection patients, Doppler-guided small boluses of colloid increased stroke volume, cardiac output, and oxygen delivery compared with conventional (central venous pressure–based) fluid management.²⁹ Gut function improved significantly faster with Doppler-guided fluid management as evidenced by a more rapid return of flatus, opening of bowels, and achievement of a full diet, and by faster discharge from the hospital. The incidence of GI complications was reduced from 45.3% in the conventional management group to 14.1% in the Doppler group. The relative risk of GI tract dysfunction was 5.3 times higher with conventional management.

 

 

OTHER STRATEGIES TO REDUCE POSTOPERATIVE GI DYSFUNCTION

In addition to fluid loading, a number of other methods have been studied in an attempt to reduce the incidence of postoperative GI tract dysfunction.

Epidural neostigmine: Improvement in some measures

Epidural neostigmine was compared with saline control in a randomized study of 45 patients scheduled for abdominal aortic surgery.³⁰ Time to first bowel sounds and time to first flatus were significantly shorter in the neostigmine group, but time to first defecation and the incidence of post­operative complications were similar between the groups.

Laxatives speed return of GI function

In a study of 53 women undergoing fast-track hysterectomy, recovery of GI tract function was faster in those randomized to receive laxatives (magnesium oxide and disodium phosphate) starting 6 hours postoperatively compared with those receiving placebo.³¹ Median time to first defecation was reduced from 69 hours in the placebo group to 45 hours in the laxative group (P < .0001), and postoperative hospitalization was shortened by a median of 1 day in the laxative group. There were no significant between-group differences in pain scores, postoperative nausea and vomiting, or the use of morphine or antiemetics.

Fentanyl reduces gastric myoelectrical activity

Intravenous administration of the opioid fentanyl significantly reduced gastric myoelectrical activity in an uncontrolled study of 20 patients undergoing elective surgery, but wide variation in effect was observed among patients.³² There was no correlation between the myoelectrical outcome and the presence of polymorphisms of the mu-opioid receptor gene.

Systemic lidocaine accelerates return of bowel function

Perioperative administration of systemic lidocaine, given as a 1.5-mg/kg bolus followed by continuous infusion at 2 mg/min, accelerated the return of bowel function and shortened the length of hospital stay compared with placebo in a randomized study of 60 colorectal surgery patients.³³

Early oral feeding cuts length of stay

A recent meta-analysis of randomized trials found that early oral intake of fluids and food after major abdominal gynecologic surgery was associated with an increased risk of nausea but a reduced length of hospital stay.³⁴ The authors recommended an individualized approach to early feeding, and called for cost-effectiveness and patient satisfaction studies.

Mosapride improves gastric emptying

Mosapride is a 5-HT₄ agonist that has been shown to improve gastric emptying in a randomized controlled study of 40 patients undergoing laparoscopic colectomy.³⁵ Time to first postoperative bowel movement, time to maximal gastric emptying rate, and postoperative hospital stay were all significantly shorter in patients receiving mosapride versus control. Mosapride is not currently approved for marketing in the United States.

Mu-opioid antagonists: Some show promise, others don’t

Mu-opioid receptor antagonists have been developed primarily to reverse opioid-induced bowel dysfunction. Commercially available drugs in this class include alvimopan, methylnaltrexone, nalbuphine, and naloxone. A recent meta-analysis of 23 randomized controlled studies of these agents for opioid-induced bowel dysfunction concluded that alvimopan and methylnaltrexone were superior to placebo but that evidence was insufficient for the safety or efficacy of naloxone and nalbuphine.³⁶

Nasogastric decompression: Usually more harm than benefit

Prophylactic nasogastric decompression is an intervention devoid of evidence. A meta-analysis of 33 studies encompassing 5,240 patients randomized to routine nasogastric tube placement, selective nasogastric tube use, or no nasogastric tube placement after abdominal surgery found no advantage to routine nasogastric tube use.³⁷ In fact, patients not receiving routine tube placement had a significantly earlier return of bowel function and a significant decrease in pulmonary complications. The incidence of anastomotic leak was not different among the groups. Routine tube use was associated with a lower incidence of vomiting but more patient discomfort. The clear conclusion is that, in most situations, elective placement of a nasogastric tube only causes harm.

Chewing gum: A simple intervention that works

In a recent meta-analysis of five randomized controlled trials, the simple intervention of gum chewing after colorectal surgery significantly accelerated the time to flatus and time to defecation, and was associated with a nonsignificant trend toward a shorter postoperative hospital stay.³⁸

CONCLUSIONS ON MANAGEMENT

Traditional measures intended to reduce the incidence of postoperative GI tract dysfunction—administration of prokinetic drugs, placement of nasogastric tubes, avoidance of food and fluids—are not beneficial and are often harmful. Administration of targeted amounts of fluid to optimize ventricular filling and end-organ perfusion has repeatedly been demonstrated to improve outcomes, particularly those related to GI tract perfusion and function. Administration of larger volumes of colloid, to achieve predetermined increases in stroke volume, improves gut perfusion and reduces the incidence of GI tract dysfunction.

Many simple, inexpensive, and readily available strategies for preventing or reversing postoperative GI tract dysfunction have some degree of evidence-based support and should be considered. I would recommend a multimodal approach that includes a limited surgical incision, regional local anesthesia without use of opioids, immediate postoperative mobilization, early enteral feeding, and postoperative gum chewing.¹ Such an approach promises to reduce GI tract dysfunction and other postoperative complications as well as to shorten hospital stay.

 

 

DISCUSSION

Question from the audience: You mentioned the selective use of nasogastric tubes. In which patients would you use them?

Dr. Mythen: For upper GI surgeries—esophagectomy, for example—a nasogastric tube is inevitable. Beyond that, the specific indications for tube placement are very limited. At our institution, we no longer place nasogastric tubes following the vast majority of GI tract operations, with esophagectomy being the exception.

Question from the audience: Would you comment on the selective contribution of thoracic epidural analgesia with respect to early feeding after abdominal or colon surgery?

Dr. Mythen: If you’re an enthusiast for thoracic epidurals, you can present the literature in a way that definitively demonstrates a huge advantage to thoracic epidurals. When they work well for the individual, they are fantastic, but you must have a very effective team and system to deliver success to the whole patient population. At our institution the failure rate 20 to 24 hours postoperatively is about 50%.

Question from the audience: I’m an internist and I’ve never heard of the esophageal Doppler-directed fluid bolus protocol—or of anyone using colloids at all. Is that something that is generally practiced in the United States?

Dr. Mythen: Some institutions are practicing goal-directed fluid management now. If you measure stroke volume and give small boluses of colloid, you need a lot less fluid to achieve a higher intravascular volume and goal. At our institution, we’ve repackaged it as “goal-directed fluid restriction” to gain acceptance among surgeons. Uptake has been slower in the United States, though studies here have reinforced the message and been supported by editorials. Guessing about fluids, which we’ve done historically, is not very smart. One thing that differentiates an anesthesiologist from an anesthetic technician is the ability to give goal-directed fluid therapy. The ability to act in a targeted fashion makes it possible to achieve an appropriate physiological goal, but it is more difficult.

Question from the audience: In terms of maintenance fluids and chloride toxicity, is there an alternative to D5 half-normal saline for maintenance fluid?

Dr. Mythen: We don’t have a very good postoperative maintenance fluid; D5 half-normal with some potassium is probably as good as it gets at present. I emphasize getting patients to drink as quickly as possible. If they’re not drinking (not using the GI tract), they need a very high level of physician input because fluid balance is rocket science. The GI tract is very clever. Once patients are drinking and eating, they’re fine, but if they still have an intravenous line in, close attention is required.

Question from the audience: Would you use lactated Ringer’s solution in a patient who is just not eating or drinking?

Dr. Mythen: I do, actually. I tend to mix it in with some D5 half-normal saline because lactated Ringer’s is a great solution. The body can use the lactate to make sugar if necessary. The brain is one of the few organs that will metabolize lactate.

Follow-up question: Would you use it at a lower rate to prevent volume overload?

Dr. Mythen: Yes, at 60 mL/hr. The important thing is that if intravenous fluids are still required, the patient needs to be in a fairly supervised, high-dependency environment. You must address the real issue: Why aren’t they drinking? If the patient is not drinking postoperatively, someone’s done a bad job or there is something that needs fixing.

Question from audience: In the operating room, do you have a preference between albumin and a high-molecular-weight hetastarch like Hextend?

Dr. Mythen: Europe is slightly different in its choice of colloids. We’ve pretty much abandoned the high-molecular-weight starches. We do not use albumin at our institution for cost reasons, and we can’t find any evidence to support its use. We would have to close one intensive care unit bed to be able to afford using albumin. We use low-molecular-weight hydroxyethyl starches, which I believe are now coming into the United States. They have no major coagulation effect.

CASE 1: RADICAL PROSTATECTOMY IN A MAN WITH ACUTE DEEP VEIN THROMBOSIS

A 69-year-old man is seen in the preoperative clinic 1 week before a scheduled radical prostatectomy. He has been diagnosed with femoral deep vein thrombosis (DVT) following a complaint of calf soreness.

Question 1.1: How would you treat him for his DVT?

A. Intravenous (IV) unfractionated heparin (UFH)

B. Low-molecular-weight heparin (LMWH)

C. Inferior vena cava (IVC) filter

D. Combination of pharmacologic therapy and then an IVC filter

Dr. Steven L. Cohn: The latest edition of the American College of Chest Physicians (ACCP) evidence-based guidelines on antithrombotic therapy recommends the use of therapeutic-dose subcutaneous LMWH over IV UFH for initial treatment of acute DVT in the outpatient or inpatient setting.¹ Additionally, indications for an IVC filter include the prevention of pulmonary embolism (PE) in a patient with DVT who requires full-dose anticoagulation but cannot receive it, as would be the case here if the patient proceeds with surgery as scheduled. So if surgery will be postponed, the best option is LMWH; if surgery will not be postponed, the best answer is a combination of pharmacologic therapy with low-dose LMWH and an IVC filter, preferably a retrievable one.²

Question 1.2: You recommend postponing surgery, but the patient is worried about metastatic disease. For how long should surgery be postponed?

A. 2 weeks

B. 1 month

C. 2 months

D. 3 months

E. 6 months

Dr. Cohn: In the absence of anticoagulation therapy, the risk of venous thromboembolism (VTE) is approximately 40% (~1% per day) during the first month following an acute VTE and then declines markedly, to approximately 10%, during the second and third months following the acute event.³ Therefore, I would suggest that the patient wait at least 1 month after an acute DVT before undergoing surgery.

Dr. BobbieJean Sweitzer: This patient is in a hypercoagulable state, and the surgery itself will induce excess hypercoagulability. With a femoral DVT already present, his risk of VTE or PE is likely to be greater than 1% per day during the first month. If he does develop a PE, it may potentially be fatal.

Question 1.3: According to the patient, the surgeon and the internist discussed options, but the surgeon “doesn’t believe in filters” and the patient doesn’t want to postpone the procedure, despite your recommendation. Two weeks later he shows up for surgery having stopped his LMWH 3 days before. What would you do?

A. Cancel the surgery and restart full-dose LMWH

B. Proceed with prophylactic-dose LMWH

C. Proceed after giving a full therapeutic dose

D. Insert a filter and give DVT prophylaxis

Dr. Cohn: A bridging protocol should have been discussed with the surgeon and anesthesiologist before the procedure. Therapeutic levels of LMWH persist as long as 18 hours after discontinuation; therefore, the ACCP recommends interrupting LMWH 24 hours before surgery.⁴

Dr. Sweitzer: The lack of a bridging protocol in this case created a problem. The patient was afraid to continue anticoagulation after hearing the internist and surgeon disagree about the plan, and thus stopped it entirely, and he did not want to delay surgery because he was fearful of metastasis. The surgeon was adamant that IVC filters don’t work. The internist was concerned that the patient was at high risk for a PE. Even though the documented risk of postponing radical prostatectomy for a short time is inconsequential, I was convinced that the patient would not believe this if metastasis were to develop in the future.

Question 1.4: How would you have managed his anticoagulation perioperatively?

A. Stop LMWH 12 hours before surgery and restart at full dose 12 to 24 hours after surgery

B. Stop LMWH 24 hours before surgery and restart at full dose 24 hours after surgery

C. Stop LMWH 24 hours before surgery and restart prophylactic dosing 12 to 24 hours after surgery, and then full-dose LMWH in 48 to 72 hours

D. Stop LMWH 24 hours before surgery and restart at full dose 72 hours after surgery

Dr. Cohn: The correct timing for stopping LMWH is 24 hours before surgery. As for how to resume anticoagulation in patients at high risk for VTE or those undergoing major surgery, the latest ACCP guidelines recommend the following⁴:

• Reinitiation of anticoagulation 12 to 24 hours postoperatively, assuming adequate hemostasis in patients not at high risk for bleeding
• Use of a prophylactic dose or no anticoagulation for up to 72 hours if the patient is at high risk for bleeding.

These recommendations are a departure from previous practice, in which we routinely restarted anticoagulation 6 to 12 hours postoperatively.

Dr. Sweitzer: According to guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA),⁵ if twice-daily LMWH is stopped 24 hours ahead of time (as long as patients have normal renal function), it is safe to perform epidural or spinal anesthesia, if either is an option. If full-dose UFH is used, the partial thrombo­plastin time (PTT) is monitored and central neuraxial blockade may be done if the PTT is in the normal range, which typically is 2 to 6 hours after UFH is stopped.

Additionally, the platelet count should be checked every 3 days postoperatively while the patient is on UFH or LMWH. It may be just as important to monitor the platelet count preoperatively if the patient has been on UFH or LMWH for an extended duration, especially if a central neuraxial anesthetic technique is planned.

Dr. Cohn: The reason for monitoring the platelet count is the potential for heparin-induced thrombocytopenia in patients on UFH. I recently encountered a patient who developed postoperative heparin-induced thrombo­cytopenia with thrombosis while on LMWH, which is relatively uncommon compared with UFH.

Case resolution

After much discussion of the risk of a significant PE with the patient, family, urologist, and vascular surgeon, it is decided that a temporary IVC filter will be placed in the operating room immediately after induction of general anesthesia and before the prostatectomy. The operation is delayed about 1 hour to allow this option. The patient is successfully treated and has the IVC filter removed 1 month postoperatively.

 

 

CASE 2: RADICAL CYSTECTOMY IN ELDERLY MAN WITH CARDIAC RISK FACTORS

A 78-year-old obese Russian-speaking man is seen in the preoperative clinic prior to a scheduled radical cystectomy for highly invasive bladder cancer. He is a poor historian and argues with the several family members accompanying him, but it is determined that his medical history includes hypertension, diabetes mellitus, a myocardial infarction (MI) 5 years previously (in Russia), and stable angina that is determined to be class II.

He had no previous work-up and no electrocardiogram (ECG). His medications are aspirin, metoprolol, and metformin. His blood pressure is 190/100 mm Hg, heart rate 90 beats per minute, and body mass index 32. On examination, there is no murmur, S3 gallop, or rales. His blood glucose is 220 mg/dL, and his creatinine is slightly elevated (1.4 mg/dL). ECG verifies a prior MI.

Question 2.1: Which of the following additional tests should be ordered preoperatively?

A. Hemoglobin (Hb) A_1c

B. Lipid profile

C. Both

D. Neither

Dr. Sweitzer: Because the surgery is not elective, no immediate benefit would be achieved by ordering either an HbA_1c or a lipid profile. However, if you view the preoperative evaluation as an opportunity to manage risk factors over the long term, then it may be a good idea to order the lipid profile because this patient has rarely engaged the health care system. Likewise, the HbA_1c can be ordered to set in place his long-term management. Sometimes we focus on the preoperative visit only in the context of the surgery, but if a test or intervention is appropriate and needed for long-term management, then it is appropriate to do now.

Dr. Cohn: There is no evidence to support using the preoperative HbA_1c to alter management decisions. I would not postpone surgery based on the HbA_1c value, as I would if his glucose level were 600 mg/dL. Most of the studies that have assessed postoperative complications based on preoperative HbA_1c did not control for postoperative glucose levels. The incidence of complications varies based on the type of complication and the type of surgery.

Similarly, I would not use lipid values to guide management of this patient. Studies suggest that perioperative statin therapy may reduce postoperative morbidity and mortality in patients undergoing vascular surgery (see article by Poldermans on page S79 of this supplement), but our patient already has indications for a statin—a remote MI and diabetes—independent of what his lipid values are.

Question 2.2: How would you manage his elevated blood pressure (190/100 mm Hg)?

A. Discontinue metoprolol and start a different antihypertensive drug

B. Increase the metoprolol dose

C. Continue metoprolol and add a second drug

D. Observe him on his current regimen

Dr. Cohn: I would increase the dose of metoprolol and consider adding another drug, in view of his heart rate (90 beats per minute) and his cardiac status. Beta-blocker therapy should not be discontinued because doing so in the perioperative period is associated with an increased risk of adverse events such as cardiac death and MI.

Dr. Sweitzer: I would push up the metoprolol a bit to reduce the heart rate, knowing that beta-blockers are probably not the most efficacious antihypertensive agents. I would caution against starting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) because he is scheduled to undergo a fairly significant procedure with expected blood loss and fluid shifts, and either of those agents in combination with a beta-blocker would be challenging to manage on the day of surgery.

Question 2.3: How would you manage his metformin perioperatively?

A. Discontinue it 48 hours preoperatively

B. Discontinue it 24 hours preoperatively

C. Withhold it on the morning of surgery

D. Continue it on the morning of surgery

Dr. Sweitzer: We routinely advise patients to hold all their oral diabetes medications the morning of surgery, primarily because many anesthesiologists are uncertain about the differing risks of hypoglycemia associated with the various oral agents.

Most of us will never see a patient who has lactic acidosis from metformin use. A systematic literature review and analysis found no increase in the risk of lactic acidosis with metformin compared with other oral hypoglycemics,⁶ so fear of lactic acidosis is not a valid reason to discontinue metformin. In fact, I think it is inappropriate to ever postpone or cancel surgery simply because the patient inadvertently took metformin on the morning of surgery. Some may argue that patients with renal insufficiency are at higher risk of lactic acidosis from metformin use on the morning of surgery, but keep in mind that renal insufficiency is a relative contra­indication to metformin use in the first place. Unless the patient is scheduled for a bilateral nephrectomy, his or her renal function is not going to be acutely reduced enough to enable a morning dose of metformin to cause lactic acidosis.

Dr. Cohn: Additionally, in a recent study of patients undergoing coronary artery bypass graft surgery (CABG), there was no increased risk of in-hospital morbidity or mortality in patients who received metformin on the morning of surgery,⁷ although I typically stop it 24 hours before major surgery.

Question 2.4: With respect to statin therapy, which course would you choose preoperatively?

A. Start a statin at a low dose

B. Start a statin at an intermediate dose

C. Start a statin at a high dose

D. Do not start a statin

Dr. Cohn: The answer to this question is not clear cut. The reason not to start a prophylactic statin would be the lack of evidence of benefit in patients undergoing noncardiac, nonvascular surgery, although there is evidence of potential benefit in patients undergoing vascular surgery.* The arguments in favor of starting a statin are that this patient has independent indications for a statin and the planned surgery is a high-risk procedure.

(* Editor’s note: In the time since this summit, results of the DECREASE-IV trial were published [Dunkelgrun et al, Ann Surg 2009; 249:921–926], showing a statisically nonsignificant trend toward improved outcomes at 30 days with fluvastatin in intermediate-risk patients undergoing noncardiovascular surgery.)

In cohort studies, perioperative death rates have been lower in statin recipients than in those not taking a statin.⁸ In the Dutch Echographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III), which randomized noncardiac vascular surgery patients to perioperative fluvastatin or placebo, rates of MI and the composite end point of nonfatal MI or cardiovascular death were significantly lower in the statin group than in the placebo group.⁹

Question 2.5: Which of the following cardiac tests would you order preoperatively?

A. Exercise ECG

B. Dobutamine stress echocardiogram

C. Dipyridamole nuclear imaging

D. Coronary angiography

E. No further cardiac testing

Dr. Cohn: I wouldn’t do any cardiac testing since this patient needs surgery for his malignancy and the results of any testing would be highly unlikely to change management, in terms of canceling the surgery. This approach is consistent with the 2007 guidelines on perioperative cardiovascular evaluation for noncardiac surgery issued by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹⁰

Dr. Sweitzer: I would differ on this question. This patient has not been evaluated adequately for his coronary artery disease. He has poor functional capacity that complicates assessment of his symptoms. He also has diabetes, so he is more likely to have silent myocardial ischemia. At age 78, he is understandably concerned about his survival: radical cystectomy is a major operation associated with significant blood loss, fluid shifts, and a long-term recuperative state. In this case, a cardiac evaluation may change management, not in terms of considering coronary revascularization before the surgery, but in terms of affecting the assessment of his chance of surviving this major operation, his life span following the operation, and his quality of life. For example, a highly positive dobutamine stress echo­cardiogram or certain wall motion abnormalities would suggest that he might not be protected even by optimal perioperative medical management.

Question 2.6: Which of the following would you do pre­operatively to assess pulmonary risk?

A. Obtain pulmonary function tests

B. Order a sleep study

C. Both

D. Neither

Dr. Sweitzer: There is no evidence supporting routine pulmonary function tests for patients undergoing procedures other than lung resection. If obstructive sleep apnea were suspected, I would order a sleep study only if I had access to one quickly to avoid delaying the surgery. Cancer surgery should never be delayed to get a sleep study. However, if this patient were seen in the primary care clinic, I would order a sleep study and, if indicated, put him on continuous positive airway pressure (CPAP). Whether or not preoperative CPAP makes a difference hasn’t been shown. No randomized controlled trials have been conducted, but there are some suggestions that the risks of ischemia and atrial arrhythmias in patients with known coronary artery disease can be reduced with CPAP. It is not always easy to initiate CPAP postoperatively because the number of CPAP machines is limited and titration by a respiratory technician is required, which is typically done in a sleep lab.

How the case was actually managed

Neither an HbA_1c measurement nor a lipid profile was ordered preoperatively, for lack of supportive evidence. The patient was continued on his beta-blocker and the dosage was increased sufficiently to control his blood pressure and heart rate. Metformin was continued, and statin therapy was begun preoperatively in light of the patient’s independent indications for it and the high-risk nature of the procedure. Stress testing was not ordered, in light of the lack of indication, given the patient’s stable angina. The patient refused a sleep study. The operation was lengthy and involved significant blood loss. The patient had a complicated postoperative course and ultimately died from multiorgan failure.

 

 

CASE 3: OPERATIONS OF VARIABLE RISK IN ELDERLY MAN WITH ACTIVE CARDIAC CONDITION

Scenario A: A 75-year-old man with diabetes, class III angina, and Q waves in inferior leads on his ECG is scheduled for elective femoropopliteal bypass surgery. His medications include isosorbide mononitrate (120 mg), amlodipine (10 mg), metoprolol controlled release (100 mg), atorvastatin (80 mg), insulin, and aspirin (81 mg). His heart rate is 64 beats per minute, blood pressure is controlled at 120/80 mm Hg, low-density lipoprotein cholesterol is 80 mg/dL, and creatinine is 1.5 μmol/L.

Scenario B: Consider the same patient undergoing elective cholecystectomy instead of a femoropopliteal bypass.

Scenario C: Consider the same patient scheduled for a cystoscopy instead of the other procedures. He had one episode of gross hematuria 1 week ago that resolved. Work-up by his urologist included a urinalysis and culture that were normal, cytology that was negative for malignancy, and a sonogram and computed tomography scan that were both negative. He has had no further bleeding and is not anemic. The urologist wants to do the cystoscopy for the sake of completeness.

Question 3.1: What would be your preoperative course of action in the above scenarios?

A. Order a dobutamine stress echocardiogram

B. Order nuclear imaging with dipyridamole or adenosine

C. Order coronary angiography

D. Order a resting two-dimensional echocardiogram

E. Continue his current medications and send to surgery with no further testing

Dr. Cohn: This is a man with an active cardiac condition and class III angina, which is considered severe angina in the ACC/AHA 2007 guidelines on peri­operative cardiac evaluation and care.¹⁰ The guidelines’ recommendation is to delay surgery for further evaluation and treatment. He is already on maximal medical therapy, which has failed to control his symptoms. He has poor exercise capacity. The only difference among the case scenarios is a variation in surgical risk.

This patient has independent indications for coronary angiography regardless of whether or not he’s undergoing surgery. He deserves evaluation for possible revascularization to improve his quality of life and symptoms.

I would send the patient to the catheterization lab in every one of these instances, with the possible exception of the cystoscopy scenario, where one could argue that revascularization with stenting would require antiplatelet therapy that might increase the bleeding risk, and also that the antiplatelet therapy would have to be interrupted for the cystoscopy, potentially increasing thrombotic risk.

Dr. Sweitzer: I disagree. The ACC/AHA 2007 guidelines do not recommend going directly to catheterization but rather recommend delaying surgery for further evaluation and treatment.¹⁰ We must ask whether this patient is truly receiving optimal medical management. After all, he is not on an ACE inhibitor or an ARB.

We must also consider whether the surgery is truly elective. In the first scenario, if he has peripheral vascular disease, he is likely to develop gangrene and have a further decrease in exercise capacity, which reduces his functional ability and increases his risk of comorbid conditions. He is at significant risk of developing worsening renal insufficiency or renal failure if he undergoes angiography. Coronary revascularization will delay treatment of his peripheral vascular disease. The Coronary Artery Revascularization Prophylaxis (CARP) trial showed no benefit of coronary revascularization relative to medical management in patients undergoing vascular surgery,¹¹ as is planned for this patient. I believe one must balance two competing risks and have an in-depth discussion with the patient.

In the second scenario, not treating gallstones or preventing cholelithiasis poses more risk to the health of this diabetic patient than does elective surgery if he needs a cholecystectomy. Emergency surgery, especially for acute cholecystitis, also significantly increases the risk of a cardiac event.

In the third scenario, the cystoscopy may uncover bladder cancer, which may be adversely affected by a delay of surgery. Regardless, the patient had gross hematuria and would be at risk for further bleeding should he undergo stenting with the requisite antiplatelet therapy.

Catheterization is not normally recommended unless CABG or stenting is being considered, yet I have seen no data that either of these procedures prolongs life except in very limited circumstances such as left main disease treated with bypass grafting. Though it is true that CABG reduces the incidence and severity of angina, it does not modify the physiologic cause of angina but rather may result in symptom improvement by damaging somatic nerve fibers to the heart. Putting a stent in this patient would be like applying a bandage: his symptoms will likely recur if he does not receive optimal medical management.

In a 2007 science advisory, several major medical societies cautioned against percutaneous coronary intervention (PCI) with drug-eluting stent placement in patients expected to undergo noncardiac surgery that would require interruption of antiplatelet therapy in the following 12 months (and against PCI with bare metal stent placement in patients undergoing such surgery in the following 4 to 6 weeks).¹² Therefore, I would not recommend catheterization for a patient whose noncardiac disease is likely to require surgery in the very near future, as is the case in each of the surgical scenarios above. One could consider noninvasive stress testing, which would be a safer approach and would almost certainly identify either significant stenosis of the left main coronary artery or three-vessel disease, which would be the only possible reasons to recommend CABG. I don’t believe there is any role for PCI for this patient.

Dr. Cohn: I argue for symptom relief even if it doesn’t prolong life. This patient cannot walk across the room without having symptoms despite taking multiple medications. I think he deserves a chance at revascularization if the angiogram shows he has a stenosis amenable to it, but I agree that a drug-eluting stent should not be placed if we know that he will undergo surgery within a few months.

 

 

CASE 4: VENTRAL HERNIA REPAIR IN A MIDDLE-AGED WOMAN

A 60-year-old woman is scheduled for ventral hernia repair. Her medical history is unremarkable, with the exception of hypertension. She denies any bleeding problems and had no complications after a laparoscopic cholecystectomy 10 years ago. She has no family history of bleeding disorders.

Question 4.1: Would you order a prothrombin time (PT)/partial thromboplastin time (PTT)?

A. Yes

B. No

Dr. Cohn: I would not.

Dr. Sweitzer: I agree.

Question 4.2: Although not requested, a PT/PTT was ordered anyway. The PT is normal (12.2 sec/12 sec) and the PTT is abnormal (40 sec/25 sec). What is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Factor VII deficiency

C. Factor IX deficiency

D. Factor XI deficiency

E. Factor XII deficiency

Dr. Cohn: The most likely cause is a sample with insufficient blood in the tube. The test wasn’t indicated in the first place, but now it must be done again.

Question 4.3: The PTT is repeated and remains abnormal: 42 sec/25 sec. Mixing studies correct the abnormality to 29 sec/25 sec. Based on this information, what is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Lupus anticoagulant

C. Prekallikrein factor deficiency

D. Factor XII deficiency

Dr. Cohn: This is not a case of lupus anticoagulant because the abnormal PTT was corrected by the mixing study. Causes of a prolonged PTT include deficiencies of factors XII, XI, and IX, so factor XII deficiency is the most likely explanation, though a deficiency higher up the coagulation cascade (ie, prekallikrein factor deficiency) is possible. In the absence of any personal or family bleeding history, it is unlikely to be a deficiency of factors VII or IX (the hemophiliac) or of factor XI, so a deficiency of factor XII or one of the prekallikrein factors is more likely.

Dr. Sweitzer: A mixing study is indeed the appropriate first step. It is ordered from the lab and involves mixing the patient’s blood with normal plasma and incubating the mixture. If the mixture corrects the PTT result, as was the case with this patient, it indicates a coagulation factor deficiency in the patient’s blood; if it doesn’t correct, that should prompt evaluation for lupus anticoagulant or the presence of some other protein or hormone that’s prolonging the PTT.

Question 4.4: How would you manage this patient perioperatively?

A. Fresh frozen plasma

B. Platelet transfusion

C. Cryoprecipitate

D. Factor VII

E. No treatment necessary

Dr. Cohn: No treatment is necessary. Factor XII deficiency does not cause bleeding, regardless of the PTT. Factor XI deficiency is associated with bleeding, but usually there is a family history or a personal history of bleeding with surgery.

Screening coagulation studies are not usually indicated in a patient without a personal or family history of bleeding, liver disease, alcohol or drug use, or current anticoagulant therapy. Such studies are usually normal in such patients, and when they are not, it’s usually because of a lab error or a disease (hypercoagulable state) or factor deficiency that does not cause bleeding

Dr. Sweitzer: However, if the PTT is prolonged, the cause should be identified, because if the patient is sent to the operating room without an explanation for the prolongation, the perioperative team might think the patient has a bleeding problem and use fresh frozen plasma too readily. Fresh frozen plasma is not appropriate for everyone and may actually make a potentially hypercoagulable state worse.

 

 

DISCUSSION

Question from the audience: It was said that use of ACE inhibitors and ARBs should be avoided around the time of surgery. I’ve done an extensive literature search and found minimal to no evidence to support this practice. To the contrary, I found fairly good evidence to indicate that heart failure can be exacerbated significantly and acutely, as early as within 24 hours, when patients are taken off their ACE inhibitor or ARB. I would like your viewpoint on this basic pathology in perioperative medicine.

Dr. Cohn: The literature on the use of ACE inhibitors or ARBs prior to noncardiac surgery consists of five studies with fewer than 500 patients in total, as recently reviewed by Rosenman et al.¹³ Although there was no excess of death or MI associated with taking these medications on the morning of surgery, they did increase the need for fluid and pressors.

Dr. Sweitzer: Patients with hypertension have bigger variations of blood pressure, both hypo- and hypertension, in the perioperative period. For this reason, it was standard of care 30 years ago to stop all antihypertensive drugs, including beta-blockers, preoperatively. We soon found that although this practice prevented many episodes of hypotension, it increased the occurrence of perioperative hypertension and the likelihood of cardiac events. It then became standard of care to always continue antihypertensive drugs on the morning of surgery. In the late 1980s and early 1990s, several studies showed that ACE inhibitors and ARBs were associated with a more profound drop in blood pressure upon induction of general anesthesia compared with other antihypertensives.

The usual ways we treat drops in blood pressure—with phenylephrine and ephedrine—are not very effective in treating hypotension associated with general anesthesia in patients taking ACE inhibitors or ARBs. Vasopressin is effective in treating refractory hypotension during surgery, but anesthesiologists don’t use it often. Reducing the doses of induction agents is another means of attenuating the hypotension induced by ACE inhibitors and ARBs.

We should not routinely stop ACE inhibitors and ARBs on the day of surgery, particularly in patients being treated for heart failure, angina, or a prior MI. My bias is to selectively hold ACE inhibitors and ARBs on the morning of surgery in patients who are undergoing a significant operation with a high likelihood of hypotension, have well-controlled preoperative blood pressure, are taking multiple antihypertensive agents, and do not have heart failure. Otherwise, patients should continue their ACE inhibitors and ARBs on the morning of surgery, and the anesthesiologist should be prepared for significant hypotension upon induction of anesthesia, alter anesthesia induction doses accordingly, have vasopressin handy, and avoid the temptation to treat hypotension with fluids or repeated doses of phenylephrine and ephedrine. The previous comment about concerns with ACE inhibitors and ARBs was in the context of initiating new therapies in the immediate preoperative period.

Question from the audience: Urinalysis is ordered for many patients undergoing orthopedic surgery, and invariably some bacteriuria is found. Can you comment on the value of urinalysis and subsequent treatment of abnormal results?

Dr. Cohn: I believe you should never order a urinalysis in an asymptomatic patient, with the exception of patients undergoing procedures that involve genitourinary or gynecologic instrumentation. Ordering a urinalysis before joint replacement has been promoted in the orthopedic literature on the theoretical grounds that bacteria might somehow seed and colonize the joint. Orthopedic surgeons like to do it, but I disregard their requests for it.

Dr. Sweitzer: One study showed that we’d need to spend $1.5 million on screening urinalysis for asymptomatic patients scheduled for joint replacement surgery in order to prevent one joint infection.¹⁴

Dr. Cohn: Also, patients are going to get their one dose of cephalosporin before surgery anyway, and that will probably knock out any bacteria that would be found on urinalysis.

Question from the audience: Can you clarify how the 2007 ACC/AHA perioperative guidelines define an active cardiac condition? The patient in your third case report had class III angina, or angina with less than usual activities, but nothing was presented to suggest that his symptoms were unstable. I would suggest that despite his class III symptoms, his angina was stable, and I would have continued down the algorithm rather than defining his cardiac condition as active and considering an intervention.

Dr. Cohn: An active cardiac condition is defined by the ACC as unstable coronary syndromes, which include acute (within the prior 7 days) or recent (within the prior 30 days) MI, unstable angina, and severe (class III or IV) angina.

CASE 1: RADICAL PROSTATECTOMY IN A MAN WITH ACUTE DEEP VEIN THROMBOSIS

A 69-year-old man is seen in the preoperative clinic 1 week before a scheduled radical prostatectomy. He has been diagnosed with femoral deep vein thrombosis (DVT) following a complaint of calf soreness.

Question 1.1: How would you treat him for his DVT?

A. Intravenous (IV) unfractionated heparin (UFH)

B. Low-molecular-weight heparin (LMWH)

C. Inferior vena cava (IVC) filter

D. Combination of pharmacologic therapy and then an IVC filter

Dr. Steven L. Cohn: The latest edition of the American College of Chest Physicians (ACCP) evidence-based guidelines on antithrombotic therapy recommends the use of therapeutic-dose subcutaneous LMWH over IV UFH for initial treatment of acute DVT in the outpatient or inpatient setting.¹ Additionally, indications for an IVC filter include the prevention of pulmonary embolism (PE) in a patient with DVT who requires full-dose anticoagulation but cannot receive it, as would be the case here if the patient proceeds with surgery as scheduled. So if surgery will be postponed, the best option is LMWH; if surgery will not be postponed, the best answer is a combination of pharmacologic therapy with low-dose LMWH and an IVC filter, preferably a retrievable one.²

Question 1.2: You recommend postponing surgery, but the patient is worried about metastatic disease. For how long should surgery be postponed?

A. 2 weeks

B. 1 month

C. 2 months

D. 3 months

E. 6 months

Dr. Cohn: In the absence of anticoagulation therapy, the risk of venous thromboembolism (VTE) is approximately 40% (~1% per day) during the first month following an acute VTE and then declines markedly, to approximately 10%, during the second and third months following the acute event.³ Therefore, I would suggest that the patient wait at least 1 month after an acute DVT before undergoing surgery.

Dr. BobbieJean Sweitzer: This patient is in a hypercoagulable state, and the surgery itself will induce excess hypercoagulability. With a femoral DVT already present, his risk of VTE or PE is likely to be greater than 1% per day during the first month. If he does develop a PE, it may potentially be fatal.

Question 1.3: According to the patient, the surgeon and the internist discussed options, but the surgeon “doesn’t believe in filters” and the patient doesn’t want to postpone the procedure, despite your recommendation. Two weeks later he shows up for surgery having stopped his LMWH 3 days before. What would you do?

A. Cancel the surgery and restart full-dose LMWH

B. Proceed with prophylactic-dose LMWH

C. Proceed after giving a full therapeutic dose

D. Insert a filter and give DVT prophylaxis

Dr. Cohn: A bridging protocol should have been discussed with the surgeon and anesthesiologist before the procedure. Therapeutic levels of LMWH persist as long as 18 hours after discontinuation; therefore, the ACCP recommends interrupting LMWH 24 hours before surgery.⁴

Dr. Sweitzer: The lack of a bridging protocol in this case created a problem. The patient was afraid to continue anticoagulation after hearing the internist and surgeon disagree about the plan, and thus stopped it entirely, and he did not want to delay surgery because he was fearful of metastasis. The surgeon was adamant that IVC filters don’t work. The internist was concerned that the patient was at high risk for a PE. Even though the documented risk of postponing radical prostatectomy for a short time is inconsequential, I was convinced that the patient would not believe this if metastasis were to develop in the future.

Question 1.4: How would you have managed his anticoagulation perioperatively?

A. Stop LMWH 12 hours before surgery and restart at full dose 12 to 24 hours after surgery

B. Stop LMWH 24 hours before surgery and restart at full dose 24 hours after surgery

C. Stop LMWH 24 hours before surgery and restart prophylactic dosing 12 to 24 hours after surgery, and then full-dose LMWH in 48 to 72 hours

D. Stop LMWH 24 hours before surgery and restart at full dose 72 hours after surgery

Dr. Cohn: The correct timing for stopping LMWH is 24 hours before surgery. As for how to resume anticoagulation in patients at high risk for VTE or those undergoing major surgery, the latest ACCP guidelines recommend the following⁴:

• Reinitiation of anticoagulation 12 to 24 hours postoperatively, assuming adequate hemostasis in patients not at high risk for bleeding
• Use of a prophylactic dose or no anticoagulation for up to 72 hours if the patient is at high risk for bleeding.

These recommendations are a departure from previous practice, in which we routinely restarted anticoagulation 6 to 12 hours postoperatively.

Dr. Sweitzer: According to guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA),⁵ if twice-daily LMWH is stopped 24 hours ahead of time (as long as patients have normal renal function), it is safe to perform epidural or spinal anesthesia, if either is an option. If full-dose UFH is used, the partial thrombo­plastin time (PTT) is monitored and central neuraxial blockade may be done if the PTT is in the normal range, which typically is 2 to 6 hours after UFH is stopped.

Additionally, the platelet count should be checked every 3 days postoperatively while the patient is on UFH or LMWH. It may be just as important to monitor the platelet count preoperatively if the patient has been on UFH or LMWH for an extended duration, especially if a central neuraxial anesthetic technique is planned.

Dr. Cohn: The reason for monitoring the platelet count is the potential for heparin-induced thrombocytopenia in patients on UFH. I recently encountered a patient who developed postoperative heparin-induced thrombo­cytopenia with thrombosis while on LMWH, which is relatively uncommon compared with UFH.

Case resolution

After much discussion of the risk of a significant PE with the patient, family, urologist, and vascular surgeon, it is decided that a temporary IVC filter will be placed in the operating room immediately after induction of general anesthesia and before the prostatectomy. The operation is delayed about 1 hour to allow this option. The patient is successfully treated and has the IVC filter removed 1 month postoperatively.

 

 

CASE 2: RADICAL CYSTECTOMY IN ELDERLY MAN WITH CARDIAC RISK FACTORS

A 78-year-old obese Russian-speaking man is seen in the preoperative clinic prior to a scheduled radical cystectomy for highly invasive bladder cancer. He is a poor historian and argues with the several family members accompanying him, but it is determined that his medical history includes hypertension, diabetes mellitus, a myocardial infarction (MI) 5 years previously (in Russia), and stable angina that is determined to be class II.

He had no previous work-up and no electrocardiogram (ECG). His medications are aspirin, metoprolol, and metformin. His blood pressure is 190/100 mm Hg, heart rate 90 beats per minute, and body mass index 32. On examination, there is no murmur, S3 gallop, or rales. His blood glucose is 220 mg/dL, and his creatinine is slightly elevated (1.4 mg/dL). ECG verifies a prior MI.

Question 2.1: Which of the following additional tests should be ordered preoperatively?

A. Hemoglobin (Hb) A_1c

B. Lipid profile

C. Both

D. Neither

Dr. Sweitzer: Because the surgery is not elective, no immediate benefit would be achieved by ordering either an HbA_1c or a lipid profile. However, if you view the preoperative evaluation as an opportunity to manage risk factors over the long term, then it may be a good idea to order the lipid profile because this patient has rarely engaged the health care system. Likewise, the HbA_1c can be ordered to set in place his long-term management. Sometimes we focus on the preoperative visit only in the context of the surgery, but if a test or intervention is appropriate and needed for long-term management, then it is appropriate to do now.

Dr. Cohn: There is no evidence to support using the preoperative HbA_1c to alter management decisions. I would not postpone surgery based on the HbA_1c value, as I would if his glucose level were 600 mg/dL. Most of the studies that have assessed postoperative complications based on preoperative HbA_1c did not control for postoperative glucose levels. The incidence of complications varies based on the type of complication and the type of surgery.

Similarly, I would not use lipid values to guide management of this patient. Studies suggest that perioperative statin therapy may reduce postoperative morbidity and mortality in patients undergoing vascular surgery (see article by Poldermans on page S79 of this supplement), but our patient already has indications for a statin—a remote MI and diabetes—independent of what his lipid values are.

Question 2.2: How would you manage his elevated blood pressure (190/100 mm Hg)?

A. Discontinue metoprolol and start a different antihypertensive drug

B. Increase the metoprolol dose

C. Continue metoprolol and add a second drug

D. Observe him on his current regimen

Dr. Cohn: I would increase the dose of metoprolol and consider adding another drug, in view of his heart rate (90 beats per minute) and his cardiac status. Beta-blocker therapy should not be discontinued because doing so in the perioperative period is associated with an increased risk of adverse events such as cardiac death and MI.

Dr. Sweitzer: I would push up the metoprolol a bit to reduce the heart rate, knowing that beta-blockers are probably not the most efficacious antihypertensive agents. I would caution against starting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) because he is scheduled to undergo a fairly significant procedure with expected blood loss and fluid shifts, and either of those agents in combination with a beta-blocker would be challenging to manage on the day of surgery.

Question 2.3: How would you manage his metformin perioperatively?

A. Discontinue it 48 hours preoperatively

B. Discontinue it 24 hours preoperatively

C. Withhold it on the morning of surgery

D. Continue it on the morning of surgery

Dr. Sweitzer: We routinely advise patients to hold all their oral diabetes medications the morning of surgery, primarily because many anesthesiologists are uncertain about the differing risks of hypoglycemia associated with the various oral agents.

Most of us will never see a patient who has lactic acidosis from metformin use. A systematic literature review and analysis found no increase in the risk of lactic acidosis with metformin compared with other oral hypoglycemics,⁶ so fear of lactic acidosis is not a valid reason to discontinue metformin. In fact, I think it is inappropriate to ever postpone or cancel surgery simply because the patient inadvertently took metformin on the morning of surgery. Some may argue that patients with renal insufficiency are at higher risk of lactic acidosis from metformin use on the morning of surgery, but keep in mind that renal insufficiency is a relative contra­indication to metformin use in the first place. Unless the patient is scheduled for a bilateral nephrectomy, his or her renal function is not going to be acutely reduced enough to enable a morning dose of metformin to cause lactic acidosis.

Dr. Cohn: Additionally, in a recent study of patients undergoing coronary artery bypass graft surgery (CABG), there was no increased risk of in-hospital morbidity or mortality in patients who received metformin on the morning of surgery,⁷ although I typically stop it 24 hours before major surgery.

Question 2.4: With respect to statin therapy, which course would you choose preoperatively?

A. Start a statin at a low dose

B. Start a statin at an intermediate dose

C. Start a statin at a high dose

D. Do not start a statin

Dr. Cohn: The answer to this question is not clear cut. The reason not to start a prophylactic statin would be the lack of evidence of benefit in patients undergoing noncardiac, nonvascular surgery, although there is evidence of potential benefit in patients undergoing vascular surgery.* The arguments in favor of starting a statin are that this patient has independent indications for a statin and the planned surgery is a high-risk procedure.

(* Editor’s note: In the time since this summit, results of the DECREASE-IV trial were published [Dunkelgrun et al, Ann Surg 2009; 249:921–926], showing a statisically nonsignificant trend toward improved outcomes at 30 days with fluvastatin in intermediate-risk patients undergoing noncardiovascular surgery.)

In cohort studies, perioperative death rates have been lower in statin recipients than in those not taking a statin.⁸ In the Dutch Echographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III), which randomized noncardiac vascular surgery patients to perioperative fluvastatin or placebo, rates of MI and the composite end point of nonfatal MI or cardiovascular death were significantly lower in the statin group than in the placebo group.⁹

Question 2.5: Which of the following cardiac tests would you order preoperatively?

A. Exercise ECG

B. Dobutamine stress echocardiogram

C. Dipyridamole nuclear imaging

D. Coronary angiography

E. No further cardiac testing

Dr. Cohn: I wouldn’t do any cardiac testing since this patient needs surgery for his malignancy and the results of any testing would be highly unlikely to change management, in terms of canceling the surgery. This approach is consistent with the 2007 guidelines on perioperative cardiovascular evaluation for noncardiac surgery issued by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹⁰

Dr. Sweitzer: I would differ on this question. This patient has not been evaluated adequately for his coronary artery disease. He has poor functional capacity that complicates assessment of his symptoms. He also has diabetes, so he is more likely to have silent myocardial ischemia. At age 78, he is understandably concerned about his survival: radical cystectomy is a major operation associated with significant blood loss, fluid shifts, and a long-term recuperative state. In this case, a cardiac evaluation may change management, not in terms of considering coronary revascularization before the surgery, but in terms of affecting the assessment of his chance of surviving this major operation, his life span following the operation, and his quality of life. For example, a highly positive dobutamine stress echo­cardiogram or certain wall motion abnormalities would suggest that he might not be protected even by optimal perioperative medical management.

Question 2.6: Which of the following would you do pre­operatively to assess pulmonary risk?

A. Obtain pulmonary function tests

B. Order a sleep study

C. Both

D. Neither

Dr. Sweitzer: There is no evidence supporting routine pulmonary function tests for patients undergoing procedures other than lung resection. If obstructive sleep apnea were suspected, I would order a sleep study only if I had access to one quickly to avoid delaying the surgery. Cancer surgery should never be delayed to get a sleep study. However, if this patient were seen in the primary care clinic, I would order a sleep study and, if indicated, put him on continuous positive airway pressure (CPAP). Whether or not preoperative CPAP makes a difference hasn’t been shown. No randomized controlled trials have been conducted, but there are some suggestions that the risks of ischemia and atrial arrhythmias in patients with known coronary artery disease can be reduced with CPAP. It is not always easy to initiate CPAP postoperatively because the number of CPAP machines is limited and titration by a respiratory technician is required, which is typically done in a sleep lab.

How the case was actually managed

Neither an HbA_1c measurement nor a lipid profile was ordered preoperatively, for lack of supportive evidence. The patient was continued on his beta-blocker and the dosage was increased sufficiently to control his blood pressure and heart rate. Metformin was continued, and statin therapy was begun preoperatively in light of the patient’s independent indications for it and the high-risk nature of the procedure. Stress testing was not ordered, in light of the lack of indication, given the patient’s stable angina. The patient refused a sleep study. The operation was lengthy and involved significant blood loss. The patient had a complicated postoperative course and ultimately died from multiorgan failure.

 

 

CASE 3: OPERATIONS OF VARIABLE RISK IN ELDERLY MAN WITH ACTIVE CARDIAC CONDITION

Scenario A: A 75-year-old man with diabetes, class III angina, and Q waves in inferior leads on his ECG is scheduled for elective femoropopliteal bypass surgery. His medications include isosorbide mononitrate (120 mg), amlodipine (10 mg), metoprolol controlled release (100 mg), atorvastatin (80 mg), insulin, and aspirin (81 mg). His heart rate is 64 beats per minute, blood pressure is controlled at 120/80 mm Hg, low-density lipoprotein cholesterol is 80 mg/dL, and creatinine is 1.5 μmol/L.

Scenario B: Consider the same patient undergoing elective cholecystectomy instead of a femoropopliteal bypass.

Scenario C: Consider the same patient scheduled for a cystoscopy instead of the other procedures. He had one episode of gross hematuria 1 week ago that resolved. Work-up by his urologist included a urinalysis and culture that were normal, cytology that was negative for malignancy, and a sonogram and computed tomography scan that were both negative. He has had no further bleeding and is not anemic. The urologist wants to do the cystoscopy for the sake of completeness.

Question 3.1: What would be your preoperative course of action in the above scenarios?

A. Order a dobutamine stress echocardiogram

B. Order nuclear imaging with dipyridamole or adenosine

C. Order coronary angiography

D. Order a resting two-dimensional echocardiogram

E. Continue his current medications and send to surgery with no further testing

Dr. Cohn: This is a man with an active cardiac condition and class III angina, which is considered severe angina in the ACC/AHA 2007 guidelines on peri­operative cardiac evaluation and care.¹⁰ The guidelines’ recommendation is to delay surgery for further evaluation and treatment. He is already on maximal medical therapy, which has failed to control his symptoms. He has poor exercise capacity. The only difference among the case scenarios is a variation in surgical risk.

This patient has independent indications for coronary angiography regardless of whether or not he’s undergoing surgery. He deserves evaluation for possible revascularization to improve his quality of life and symptoms.

I would send the patient to the catheterization lab in every one of these instances, with the possible exception of the cystoscopy scenario, where one could argue that revascularization with stenting would require antiplatelet therapy that might increase the bleeding risk, and also that the antiplatelet therapy would have to be interrupted for the cystoscopy, potentially increasing thrombotic risk.

Dr. Sweitzer: I disagree. The ACC/AHA 2007 guidelines do not recommend going directly to catheterization but rather recommend delaying surgery for further evaluation and treatment.¹⁰ We must ask whether this patient is truly receiving optimal medical management. After all, he is not on an ACE inhibitor or an ARB.

We must also consider whether the surgery is truly elective. In the first scenario, if he has peripheral vascular disease, he is likely to develop gangrene and have a further decrease in exercise capacity, which reduces his functional ability and increases his risk of comorbid conditions. He is at significant risk of developing worsening renal insufficiency or renal failure if he undergoes angiography. Coronary revascularization will delay treatment of his peripheral vascular disease. The Coronary Artery Revascularization Prophylaxis (CARP) trial showed no benefit of coronary revascularization relative to medical management in patients undergoing vascular surgery,¹¹ as is planned for this patient. I believe one must balance two competing risks and have an in-depth discussion with the patient.

In the second scenario, not treating gallstones or preventing cholelithiasis poses more risk to the health of this diabetic patient than does elective surgery if he needs a cholecystectomy. Emergency surgery, especially for acute cholecystitis, also significantly increases the risk of a cardiac event.

In the third scenario, the cystoscopy may uncover bladder cancer, which may be adversely affected by a delay of surgery. Regardless, the patient had gross hematuria and would be at risk for further bleeding should he undergo stenting with the requisite antiplatelet therapy.

Catheterization is not normally recommended unless CABG or stenting is being considered, yet I have seen no data that either of these procedures prolongs life except in very limited circumstances such as left main disease treated with bypass grafting. Though it is true that CABG reduces the incidence and severity of angina, it does not modify the physiologic cause of angina but rather may result in symptom improvement by damaging somatic nerve fibers to the heart. Putting a stent in this patient would be like applying a bandage: his symptoms will likely recur if he does not receive optimal medical management.

In a 2007 science advisory, several major medical societies cautioned against percutaneous coronary intervention (PCI) with drug-eluting stent placement in patients expected to undergo noncardiac surgery that would require interruption of antiplatelet therapy in the following 12 months (and against PCI with bare metal stent placement in patients undergoing such surgery in the following 4 to 6 weeks).¹² Therefore, I would not recommend catheterization for a patient whose noncardiac disease is likely to require surgery in the very near future, as is the case in each of the surgical scenarios above. One could consider noninvasive stress testing, which would be a safer approach and would almost certainly identify either significant stenosis of the left main coronary artery or three-vessel disease, which would be the only possible reasons to recommend CABG. I don’t believe there is any role for PCI for this patient.

Dr. Cohn: I argue for symptom relief even if it doesn’t prolong life. This patient cannot walk across the room without having symptoms despite taking multiple medications. I think he deserves a chance at revascularization if the angiogram shows he has a stenosis amenable to it, but I agree that a drug-eluting stent should not be placed if we know that he will undergo surgery within a few months.

 

 

CASE 4: VENTRAL HERNIA REPAIR IN A MIDDLE-AGED WOMAN

A 60-year-old woman is scheduled for ventral hernia repair. Her medical history is unremarkable, with the exception of hypertension. She denies any bleeding problems and had no complications after a laparoscopic cholecystectomy 10 years ago. She has no family history of bleeding disorders.

Question 4.1: Would you order a prothrombin time (PT)/partial thromboplastin time (PTT)?

A. Yes

B. No

Dr. Cohn: I would not.

Dr. Sweitzer: I agree.

Question 4.2: Although not requested, a PT/PTT was ordered anyway. The PT is normal (12.2 sec/12 sec) and the PTT is abnormal (40 sec/25 sec). What is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Factor VII deficiency

C. Factor IX deficiency

D. Factor XI deficiency

E. Factor XII deficiency

Dr. Cohn: The most likely cause is a sample with insufficient blood in the tube. The test wasn’t indicated in the first place, but now it must be done again.

Question 4.3: The PTT is repeated and remains abnormal: 42 sec/25 sec. Mixing studies correct the abnormality to 29 sec/25 sec. Based on this information, what is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Lupus anticoagulant

C. Prekallikrein factor deficiency

D. Factor XII deficiency

Dr. Cohn: This is not a case of lupus anticoagulant because the abnormal PTT was corrected by the mixing study. Causes of a prolonged PTT include deficiencies of factors XII, XI, and IX, so factor XII deficiency is the most likely explanation, though a deficiency higher up the coagulation cascade (ie, prekallikrein factor deficiency) is possible. In the absence of any personal or family bleeding history, it is unlikely to be a deficiency of factors VII or IX (the hemophiliac) or of factor XI, so a deficiency of factor XII or one of the prekallikrein factors is more likely.

Dr. Sweitzer: A mixing study is indeed the appropriate first step. It is ordered from the lab and involves mixing the patient’s blood with normal plasma and incubating the mixture. If the mixture corrects the PTT result, as was the case with this patient, it indicates a coagulation factor deficiency in the patient’s blood; if it doesn’t correct, that should prompt evaluation for lupus anticoagulant or the presence of some other protein or hormone that’s prolonging the PTT.

Question 4.4: How would you manage this patient perioperatively?

A. Fresh frozen plasma

B. Platelet transfusion

C. Cryoprecipitate

D. Factor VII

E. No treatment necessary

Dr. Cohn: No treatment is necessary. Factor XII deficiency does not cause bleeding, regardless of the PTT. Factor XI deficiency is associated with bleeding, but usually there is a family history or a personal history of bleeding with surgery.

Screening coagulation studies are not usually indicated in a patient without a personal or family history of bleeding, liver disease, alcohol or drug use, or current anticoagulant therapy. Such studies are usually normal in such patients, and when they are not, it’s usually because of a lab error or a disease (hypercoagulable state) or factor deficiency that does not cause bleeding

Dr. Sweitzer: However, if the PTT is prolonged, the cause should be identified, because if the patient is sent to the operating room without an explanation for the prolongation, the perioperative team might think the patient has a bleeding problem and use fresh frozen plasma too readily. Fresh frozen plasma is not appropriate for everyone and may actually make a potentially hypercoagulable state worse.

 

 

DISCUSSION

Question from the audience: It was said that use of ACE inhibitors and ARBs should be avoided around the time of surgery. I’ve done an extensive literature search and found minimal to no evidence to support this practice. To the contrary, I found fairly good evidence to indicate that heart failure can be exacerbated significantly and acutely, as early as within 24 hours, when patients are taken off their ACE inhibitor or ARB. I would like your viewpoint on this basic pathology in perioperative medicine.

Dr. Cohn: The literature on the use of ACE inhibitors or ARBs prior to noncardiac surgery consists of five studies with fewer than 500 patients in total, as recently reviewed by Rosenman et al.¹³ Although there was no excess of death or MI associated with taking these medications on the morning of surgery, they did increase the need for fluid and pressors.

Dr. Sweitzer: Patients with hypertension have bigger variations of blood pressure, both hypo- and hypertension, in the perioperative period. For this reason, it was standard of care 30 years ago to stop all antihypertensive drugs, including beta-blockers, preoperatively. We soon found that although this practice prevented many episodes of hypotension, it increased the occurrence of perioperative hypertension and the likelihood of cardiac events. It then became standard of care to always continue antihypertensive drugs on the morning of surgery. In the late 1980s and early 1990s, several studies showed that ACE inhibitors and ARBs were associated with a more profound drop in blood pressure upon induction of general anesthesia compared with other antihypertensives.

The usual ways we treat drops in blood pressure—with phenylephrine and ephedrine—are not very effective in treating hypotension associated with general anesthesia in patients taking ACE inhibitors or ARBs. Vasopressin is effective in treating refractory hypotension during surgery, but anesthesiologists don’t use it often. Reducing the doses of induction agents is another means of attenuating the hypotension induced by ACE inhibitors and ARBs.

We should not routinely stop ACE inhibitors and ARBs on the day of surgery, particularly in patients being treated for heart failure, angina, or a prior MI. My bias is to selectively hold ACE inhibitors and ARBs on the morning of surgery in patients who are undergoing a significant operation with a high likelihood of hypotension, have well-controlled preoperative blood pressure, are taking multiple antihypertensive agents, and do not have heart failure. Otherwise, patients should continue their ACE inhibitors and ARBs on the morning of surgery, and the anesthesiologist should be prepared for significant hypotension upon induction of anesthesia, alter anesthesia induction doses accordingly, have vasopressin handy, and avoid the temptation to treat hypotension with fluids or repeated doses of phenylephrine and ephedrine. The previous comment about concerns with ACE inhibitors and ARBs was in the context of initiating new therapies in the immediate preoperative period.

Question from the audience: Urinalysis is ordered for many patients undergoing orthopedic surgery, and invariably some bacteriuria is found. Can you comment on the value of urinalysis and subsequent treatment of abnormal results?

Dr. Cohn: I believe you should never order a urinalysis in an asymptomatic patient, with the exception of patients undergoing procedures that involve genitourinary or gynecologic instrumentation. Ordering a urinalysis before joint replacement has been promoted in the orthopedic literature on the theoretical grounds that bacteria might somehow seed and colonize the joint. Orthopedic surgeons like to do it, but I disregard their requests for it.

Dr. Sweitzer: One study showed that we’d need to spend $1.5 million on screening urinalysis for asymptomatic patients scheduled for joint replacement surgery in order to prevent one joint infection.¹⁴

Dr. Cohn: Also, patients are going to get their one dose of cephalosporin before surgery anyway, and that will probably knock out any bacteria that would be found on urinalysis.

Question from the audience: Can you clarify how the 2007 ACC/AHA perioperative guidelines define an active cardiac condition? The patient in your third case report had class III angina, or angina with less than usual activities, but nothing was presented to suggest that his symptoms were unstable. I would suggest that despite his class III symptoms, his angina was stable, and I would have continued down the algorithm rather than defining his cardiac condition as active and considering an intervention.

Dr. Cohn: An active cardiac condition is defined by the ACC as unstable coronary syndromes, which include acute (within the prior 7 days) or recent (within the prior 30 days) MI, unstable angina, and severe (class III or IV) angina.

CASE 1: RADICAL PROSTATECTOMY IN A MAN WITH ACUTE DEEP VEIN THROMBOSIS

A 69-year-old man is seen in the preoperative clinic 1 week before a scheduled radical prostatectomy. He has been diagnosed with femoral deep vein thrombosis (DVT) following a complaint of calf soreness.

Question 1.1: How would you treat him for his DVT?

A. Intravenous (IV) unfractionated heparin (UFH)

B. Low-molecular-weight heparin (LMWH)

C. Inferior vena cava (IVC) filter

D. Combination of pharmacologic therapy and then an IVC filter

Dr. Steven L. Cohn: The latest edition of the American College of Chest Physicians (ACCP) evidence-based guidelines on antithrombotic therapy recommends the use of therapeutic-dose subcutaneous LMWH over IV UFH for initial treatment of acute DVT in the outpatient or inpatient setting.¹ Additionally, indications for an IVC filter include the prevention of pulmonary embolism (PE) in a patient with DVT who requires full-dose anticoagulation but cannot receive it, as would be the case here if the patient proceeds with surgery as scheduled. So if surgery will be postponed, the best option is LMWH; if surgery will not be postponed, the best answer is a combination of pharmacologic therapy with low-dose LMWH and an IVC filter, preferably a retrievable one.²

Question 1.2: You recommend postponing surgery, but the patient is worried about metastatic disease. For how long should surgery be postponed?

A. 2 weeks

B. 1 month

C. 2 months

D. 3 months

E. 6 months

Dr. Cohn: In the absence of anticoagulation therapy, the risk of venous thromboembolism (VTE) is approximately 40% (~1% per day) during the first month following an acute VTE and then declines markedly, to approximately 10%, during the second and third months following the acute event.³ Therefore, I would suggest that the patient wait at least 1 month after an acute DVT before undergoing surgery.

Dr. BobbieJean Sweitzer: This patient is in a hypercoagulable state, and the surgery itself will induce excess hypercoagulability. With a femoral DVT already present, his risk of VTE or PE is likely to be greater than 1% per day during the first month. If he does develop a PE, it may potentially be fatal.

Question 1.3: According to the patient, the surgeon and the internist discussed options, but the surgeon “doesn’t believe in filters” and the patient doesn’t want to postpone the procedure, despite your recommendation. Two weeks later he shows up for surgery having stopped his LMWH 3 days before. What would you do?

A. Cancel the surgery and restart full-dose LMWH

B. Proceed with prophylactic-dose LMWH

C. Proceed after giving a full therapeutic dose

D. Insert a filter and give DVT prophylaxis

Dr. Cohn: A bridging protocol should have been discussed with the surgeon and anesthesiologist before the procedure. Therapeutic levels of LMWH persist as long as 18 hours after discontinuation; therefore, the ACCP recommends interrupting LMWH 24 hours before surgery.⁴

Dr. Sweitzer: The lack of a bridging protocol in this case created a problem. The patient was afraid to continue anticoagulation after hearing the internist and surgeon disagree about the plan, and thus stopped it entirely, and he did not want to delay surgery because he was fearful of metastasis. The surgeon was adamant that IVC filters don’t work. The internist was concerned that the patient was at high risk for a PE. Even though the documented risk of postponing radical prostatectomy for a short time is inconsequential, I was convinced that the patient would not believe this if metastasis were to develop in the future.

Question 1.4: How would you have managed his anticoagulation perioperatively?

A. Stop LMWH 12 hours before surgery and restart at full dose 12 to 24 hours after surgery

B. Stop LMWH 24 hours before surgery and restart at full dose 24 hours after surgery

C. Stop LMWH 24 hours before surgery and restart prophylactic dosing 12 to 24 hours after surgery, and then full-dose LMWH in 48 to 72 hours

D. Stop LMWH 24 hours before surgery and restart at full dose 72 hours after surgery

Dr. Cohn: The correct timing for stopping LMWH is 24 hours before surgery. As for how to resume anticoagulation in patients at high risk for VTE or those undergoing major surgery, the latest ACCP guidelines recommend the following⁴:

• Reinitiation of anticoagulation 12 to 24 hours postoperatively, assuming adequate hemostasis in patients not at high risk for bleeding
• Use of a prophylactic dose or no anticoagulation for up to 72 hours if the patient is at high risk for bleeding.

These recommendations are a departure from previous practice, in which we routinely restarted anticoagulation 6 to 12 hours postoperatively.

Dr. Sweitzer: According to guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA),⁵ if twice-daily LMWH is stopped 24 hours ahead of time (as long as patients have normal renal function), it is safe to perform epidural or spinal anesthesia, if either is an option. If full-dose UFH is used, the partial thrombo­plastin time (PTT) is monitored and central neuraxial blockade may be done if the PTT is in the normal range, which typically is 2 to 6 hours after UFH is stopped.

Additionally, the platelet count should be checked every 3 days postoperatively while the patient is on UFH or LMWH. It may be just as important to monitor the platelet count preoperatively if the patient has been on UFH or LMWH for an extended duration, especially if a central neuraxial anesthetic technique is planned.

Dr. Cohn: The reason for monitoring the platelet count is the potential for heparin-induced thrombocytopenia in patients on UFH. I recently encountered a patient who developed postoperative heparin-induced thrombo­cytopenia with thrombosis while on LMWH, which is relatively uncommon compared with UFH.

Case resolution

After much discussion of the risk of a significant PE with the patient, family, urologist, and vascular surgeon, it is decided that a temporary IVC filter will be placed in the operating room immediately after induction of general anesthesia and before the prostatectomy. The operation is delayed about 1 hour to allow this option. The patient is successfully treated and has the IVC filter removed 1 month postoperatively.

 

 

CASE 2: RADICAL CYSTECTOMY IN ELDERLY MAN WITH CARDIAC RISK FACTORS

A 78-year-old obese Russian-speaking man is seen in the preoperative clinic prior to a scheduled radical cystectomy for highly invasive bladder cancer. He is a poor historian and argues with the several family members accompanying him, but it is determined that his medical history includes hypertension, diabetes mellitus, a myocardial infarction (MI) 5 years previously (in Russia), and stable angina that is determined to be class II.

He had no previous work-up and no electrocardiogram (ECG). His medications are aspirin, metoprolol, and metformin. His blood pressure is 190/100 mm Hg, heart rate 90 beats per minute, and body mass index 32. On examination, there is no murmur, S3 gallop, or rales. His blood glucose is 220 mg/dL, and his creatinine is slightly elevated (1.4 mg/dL). ECG verifies a prior MI.

Question 2.1: Which of the following additional tests should be ordered preoperatively?

A. Hemoglobin (Hb) A_1c

B. Lipid profile

C. Both

D. Neither

Dr. Sweitzer: Because the surgery is not elective, no immediate benefit would be achieved by ordering either an HbA_1c or a lipid profile. However, if you view the preoperative evaluation as an opportunity to manage risk factors over the long term, then it may be a good idea to order the lipid profile because this patient has rarely engaged the health care system. Likewise, the HbA_1c can be ordered to set in place his long-term management. Sometimes we focus on the preoperative visit only in the context of the surgery, but if a test or intervention is appropriate and needed for long-term management, then it is appropriate to do now.

Dr. Cohn: There is no evidence to support using the preoperative HbA_1c to alter management decisions. I would not postpone surgery based on the HbA_1c value, as I would if his glucose level were 600 mg/dL. Most of the studies that have assessed postoperative complications based on preoperative HbA_1c did not control for postoperative glucose levels. The incidence of complications varies based on the type of complication and the type of surgery.

Similarly, I would not use lipid values to guide management of this patient. Studies suggest that perioperative statin therapy may reduce postoperative morbidity and mortality in patients undergoing vascular surgery (see article by Poldermans on page S79 of this supplement), but our patient already has indications for a statin—a remote MI and diabetes—independent of what his lipid values are.

Question 2.2: How would you manage his elevated blood pressure (190/100 mm Hg)?

A. Discontinue metoprolol and start a different antihypertensive drug

B. Increase the metoprolol dose

C. Continue metoprolol and add a second drug

D. Observe him on his current regimen

Dr. Cohn: I would increase the dose of metoprolol and consider adding another drug, in view of his heart rate (90 beats per minute) and his cardiac status. Beta-blocker therapy should not be discontinued because doing so in the perioperative period is associated with an increased risk of adverse events such as cardiac death and MI.

Dr. Sweitzer: I would push up the metoprolol a bit to reduce the heart rate, knowing that beta-blockers are probably not the most efficacious antihypertensive agents. I would caution against starting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) because he is scheduled to undergo a fairly significant procedure with expected blood loss and fluid shifts, and either of those agents in combination with a beta-blocker would be challenging to manage on the day of surgery.

Question 2.3: How would you manage his metformin perioperatively?

A. Discontinue it 48 hours preoperatively

B. Discontinue it 24 hours preoperatively

C. Withhold it on the morning of surgery

D. Continue it on the morning of surgery

Dr. Sweitzer: We routinely advise patients to hold all their oral diabetes medications the morning of surgery, primarily because many anesthesiologists are uncertain about the differing risks of hypoglycemia associated with the various oral agents.

Most of us will never see a patient who has lactic acidosis from metformin use. A systematic literature review and analysis found no increase in the risk of lactic acidosis with metformin compared with other oral hypoglycemics,⁶ so fear of lactic acidosis is not a valid reason to discontinue metformin. In fact, I think it is inappropriate to ever postpone or cancel surgery simply because the patient inadvertently took metformin on the morning of surgery. Some may argue that patients with renal insufficiency are at higher risk of lactic acidosis from metformin use on the morning of surgery, but keep in mind that renal insufficiency is a relative contra­indication to metformin use in the first place. Unless the patient is scheduled for a bilateral nephrectomy, his or her renal function is not going to be acutely reduced enough to enable a morning dose of metformin to cause lactic acidosis.

Dr. Cohn: Additionally, in a recent study of patients undergoing coronary artery bypass graft surgery (CABG), there was no increased risk of in-hospital morbidity or mortality in patients who received metformin on the morning of surgery,⁷ although I typically stop it 24 hours before major surgery.

Question 2.4: With respect to statin therapy, which course would you choose preoperatively?

A. Start a statin at a low dose

B. Start a statin at an intermediate dose

C. Start a statin at a high dose

D. Do not start a statin

Dr. Cohn: The answer to this question is not clear cut. The reason not to start a prophylactic statin would be the lack of evidence of benefit in patients undergoing noncardiac, nonvascular surgery, although there is evidence of potential benefit in patients undergoing vascular surgery.* The arguments in favor of starting a statin are that this patient has independent indications for a statin and the planned surgery is a high-risk procedure.

(* Editor’s note: In the time since this summit, results of the DECREASE-IV trial were published [Dunkelgrun et al, Ann Surg 2009; 249:921–926], showing a statisically nonsignificant trend toward improved outcomes at 30 days with fluvastatin in intermediate-risk patients undergoing noncardiovascular surgery.)

In cohort studies, perioperative death rates have been lower in statin recipients than in those not taking a statin.⁸ In the Dutch Echographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III), which randomized noncardiac vascular surgery patients to perioperative fluvastatin or placebo, rates of MI and the composite end point of nonfatal MI or cardiovascular death were significantly lower in the statin group than in the placebo group.⁹

Question 2.5: Which of the following cardiac tests would you order preoperatively?

A. Exercise ECG

B. Dobutamine stress echocardiogram

C. Dipyridamole nuclear imaging

D. Coronary angiography

E. No further cardiac testing

Dr. Cohn: I wouldn’t do any cardiac testing since this patient needs surgery for his malignancy and the results of any testing would be highly unlikely to change management, in terms of canceling the surgery. This approach is consistent with the 2007 guidelines on perioperative cardiovascular evaluation for noncardiac surgery issued by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹⁰

Dr. Sweitzer: I would differ on this question. This patient has not been evaluated adequately for his coronary artery disease. He has poor functional capacity that complicates assessment of his symptoms. He also has diabetes, so he is more likely to have silent myocardial ischemia. At age 78, he is understandably concerned about his survival: radical cystectomy is a major operation associated with significant blood loss, fluid shifts, and a long-term recuperative state. In this case, a cardiac evaluation may change management, not in terms of considering coronary revascularization before the surgery, but in terms of affecting the assessment of his chance of surviving this major operation, his life span following the operation, and his quality of life. For example, a highly positive dobutamine stress echo­cardiogram or certain wall motion abnormalities would suggest that he might not be protected even by optimal perioperative medical management.

Question 2.6: Which of the following would you do pre­operatively to assess pulmonary risk?

A. Obtain pulmonary function tests

B. Order a sleep study

C. Both

D. Neither

Dr. Sweitzer: There is no evidence supporting routine pulmonary function tests for patients undergoing procedures other than lung resection. If obstructive sleep apnea were suspected, I would order a sleep study only if I had access to one quickly to avoid delaying the surgery. Cancer surgery should never be delayed to get a sleep study. However, if this patient were seen in the primary care clinic, I would order a sleep study and, if indicated, put him on continuous positive airway pressure (CPAP). Whether or not preoperative CPAP makes a difference hasn’t been shown. No randomized controlled trials have been conducted, but there are some suggestions that the risks of ischemia and atrial arrhythmias in patients with known coronary artery disease can be reduced with CPAP. It is not always easy to initiate CPAP postoperatively because the number of CPAP machines is limited and titration by a respiratory technician is required, which is typically done in a sleep lab.

How the case was actually managed

Neither an HbA_1c measurement nor a lipid profile was ordered preoperatively, for lack of supportive evidence. The patient was continued on his beta-blocker and the dosage was increased sufficiently to control his blood pressure and heart rate. Metformin was continued, and statin therapy was begun preoperatively in light of the patient’s independent indications for it and the high-risk nature of the procedure. Stress testing was not ordered, in light of the lack of indication, given the patient’s stable angina. The patient refused a sleep study. The operation was lengthy and involved significant blood loss. The patient had a complicated postoperative course and ultimately died from multiorgan failure.

 

 

CASE 3: OPERATIONS OF VARIABLE RISK IN ELDERLY MAN WITH ACTIVE CARDIAC CONDITION

Scenario A: A 75-year-old man with diabetes, class III angina, and Q waves in inferior leads on his ECG is scheduled for elective femoropopliteal bypass surgery. His medications include isosorbide mononitrate (120 mg), amlodipine (10 mg), metoprolol controlled release (100 mg), atorvastatin (80 mg), insulin, and aspirin (81 mg). His heart rate is 64 beats per minute, blood pressure is controlled at 120/80 mm Hg, low-density lipoprotein cholesterol is 80 mg/dL, and creatinine is 1.5 μmol/L.

Scenario B: Consider the same patient undergoing elective cholecystectomy instead of a femoropopliteal bypass.

Scenario C: Consider the same patient scheduled for a cystoscopy instead of the other procedures. He had one episode of gross hematuria 1 week ago that resolved. Work-up by his urologist included a urinalysis and culture that were normal, cytology that was negative for malignancy, and a sonogram and computed tomography scan that were both negative. He has had no further bleeding and is not anemic. The urologist wants to do the cystoscopy for the sake of completeness.

Question 3.1: What would be your preoperative course of action in the above scenarios?

A. Order a dobutamine stress echocardiogram

B. Order nuclear imaging with dipyridamole or adenosine

C. Order coronary angiography

D. Order a resting two-dimensional echocardiogram

E. Continue his current medications and send to surgery with no further testing

Dr. Cohn: This is a man with an active cardiac condition and class III angina, which is considered severe angina in the ACC/AHA 2007 guidelines on peri­operative cardiac evaluation and care.¹⁰ The guidelines’ recommendation is to delay surgery for further evaluation and treatment. He is already on maximal medical therapy, which has failed to control his symptoms. He has poor exercise capacity. The only difference among the case scenarios is a variation in surgical risk.

This patient has independent indications for coronary angiography regardless of whether or not he’s undergoing surgery. He deserves evaluation for possible revascularization to improve his quality of life and symptoms.

I would send the patient to the catheterization lab in every one of these instances, with the possible exception of the cystoscopy scenario, where one could argue that revascularization with stenting would require antiplatelet therapy that might increase the bleeding risk, and also that the antiplatelet therapy would have to be interrupted for the cystoscopy, potentially increasing thrombotic risk.

Dr. Sweitzer: I disagree. The ACC/AHA 2007 guidelines do not recommend going directly to catheterization but rather recommend delaying surgery for further evaluation and treatment.¹⁰ We must ask whether this patient is truly receiving optimal medical management. After all, he is not on an ACE inhibitor or an ARB.

We must also consider whether the surgery is truly elective. In the first scenario, if he has peripheral vascular disease, he is likely to develop gangrene and have a further decrease in exercise capacity, which reduces his functional ability and increases his risk of comorbid conditions. He is at significant risk of developing worsening renal insufficiency or renal failure if he undergoes angiography. Coronary revascularization will delay treatment of his peripheral vascular disease. The Coronary Artery Revascularization Prophylaxis (CARP) trial showed no benefit of coronary revascularization relative to medical management in patients undergoing vascular surgery,¹¹ as is planned for this patient. I believe one must balance two competing risks and have an in-depth discussion with the patient.

In the second scenario, not treating gallstones or preventing cholelithiasis poses more risk to the health of this diabetic patient than does elective surgery if he needs a cholecystectomy. Emergency surgery, especially for acute cholecystitis, also significantly increases the risk of a cardiac event.

In the third scenario, the cystoscopy may uncover bladder cancer, which may be adversely affected by a delay of surgery. Regardless, the patient had gross hematuria and would be at risk for further bleeding should he undergo stenting with the requisite antiplatelet therapy.

Catheterization is not normally recommended unless CABG or stenting is being considered, yet I have seen no data that either of these procedures prolongs life except in very limited circumstances such as left main disease treated with bypass grafting. Though it is true that CABG reduces the incidence and severity of angina, it does not modify the physiologic cause of angina but rather may result in symptom improvement by damaging somatic nerve fibers to the heart. Putting a stent in this patient would be like applying a bandage: his symptoms will likely recur if he does not receive optimal medical management.

In a 2007 science advisory, several major medical societies cautioned against percutaneous coronary intervention (PCI) with drug-eluting stent placement in patients expected to undergo noncardiac surgery that would require interruption of antiplatelet therapy in the following 12 months (and against PCI with bare metal stent placement in patients undergoing such surgery in the following 4 to 6 weeks).¹² Therefore, I would not recommend catheterization for a patient whose noncardiac disease is likely to require surgery in the very near future, as is the case in each of the surgical scenarios above. One could consider noninvasive stress testing, which would be a safer approach and would almost certainly identify either significant stenosis of the left main coronary artery or three-vessel disease, which would be the only possible reasons to recommend CABG. I don’t believe there is any role for PCI for this patient.

Dr. Cohn: I argue for symptom relief even if it doesn’t prolong life. This patient cannot walk across the room without having symptoms despite taking multiple medications. I think he deserves a chance at revascularization if the angiogram shows he has a stenosis amenable to it, but I agree that a drug-eluting stent should not be placed if we know that he will undergo surgery within a few months.

 

 

CASE 4: VENTRAL HERNIA REPAIR IN A MIDDLE-AGED WOMAN

A 60-year-old woman is scheduled for ventral hernia repair. Her medical history is unremarkable, with the exception of hypertension. She denies any bleeding problems and had no complications after a laparoscopic cholecystectomy 10 years ago. She has no family history of bleeding disorders.

Question 4.1: Would you order a prothrombin time (PT)/partial thromboplastin time (PTT)?

A. Yes

B. No

Dr. Cohn: I would not.

Dr. Sweitzer: I agree.

Question 4.2: Although not requested, a PT/PTT was ordered anyway. The PT is normal (12.2 sec/12 sec) and the PTT is abnormal (40 sec/25 sec). What is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Factor VII deficiency

C. Factor IX deficiency

D. Factor XI deficiency

E. Factor XII deficiency

Dr. Cohn: The most likely cause is a sample with insufficient blood in the tube. The test wasn’t indicated in the first place, but now it must be done again.

Question 4.3: The PTT is repeated and remains abnormal: 42 sec/25 sec. Mixing studies correct the abnormality to 29 sec/25 sec. Based on this information, what is the most likely cause of the PTT abnormality?

A. Laboratory error

B. Lupus anticoagulant

C. Prekallikrein factor deficiency

D. Factor XII deficiency

Dr. Cohn: This is not a case of lupus anticoagulant because the abnormal PTT was corrected by the mixing study. Causes of a prolonged PTT include deficiencies of factors XII, XI, and IX, so factor XII deficiency is the most likely explanation, though a deficiency higher up the coagulation cascade (ie, prekallikrein factor deficiency) is possible. In the absence of any personal or family bleeding history, it is unlikely to be a deficiency of factors VII or IX (the hemophiliac) or of factor XI, so a deficiency of factor XII or one of the prekallikrein factors is more likely.

Dr. Sweitzer: A mixing study is indeed the appropriate first step. It is ordered from the lab and involves mixing the patient’s blood with normal plasma and incubating the mixture. If the mixture corrects the PTT result, as was the case with this patient, it indicates a coagulation factor deficiency in the patient’s blood; if it doesn’t correct, that should prompt evaluation for lupus anticoagulant or the presence of some other protein or hormone that’s prolonging the PTT.

Question 4.4: How would you manage this patient perioperatively?

A. Fresh frozen plasma

B. Platelet transfusion

C. Cryoprecipitate

D. Factor VII

E. No treatment necessary

Dr. Cohn: No treatment is necessary. Factor XII deficiency does not cause bleeding, regardless of the PTT. Factor XI deficiency is associated with bleeding, but usually there is a family history or a personal history of bleeding with surgery.

Screening coagulation studies are not usually indicated in a patient without a personal or family history of bleeding, liver disease, alcohol or drug use, or current anticoagulant therapy. Such studies are usually normal in such patients, and when they are not, it’s usually because of a lab error or a disease (hypercoagulable state) or factor deficiency that does not cause bleeding

Dr. Sweitzer: However, if the PTT is prolonged, the cause should be identified, because if the patient is sent to the operating room without an explanation for the prolongation, the perioperative team might think the patient has a bleeding problem and use fresh frozen plasma too readily. Fresh frozen plasma is not appropriate for everyone and may actually make a potentially hypercoagulable state worse.

 

 

DISCUSSION

Question from the audience: It was said that use of ACE inhibitors and ARBs should be avoided around the time of surgery. I’ve done an extensive literature search and found minimal to no evidence to support this practice. To the contrary, I found fairly good evidence to indicate that heart failure can be exacerbated significantly and acutely, as early as within 24 hours, when patients are taken off their ACE inhibitor or ARB. I would like your viewpoint on this basic pathology in perioperative medicine.

Dr. Cohn: The literature on the use of ACE inhibitors or ARBs prior to noncardiac surgery consists of five studies with fewer than 500 patients in total, as recently reviewed by Rosenman et al.¹³ Although there was no excess of death or MI associated with taking these medications on the morning of surgery, they did increase the need for fluid and pressors.

Dr. Sweitzer: Patients with hypertension have bigger variations of blood pressure, both hypo- and hypertension, in the perioperative period. For this reason, it was standard of care 30 years ago to stop all antihypertensive drugs, including beta-blockers, preoperatively. We soon found that although this practice prevented many episodes of hypotension, it increased the occurrence of perioperative hypertension and the likelihood of cardiac events. It then became standard of care to always continue antihypertensive drugs on the morning of surgery. In the late 1980s and early 1990s, several studies showed that ACE inhibitors and ARBs were associated with a more profound drop in blood pressure upon induction of general anesthesia compared with other antihypertensives.

The usual ways we treat drops in blood pressure—with phenylephrine and ephedrine—are not very effective in treating hypotension associated with general anesthesia in patients taking ACE inhibitors or ARBs. Vasopressin is effective in treating refractory hypotension during surgery, but anesthesiologists don’t use it often. Reducing the doses of induction agents is another means of attenuating the hypotension induced by ACE inhibitors and ARBs.

We should not routinely stop ACE inhibitors and ARBs on the day of surgery, particularly in patients being treated for heart failure, angina, or a prior MI. My bias is to selectively hold ACE inhibitors and ARBs on the morning of surgery in patients who are undergoing a significant operation with a high likelihood of hypotension, have well-controlled preoperative blood pressure, are taking multiple antihypertensive agents, and do not have heart failure. Otherwise, patients should continue their ACE inhibitors and ARBs on the morning of surgery, and the anesthesiologist should be prepared for significant hypotension upon induction of anesthesia, alter anesthesia induction doses accordingly, have vasopressin handy, and avoid the temptation to treat hypotension with fluids or repeated doses of phenylephrine and ephedrine. The previous comment about concerns with ACE inhibitors and ARBs was in the context of initiating new therapies in the immediate preoperative period.

Question from the audience: Urinalysis is ordered for many patients undergoing orthopedic surgery, and invariably some bacteriuria is found. Can you comment on the value of urinalysis and subsequent treatment of abnormal results?

Dr. Cohn: I believe you should never order a urinalysis in an asymptomatic patient, with the exception of patients undergoing procedures that involve genitourinary or gynecologic instrumentation. Ordering a urinalysis before joint replacement has been promoted in the orthopedic literature on the theoretical grounds that bacteria might somehow seed and colonize the joint. Orthopedic surgeons like to do it, but I disregard their requests for it.

Dr. Sweitzer: One study showed that we’d need to spend $1.5 million on screening urinalysis for asymptomatic patients scheduled for joint replacement surgery in order to prevent one joint infection.¹⁴

Dr. Cohn: Also, patients are going to get their one dose of cephalosporin before surgery anyway, and that will probably knock out any bacteria that would be found on urinalysis.

Question from the audience: Can you clarify how the 2007 ACC/AHA perioperative guidelines define an active cardiac condition? The patient in your third case report had class III angina, or angina with less than usual activities, but nothing was presented to suggest that his symptoms were unstable. I would suggest that despite his class III symptoms, his angina was stable, and I would have continued down the algorithm rather than defining his cardiac condition as active and considering an intervention.

Dr. Cohn: An active cardiac condition is defined by the ACC as unstable coronary syndromes, which include acute (within the prior 7 days) or recent (within the prior 30 days) MI, unstable angina, and severe (class III or IV) angina.

Current uncertainty over the best approach for preventing fatal perioperative myocardial infarction (MI) lies in our inability, despite sophisticated testing methods, to detect unstable coronary plaque prior to surgery. Unstable plaque can be present in patients with coronary lumina that appear normal on coronary angiography. Therefore, reliance on medical therapy to blunt inflammation is currently the best practice for minimizing the risk that unstable plaque poses.

Perioperative use of statins is a cornerstone of such therapy. This article briefly reviews the rationale for perioperative statin use in the setting of noncardiac surgery, presents the latest evidence on the clinical effects of perioperative statin use, and considers the potential role for statins in promoting recovery from acute kidney injury after vascular surgery.

FATAL MI: ORIGINS AND APPROACHES TO RISK REDUCTION

Fatal perioperative MI has two potential origins.^1,2 One is a culprit coronary plaque that fissures and ruptures, causing a cascade of thrombogenic events (hemorrhage and thrombosis) inside the vessel wall, culminating in an MI. Less often, fatal perioperative MI results from long-lasting myocardial ischemia (a demand/supply mismatch of oxygen), typically as a consequence of a fixed coronary stenosis.

In nearly half of patients with fatal MI, coronary inflammation is a key contributor. In the perioperative setting, surgical stress induces the release of inflammatory cytokines that disrupt smooth muscle cells in the endothelium and contribute to disruption of a non­obstructing coronary plaque, predisposing to acute thrombus formation.

Risk reduction depends on pathophysiology

Strategies for minimizing the risk of perioperative MI depend on the pathophysiology involved. In the case of oxygen demand/supply mismatch as a result of flow-limiting stenosis, a beta-blocker and coronary revascularization, if possible, may be useful.

In the more common case of unstable plaque, a multifactorial strategy appears optimal, involving the following:

• Statin therapy to reduce coronary inflammation
• Aspirin to blunt the prothrombotic milieu postoperatively
• Chronic low-dose beta-blockade to decrease myocardial oxygen demand or inhibit plaque rupture.

A particular role for statins

Ridker et al found that patients with an acute coronary syndrome who experience a decline in high-sensitivity C-reactive protein (hsCRP) level after treatment with a statin have improved clinical outcomes compared with those whose hsCRP level remains high, regardless of their resultant low-density lipoprotein (LDL) cholesterol level.³

Among surgical patients, those most at risk for poor cardiovascular outcomes are those who undergo vascular surgery. In Europe, the cardiovascular death rate in such patients is approximately 2%.⁴

Retrospective cohort data and data from randomized clinical trials have demonstrated reductions in perioperative cardiac complications with statin use in patients undergoing various types of noncardiac vascular surgery.^5–9 In light of these data, my colleagues and I recently undertook a prospective study to examine the effect of perioperative statin use on cardiovascular complications in patients undergoing vascular surgery.¹⁰ Key details and findings are surveyed in the following section.

DECREASE III: PROSPECTIVE EVIDENCE FOR ISCHEMIC BENEFIT FROM PERIOPERATIVE STATINS

The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III) was conducted at a single center (Erasmus Medical Center, Rotterdam, the Netherlands) in a randomized, double-blind, placebo-controlled manner.¹⁰

Patients and study design

The study population included 497 statin-naïve patients who were scheduled for one of four noncardiac vascular surgical procedures (repair or revascularization for abdominal aortic aneurysm, abdominal aortic stenosis, lower limb arterial stenosis, or carotid artery stenosis). Patients with unstable coronary artery disease or left main disease were excluded.

Patients were randomized to placebo or extended-release fluvastatin (80 mg/day) starting on the day of randomization, which was a median of 37 days before surgery. Treatment was continued until 30 days after surgery.

Extended-release fluvastatin was chosen because its long half-life permits a bridge to the early postoperative period, during which oral medications are not permitted in patients undergoing high-risk vascular surgery.

The primary end point was the occurrence of myocardial ischemia as assessed by three methods:

• Holter monitoring during the first 72 postoperative hours
• Measurement of troponin T on days 1, 3, 7, and 30
• Additional electrocardiographic recordings on days 7 and 30.

The secondary end point was a composite of cardio­vascular death and nonfatal MI during the first 30 postoperative days.

Baseline characteristics were similar between the two randomized groups, with a median age approaching 66 years. About three-fourths of the patients were male, one-fourth had a history of MI, one-fourth had angina pectoris, one-fifth had diabetes mellitus, and nearly 30% had a history of cerebrovascular accident or transient ischemic attack.

All patients were being treated with a beta-blocker, about 60% with antiplatelet therapy, more than one-fourth with anticoagulant therapy, nearly half with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and more than one-fourth with diuretics. There were no significant differences between the groups in the proportion of patients on each of these therapies.

Results: Reductions in inflammatory markers

Baseline levels of hsCRP and interleukin-6 (IL-6) were comparable between the groups. In patients randomized to placebo, the hsCRP level increased by 3%, from a median of 5.80 mg/L at randomization to 6.00 mg/L immediately prior to surgery. In contrast, the hsCRP level in patients randomized to extended-release fluvastatin decreased by 21%, from a median of 5.93 mg/L to 4.66 mg/L. The between-group difference in the change in hsCRP level was statistically significant (P < .001). There was also a significantly greater reduction from baseline in median level of IL-6 among fluvastatin recipients compared with placebo recipients (–33% vs –4%; P < .001).

The specificity of hsCRP for cardiac inflammation is not yet known, but measures of hsCRP and IL-6 can provide a fingerprint of inflammatory activity prior to surgery. Other inflammatory and noninflammatory markers are being investigated to better identify (prior to surgery) those high-risk patients most likely to benefit from perioperative statin use.

 

 

Results: Favorable effect on clinical end points

The incidence of the primary end point—myocardial ischemia 30 days after surgery—was significantly lower in the patients randomized to extended-release fluva­statin compared with placebo (10.9% vs 18.9%; P = .016), as was the incidence of the secondary end point of cardiovascular death or nonfatal MI (4.8% vs 10.1%; P = .039).

The number needed to treat (NNT) to prevent one occurrence of myocardial ischemia was 13; the NNT to prevent one nonfatal MI was 36; and the NNT to prevent one cardiovascular death was 42 (Table 1).

Safety: No effects on liver function or evidence of increased myopathy

No significant differences were seen between the study arms in safety end points, including discontinuation of study drug, the incidence of creatine kinase (CK) elevations above 10 times the upper limit of normal, median CK levels, the incidence of alanine aminotransferase (ALT) elevations above three times the upper limit of normal, and median ALT levels (Table 2). Receipt of general anesthesia prevented monitoring for symptoms of myopathy and rhabdomyolysis.

We concluded that initiation of therapy with a long-acting statin should be considered in statin-naïve patients undergoing vascular surgery.

PERIOPERATIVE STATIN USE: PRACTICAL CONSIDERATIONS

Inflammation, not cholesterol, should be the target

The optimal statin choice and the target level of LDL cholesterol immediately prior to surgery remain controversial. It may be that the more potent statins induce more side effects during surgery, but any such claim is speculative since no comparative studies exist. Regardless, the purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery, with the long-term goal being achievement of recommended target lipid levels.

In particular, patients with peripheral arterial disease should have a statin initiated prior to high-risk vascular surgery (if they are not already receiving one), to increase the odds of recovering renal function after surgery (see section below) and to improve long-term outcomes.

Who are the best candidates?

Patients with multiple cardiac risk factors represent an especially high-risk group that benefits the most from statin therapy prior to vascular surgery, as they are likely to have more extensive disease and more extensive inflammation in the coronary artery tree.

Given the low incidence of side effects associated with statins, initiating a statin in patients with multiple cardiac risk factors who are undergoing intermediate-risk surgery may seem appropriate, but no data from large randomized trials are available to support this practice. Caution is in order when extrapolating data from studies conducted in the high-risk vascular surgery context to other surgical settings, since statins may pose hidden side effects such as liver dysfunction and myopathy, which may be missed in patients under anesthesia.

My personal practice is to initiate a statin prior to high-risk surgery or in patients with multiple cardiac risk factors if the risk-factor profile presents a clear indication for long-term statin use. If no risk factors are present, I am more reluctant to initiate a statin because of a lack of supportive data.

Beware the rebound effect with statin withdrawal

Statin withdrawal for several days following surgery is a common practice, since statins are given orally and their pleiotropic effects are underappreciated.

A withdrawal effect leading to abrogation of clinical benefit has been observed with perioperative use of short-acting statins, whose anti-inflammatory properties do not effectively extend to the postoperative period. Acute withdrawal has been associated with an increase in markers of inflammation and oxidative stress, and an increase in cardiac events has been observed with acute withdrawal of statins during periods of instability when compared with continuation of statin therapy.¹¹

For these reasons, a long-acting statin is preferred preoperatively in patients whose oral intake will be compromised for several days after surgery (eg, in gastric surgery). The optimal statin for preventing the withdrawal effect is unknown. We chose extended-release fluvastatin in DECREASE III because its biological effect appears to last at least 4 days¹² even though analysis of serum levels of the drug indicates a shorter half-life.

 

 

ANOTHER POTENTIAL BENEFIT: ENHANCED RECOVERY OF KIDNEY FUNCTION

Postoperative renal dysfunction is an ominous sign

Renal ischemic reperfusion injury is inevitable after vascular surgery that requires aortic cross-clamping. This is significant, as renal dysfunction after surgery is an ominous long-term sign that indicates abundant atherosclerosis. Complete recovery after acute kidney injury portends an improved long-term outcome, whereas patients with persistent renal dysfunction after vascular surgery have poor long-term outcomes.

A benefit from statins?

Statins may offer an effective means of preventing or shortening the course of acute kidney injury after surgery. Statins have been reported to lengthen survival of chronic kidney disease patients with sepsis or infectious complications and to improve the course of acute kidney injury in aging rats.^13–15 These findings prompted my colleagues and I to conduct a retrospective study to evaluate whether statins may ameliorate reperfusion injury in the kidney after aortic cross-clamping.¹⁶

Promising findings from an observational review

We reviewed the records of all patients who had undergone vascular surgery at Erasmus Medical Center from January 1995 to June 2006 to examine the relation between preoperative statin use and renal function after suprarenal aortic cross-clamping.¹⁶ Of the 1,944 patients who met inclusion criteria, 515 (26.5%) were statin users. Postoperative kidney injury was defined as more than a 10% reduction in creatinine clearance on postoperative day 1 or 2 compared with baseline. Recovery of kidney function was defined as a creatinine clearance of greater than 90% of the baseline value by postoperative day 3.

The clinical characteristics of the populations with and without kidney injury after aortic cross-clamping were similar, including baseline creatinine clearance and serum creatinine.

Acute kidney injury within 2 days of surgery occurred in 664 patients (34%), of which 313 (47%) had complete recovery of kidney function at postoperative day 3. Although the incidence of postoperative kidney injury was similar among statin users and nonusers, statin use was associated with an increased chance of complete recovery of kidney function at day 3 (odds ratio = 2.0; 95% CI, 1.0–3.8).

All-cause mortality was assessed during a mean follow-up of 6.24 years. Statin use was associated with improved long-term survival, regardless of any change in kidney function (hazard ratio for death = 0.60; 95% CI, 0.48–0.75). Among the four broad patient groups, survival was highest among statin users with no postoperative kidney injury, followed by statin users who had kidney injury, then by nonusers of statins with no kidney injury, and finally by nonusers of statins who had kidney injury.

We concluded that perioperative statin use was associated with clinically significant recovery from acute kidney injury after high-risk vascular surgery and, more importantly, with improved long-term survival regardless of the presence of kidney injury. These promising findings require confirmation in prospective trials.

SUMMARY

Vascular surgery carries a high risk of perioperative mortality. Perioperative use of extended-release fluvastatin is associated with a reduced incidence of myocardial ischemia and the composite of MI and cardiovascular death at 30 days following surgery. These beneficial clinical outcomes are achieved without an increase in the incidence of side effects, including liver dysfunction and myopathy. Preoperative initiation of a long-acting statin is a reasonable strategy for reducing the risks associated with vascular surgery, and offers a bridge to postoperative statin continuation to blunt the inflammatory stress of surgery. Ischemic reperfusion injury is a major cause of renal dysfunction following vascular surgery. Statin therapy appears to help restore kidney function after aortic cross-clamping in patients undergoing high-risk vascular surgery.

DISCUSSION

Question from the audience: The majority of patients randomized in DECREASE III had relatively normal cholesterol levels. Do you believe those patients are biologically different from patients with physiologic vascular disease and elevated cholesterol levels?

Dr. Poldermans: We enrolled patients with various baseline cholesterol levels, and we found that these levels were not related to postoperative outcome. It would be a good idea to examine inflammation status just prior to surgery in patients with lower cholesterol levels to see if they have different outcomes from those with high cholesterol.

Question from the audience: If a patient is already on a short-acting statin and we know that he or she won’t be able to take a statin postoperatively, should we change to a long-acting statin just prior to surgery?

Dr. Poldermans: To be honest, this is a financial issue. If you have the opportunity, the best course would be to prescribe a statin with a prolonged half-life or an extended-release formulation. Of course, it’s not always possible to prescribe one particular statin. You have to negotiate what is feasible and hope to initiate the statin as early as possible to reduce risk.

Question from the audience: In studies conducted outside the perioperative setting, such as PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and a substudy of REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering), it took about 30 days after statin initiation for hsCRP levels to minimize, and at least that long for halting of plaque progression to be detected by intravascular ultrasonography. Given that, does it make sense to delay nonurgent surgery in a patient in whom you’re worried about a postoperative MI?

Dr. Poldermans: Rat studies show improved blood flow and reduced thrombosis within hours of statin initiation. In the perioperative setting, therefore, initiating a statin within 30 days may be appropriate, but nobody knows the exact timing for optimal effect. Since there are no data to answer this question, I would not postpone surgery for this reason.

Current uncertainty over the best approach for preventing fatal perioperative myocardial infarction (MI) lies in our inability, despite sophisticated testing methods, to detect unstable coronary plaque prior to surgery. Unstable plaque can be present in patients with coronary lumina that appear normal on coronary angiography. Therefore, reliance on medical therapy to blunt inflammation is currently the best practice for minimizing the risk that unstable plaque poses.

Perioperative use of statins is a cornerstone of such therapy. This article briefly reviews the rationale for perioperative statin use in the setting of noncardiac surgery, presents the latest evidence on the clinical effects of perioperative statin use, and considers the potential role for statins in promoting recovery from acute kidney injury after vascular surgery.

FATAL MI: ORIGINS AND APPROACHES TO RISK REDUCTION

Fatal perioperative MI has two potential origins.^1,2 One is a culprit coronary plaque that fissures and ruptures, causing a cascade of thrombogenic events (hemorrhage and thrombosis) inside the vessel wall, culminating in an MI. Less often, fatal perioperative MI results from long-lasting myocardial ischemia (a demand/supply mismatch of oxygen), typically as a consequence of a fixed coronary stenosis.

In nearly half of patients with fatal MI, coronary inflammation is a key contributor. In the perioperative setting, surgical stress induces the release of inflammatory cytokines that disrupt smooth muscle cells in the endothelium and contribute to disruption of a non­obstructing coronary plaque, predisposing to acute thrombus formation.

Risk reduction depends on pathophysiology

Strategies for minimizing the risk of perioperative MI depend on the pathophysiology involved. In the case of oxygen demand/supply mismatch as a result of flow-limiting stenosis, a beta-blocker and coronary revascularization, if possible, may be useful.

In the more common case of unstable plaque, a multifactorial strategy appears optimal, involving the following:

• Statin therapy to reduce coronary inflammation
• Aspirin to blunt the prothrombotic milieu postoperatively
• Chronic low-dose beta-blockade to decrease myocardial oxygen demand or inhibit plaque rupture.

A particular role for statins

Ridker et al found that patients with an acute coronary syndrome who experience a decline in high-sensitivity C-reactive protein (hsCRP) level after treatment with a statin have improved clinical outcomes compared with those whose hsCRP level remains high, regardless of their resultant low-density lipoprotein (LDL) cholesterol level.³

Among surgical patients, those most at risk for poor cardiovascular outcomes are those who undergo vascular surgery. In Europe, the cardiovascular death rate in such patients is approximately 2%.⁴

Retrospective cohort data and data from randomized clinical trials have demonstrated reductions in perioperative cardiac complications with statin use in patients undergoing various types of noncardiac vascular surgery.^5–9 In light of these data, my colleagues and I recently undertook a prospective study to examine the effect of perioperative statin use on cardiovascular complications in patients undergoing vascular surgery.¹⁰ Key details and findings are surveyed in the following section.

DECREASE III: PROSPECTIVE EVIDENCE FOR ISCHEMIC BENEFIT FROM PERIOPERATIVE STATINS

The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III) was conducted at a single center (Erasmus Medical Center, Rotterdam, the Netherlands) in a randomized, double-blind, placebo-controlled manner.¹⁰

Patients and study design

The study population included 497 statin-naïve patients who were scheduled for one of four noncardiac vascular surgical procedures (repair or revascularization for abdominal aortic aneurysm, abdominal aortic stenosis, lower limb arterial stenosis, or carotid artery stenosis). Patients with unstable coronary artery disease or left main disease were excluded.

Patients were randomized to placebo or extended-release fluvastatin (80 mg/day) starting on the day of randomization, which was a median of 37 days before surgery. Treatment was continued until 30 days after surgery.

Extended-release fluvastatin was chosen because its long half-life permits a bridge to the early postoperative period, during which oral medications are not permitted in patients undergoing high-risk vascular surgery.

The primary end point was the occurrence of myocardial ischemia as assessed by three methods:

• Holter monitoring during the first 72 postoperative hours
• Measurement of troponin T on days 1, 3, 7, and 30
• Additional electrocardiographic recordings on days 7 and 30.

The secondary end point was a composite of cardio­vascular death and nonfatal MI during the first 30 postoperative days.

Baseline characteristics were similar between the two randomized groups, with a median age approaching 66 years. About three-fourths of the patients were male, one-fourth had a history of MI, one-fourth had angina pectoris, one-fifth had diabetes mellitus, and nearly 30% had a history of cerebrovascular accident or transient ischemic attack.

All patients were being treated with a beta-blocker, about 60% with antiplatelet therapy, more than one-fourth with anticoagulant therapy, nearly half with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and more than one-fourth with diuretics. There were no significant differences between the groups in the proportion of patients on each of these therapies.

Results: Reductions in inflammatory markers

Baseline levels of hsCRP and interleukin-6 (IL-6) were comparable between the groups. In patients randomized to placebo, the hsCRP level increased by 3%, from a median of 5.80 mg/L at randomization to 6.00 mg/L immediately prior to surgery. In contrast, the hsCRP level in patients randomized to extended-release fluvastatin decreased by 21%, from a median of 5.93 mg/L to 4.66 mg/L. The between-group difference in the change in hsCRP level was statistically significant (P < .001). There was also a significantly greater reduction from baseline in median level of IL-6 among fluvastatin recipients compared with placebo recipients (–33% vs –4%; P < .001).

The specificity of hsCRP for cardiac inflammation is not yet known, but measures of hsCRP and IL-6 can provide a fingerprint of inflammatory activity prior to surgery. Other inflammatory and noninflammatory markers are being investigated to better identify (prior to surgery) those high-risk patients most likely to benefit from perioperative statin use.

 

 

Results: Favorable effect on clinical end points

The incidence of the primary end point—myocardial ischemia 30 days after surgery—was significantly lower in the patients randomized to extended-release fluva­statin compared with placebo (10.9% vs 18.9%; P = .016), as was the incidence of the secondary end point of cardiovascular death or nonfatal MI (4.8% vs 10.1%; P = .039).

The number needed to treat (NNT) to prevent one occurrence of myocardial ischemia was 13; the NNT to prevent one nonfatal MI was 36; and the NNT to prevent one cardiovascular death was 42 (Table 1).

Safety: No effects on liver function or evidence of increased myopathy

No significant differences were seen between the study arms in safety end points, including discontinuation of study drug, the incidence of creatine kinase (CK) elevations above 10 times the upper limit of normal, median CK levels, the incidence of alanine aminotransferase (ALT) elevations above three times the upper limit of normal, and median ALT levels (Table 2). Receipt of general anesthesia prevented monitoring for symptoms of myopathy and rhabdomyolysis.

We concluded that initiation of therapy with a long-acting statin should be considered in statin-naïve patients undergoing vascular surgery.

PERIOPERATIVE STATIN USE: PRACTICAL CONSIDERATIONS

Inflammation, not cholesterol, should be the target

The optimal statin choice and the target level of LDL cholesterol immediately prior to surgery remain controversial. It may be that the more potent statins induce more side effects during surgery, but any such claim is speculative since no comparative studies exist. Regardless, the purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery, with the long-term goal being achievement of recommended target lipid levels.

In particular, patients with peripheral arterial disease should have a statin initiated prior to high-risk vascular surgery (if they are not already receiving one), to increase the odds of recovering renal function after surgery (see section below) and to improve long-term outcomes.

Who are the best candidates?

Patients with multiple cardiac risk factors represent an especially high-risk group that benefits the most from statin therapy prior to vascular surgery, as they are likely to have more extensive disease and more extensive inflammation in the coronary artery tree.

Given the low incidence of side effects associated with statins, initiating a statin in patients with multiple cardiac risk factors who are undergoing intermediate-risk surgery may seem appropriate, but no data from large randomized trials are available to support this practice. Caution is in order when extrapolating data from studies conducted in the high-risk vascular surgery context to other surgical settings, since statins may pose hidden side effects such as liver dysfunction and myopathy, which may be missed in patients under anesthesia.

My personal practice is to initiate a statin prior to high-risk surgery or in patients with multiple cardiac risk factors if the risk-factor profile presents a clear indication for long-term statin use. If no risk factors are present, I am more reluctant to initiate a statin because of a lack of supportive data.

Beware the rebound effect with statin withdrawal

Statin withdrawal for several days following surgery is a common practice, since statins are given orally and their pleiotropic effects are underappreciated.

A withdrawal effect leading to abrogation of clinical benefit has been observed with perioperative use of short-acting statins, whose anti-inflammatory properties do not effectively extend to the postoperative period. Acute withdrawal has been associated with an increase in markers of inflammation and oxidative stress, and an increase in cardiac events has been observed with acute withdrawal of statins during periods of instability when compared with continuation of statin therapy.¹¹

For these reasons, a long-acting statin is preferred preoperatively in patients whose oral intake will be compromised for several days after surgery (eg, in gastric surgery). The optimal statin for preventing the withdrawal effect is unknown. We chose extended-release fluvastatin in DECREASE III because its biological effect appears to last at least 4 days¹² even though analysis of serum levels of the drug indicates a shorter half-life.

 

 

ANOTHER POTENTIAL BENEFIT: ENHANCED RECOVERY OF KIDNEY FUNCTION

Postoperative renal dysfunction is an ominous sign

Renal ischemic reperfusion injury is inevitable after vascular surgery that requires aortic cross-clamping. This is significant, as renal dysfunction after surgery is an ominous long-term sign that indicates abundant atherosclerosis. Complete recovery after acute kidney injury portends an improved long-term outcome, whereas patients with persistent renal dysfunction after vascular surgery have poor long-term outcomes.

A benefit from statins?

Statins may offer an effective means of preventing or shortening the course of acute kidney injury after surgery. Statins have been reported to lengthen survival of chronic kidney disease patients with sepsis or infectious complications and to improve the course of acute kidney injury in aging rats.^13–15 These findings prompted my colleagues and I to conduct a retrospective study to evaluate whether statins may ameliorate reperfusion injury in the kidney after aortic cross-clamping.¹⁶

Promising findings from an observational review

We reviewed the records of all patients who had undergone vascular surgery at Erasmus Medical Center from January 1995 to June 2006 to examine the relation between preoperative statin use and renal function after suprarenal aortic cross-clamping.¹⁶ Of the 1,944 patients who met inclusion criteria, 515 (26.5%) were statin users. Postoperative kidney injury was defined as more than a 10% reduction in creatinine clearance on postoperative day 1 or 2 compared with baseline. Recovery of kidney function was defined as a creatinine clearance of greater than 90% of the baseline value by postoperative day 3.

The clinical characteristics of the populations with and without kidney injury after aortic cross-clamping were similar, including baseline creatinine clearance and serum creatinine.

Acute kidney injury within 2 days of surgery occurred in 664 patients (34%), of which 313 (47%) had complete recovery of kidney function at postoperative day 3. Although the incidence of postoperative kidney injury was similar among statin users and nonusers, statin use was associated with an increased chance of complete recovery of kidney function at day 3 (odds ratio = 2.0; 95% CI, 1.0–3.8).

All-cause mortality was assessed during a mean follow-up of 6.24 years. Statin use was associated with improved long-term survival, regardless of any change in kidney function (hazard ratio for death = 0.60; 95% CI, 0.48–0.75). Among the four broad patient groups, survival was highest among statin users with no postoperative kidney injury, followed by statin users who had kidney injury, then by nonusers of statins with no kidney injury, and finally by nonusers of statins who had kidney injury.

We concluded that perioperative statin use was associated with clinically significant recovery from acute kidney injury after high-risk vascular surgery and, more importantly, with improved long-term survival regardless of the presence of kidney injury. These promising findings require confirmation in prospective trials.

SUMMARY

Vascular surgery carries a high risk of perioperative mortality. Perioperative use of extended-release fluvastatin is associated with a reduced incidence of myocardial ischemia and the composite of MI and cardiovascular death at 30 days following surgery. These beneficial clinical outcomes are achieved without an increase in the incidence of side effects, including liver dysfunction and myopathy. Preoperative initiation of a long-acting statin is a reasonable strategy for reducing the risks associated with vascular surgery, and offers a bridge to postoperative statin continuation to blunt the inflammatory stress of surgery. Ischemic reperfusion injury is a major cause of renal dysfunction following vascular surgery. Statin therapy appears to help restore kidney function after aortic cross-clamping in patients undergoing high-risk vascular surgery.

DISCUSSION

Question from the audience: The majority of patients randomized in DECREASE III had relatively normal cholesterol levels. Do you believe those patients are biologically different from patients with physiologic vascular disease and elevated cholesterol levels?

Dr. Poldermans: We enrolled patients with various baseline cholesterol levels, and we found that these levels were not related to postoperative outcome. It would be a good idea to examine inflammation status just prior to surgery in patients with lower cholesterol levels to see if they have different outcomes from those with high cholesterol.

Question from the audience: If a patient is already on a short-acting statin and we know that he or she won’t be able to take a statin postoperatively, should we change to a long-acting statin just prior to surgery?

Dr. Poldermans: To be honest, this is a financial issue. If you have the opportunity, the best course would be to prescribe a statin with a prolonged half-life or an extended-release formulation. Of course, it’s not always possible to prescribe one particular statin. You have to negotiate what is feasible and hope to initiate the statin as early as possible to reduce risk.

Question from the audience: In studies conducted outside the perioperative setting, such as PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and a substudy of REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering), it took about 30 days after statin initiation for hsCRP levels to minimize, and at least that long for halting of plaque progression to be detected by intravascular ultrasonography. Given that, does it make sense to delay nonurgent surgery in a patient in whom you’re worried about a postoperative MI?

Dr. Poldermans: Rat studies show improved blood flow and reduced thrombosis within hours of statin initiation. In the perioperative setting, therefore, initiating a statin within 30 days may be appropriate, but nobody knows the exact timing for optimal effect. Since there are no data to answer this question, I would not postpone surgery for this reason.

Current uncertainty over the best approach for preventing fatal perioperative myocardial infarction (MI) lies in our inability, despite sophisticated testing methods, to detect unstable coronary plaque prior to surgery. Unstable plaque can be present in patients with coronary lumina that appear normal on coronary angiography. Therefore, reliance on medical therapy to blunt inflammation is currently the best practice for minimizing the risk that unstable plaque poses.

Perioperative use of statins is a cornerstone of such therapy. This article briefly reviews the rationale for perioperative statin use in the setting of noncardiac surgery, presents the latest evidence on the clinical effects of perioperative statin use, and considers the potential role for statins in promoting recovery from acute kidney injury after vascular surgery.

FATAL MI: ORIGINS AND APPROACHES TO RISK REDUCTION

Fatal perioperative MI has two potential origins.^1,2 One is a culprit coronary plaque that fissures and ruptures, causing a cascade of thrombogenic events (hemorrhage and thrombosis) inside the vessel wall, culminating in an MI. Less often, fatal perioperative MI results from long-lasting myocardial ischemia (a demand/supply mismatch of oxygen), typically as a consequence of a fixed coronary stenosis.

In nearly half of patients with fatal MI, coronary inflammation is a key contributor. In the perioperative setting, surgical stress induces the release of inflammatory cytokines that disrupt smooth muscle cells in the endothelium and contribute to disruption of a non­obstructing coronary plaque, predisposing to acute thrombus formation.

Risk reduction depends on pathophysiology

Strategies for minimizing the risk of perioperative MI depend on the pathophysiology involved. In the case of oxygen demand/supply mismatch as a result of flow-limiting stenosis, a beta-blocker and coronary revascularization, if possible, may be useful.

In the more common case of unstable plaque, a multifactorial strategy appears optimal, involving the following:

• Statin therapy to reduce coronary inflammation
• Aspirin to blunt the prothrombotic milieu postoperatively
• Chronic low-dose beta-blockade to decrease myocardial oxygen demand or inhibit plaque rupture.

A particular role for statins

Ridker et al found that patients with an acute coronary syndrome who experience a decline in high-sensitivity C-reactive protein (hsCRP) level after treatment with a statin have improved clinical outcomes compared with those whose hsCRP level remains high, regardless of their resultant low-density lipoprotein (LDL) cholesterol level.³

Among surgical patients, those most at risk for poor cardiovascular outcomes are those who undergo vascular surgery. In Europe, the cardiovascular death rate in such patients is approximately 2%.⁴

Retrospective cohort data and data from randomized clinical trials have demonstrated reductions in perioperative cardiac complications with statin use in patients undergoing various types of noncardiac vascular surgery.^5–9 In light of these data, my colleagues and I recently undertook a prospective study to examine the effect of perioperative statin use on cardiovascular complications in patients undergoing vascular surgery.¹⁰ Key details and findings are surveyed in the following section.

DECREASE III: PROSPECTIVE EVIDENCE FOR ISCHEMIC BENEFIT FROM PERIOPERATIVE STATINS

The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III) was conducted at a single center (Erasmus Medical Center, Rotterdam, the Netherlands) in a randomized, double-blind, placebo-controlled manner.¹⁰

Patients and study design

The study population included 497 statin-naïve patients who were scheduled for one of four noncardiac vascular surgical procedures (repair or revascularization for abdominal aortic aneurysm, abdominal aortic stenosis, lower limb arterial stenosis, or carotid artery stenosis). Patients with unstable coronary artery disease or left main disease were excluded.

Patients were randomized to placebo or extended-release fluvastatin (80 mg/day) starting on the day of randomization, which was a median of 37 days before surgery. Treatment was continued until 30 days after surgery.

Extended-release fluvastatin was chosen because its long half-life permits a bridge to the early postoperative period, during which oral medications are not permitted in patients undergoing high-risk vascular surgery.

The primary end point was the occurrence of myocardial ischemia as assessed by three methods:

• Holter monitoring during the first 72 postoperative hours
• Measurement of troponin T on days 1, 3, 7, and 30
• Additional electrocardiographic recordings on days 7 and 30.

The secondary end point was a composite of cardio­vascular death and nonfatal MI during the first 30 postoperative days.

Baseline characteristics were similar between the two randomized groups, with a median age approaching 66 years. About three-fourths of the patients were male, one-fourth had a history of MI, one-fourth had angina pectoris, one-fifth had diabetes mellitus, and nearly 30% had a history of cerebrovascular accident or transient ischemic attack.

All patients were being treated with a beta-blocker, about 60% with antiplatelet therapy, more than one-fourth with anticoagulant therapy, nearly half with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and more than one-fourth with diuretics. There were no significant differences between the groups in the proportion of patients on each of these therapies.

Results: Reductions in inflammatory markers

Baseline levels of hsCRP and interleukin-6 (IL-6) were comparable between the groups. In patients randomized to placebo, the hsCRP level increased by 3%, from a median of 5.80 mg/L at randomization to 6.00 mg/L immediately prior to surgery. In contrast, the hsCRP level in patients randomized to extended-release fluvastatin decreased by 21%, from a median of 5.93 mg/L to 4.66 mg/L. The between-group difference in the change in hsCRP level was statistically significant (P < .001). There was also a significantly greater reduction from baseline in median level of IL-6 among fluvastatin recipients compared with placebo recipients (–33% vs –4%; P < .001).

The specificity of hsCRP for cardiac inflammation is not yet known, but measures of hsCRP and IL-6 can provide a fingerprint of inflammatory activity prior to surgery. Other inflammatory and noninflammatory markers are being investigated to better identify (prior to surgery) those high-risk patients most likely to benefit from perioperative statin use.

 

 

Results: Favorable effect on clinical end points

The incidence of the primary end point—myocardial ischemia 30 days after surgery—was significantly lower in the patients randomized to extended-release fluva­statin compared with placebo (10.9% vs 18.9%; P = .016), as was the incidence of the secondary end point of cardiovascular death or nonfatal MI (4.8% vs 10.1%; P = .039).

The number needed to treat (NNT) to prevent one occurrence of myocardial ischemia was 13; the NNT to prevent one nonfatal MI was 36; and the NNT to prevent one cardiovascular death was 42 (Table 1).

Safety: No effects on liver function or evidence of increased myopathy

No significant differences were seen between the study arms in safety end points, including discontinuation of study drug, the incidence of creatine kinase (CK) elevations above 10 times the upper limit of normal, median CK levels, the incidence of alanine aminotransferase (ALT) elevations above three times the upper limit of normal, and median ALT levels (Table 2). Receipt of general anesthesia prevented monitoring for symptoms of myopathy and rhabdomyolysis.

We concluded that initiation of therapy with a long-acting statin should be considered in statin-naïve patients undergoing vascular surgery.

PERIOPERATIVE STATIN USE: PRACTICAL CONSIDERATIONS

Inflammation, not cholesterol, should be the target

The optimal statin choice and the target level of LDL cholesterol immediately prior to surgery remain controversial. It may be that the more potent statins induce more side effects during surgery, but any such claim is speculative since no comparative studies exist. Regardless, the purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery, with the long-term goal being achievement of recommended target lipid levels.

In particular, patients with peripheral arterial disease should have a statin initiated prior to high-risk vascular surgery (if they are not already receiving one), to increase the odds of recovering renal function after surgery (see section below) and to improve long-term outcomes.

Who are the best candidates?

Patients with multiple cardiac risk factors represent an especially high-risk group that benefits the most from statin therapy prior to vascular surgery, as they are likely to have more extensive disease and more extensive inflammation in the coronary artery tree.

Given the low incidence of side effects associated with statins, initiating a statin in patients with multiple cardiac risk factors who are undergoing intermediate-risk surgery may seem appropriate, but no data from large randomized trials are available to support this practice. Caution is in order when extrapolating data from studies conducted in the high-risk vascular surgery context to other surgical settings, since statins may pose hidden side effects such as liver dysfunction and myopathy, which may be missed in patients under anesthesia.

My personal practice is to initiate a statin prior to high-risk surgery or in patients with multiple cardiac risk factors if the risk-factor profile presents a clear indication for long-term statin use. If no risk factors are present, I am more reluctant to initiate a statin because of a lack of supportive data.

Beware the rebound effect with statin withdrawal

Statin withdrawal for several days following surgery is a common practice, since statins are given orally and their pleiotropic effects are underappreciated.

A withdrawal effect leading to abrogation of clinical benefit has been observed with perioperative use of short-acting statins, whose anti-inflammatory properties do not effectively extend to the postoperative period. Acute withdrawal has been associated with an increase in markers of inflammation and oxidative stress, and an increase in cardiac events has been observed with acute withdrawal of statins during periods of instability when compared with continuation of statin therapy.¹¹

For these reasons, a long-acting statin is preferred preoperatively in patients whose oral intake will be compromised for several days after surgery (eg, in gastric surgery). The optimal statin for preventing the withdrawal effect is unknown. We chose extended-release fluvastatin in DECREASE III because its biological effect appears to last at least 4 days¹² even though analysis of serum levels of the drug indicates a shorter half-life.

 

 

ANOTHER POTENTIAL BENEFIT: ENHANCED RECOVERY OF KIDNEY FUNCTION

Postoperative renal dysfunction is an ominous sign

Renal ischemic reperfusion injury is inevitable after vascular surgery that requires aortic cross-clamping. This is significant, as renal dysfunction after surgery is an ominous long-term sign that indicates abundant atherosclerosis. Complete recovery after acute kidney injury portends an improved long-term outcome, whereas patients with persistent renal dysfunction after vascular surgery have poor long-term outcomes.

A benefit from statins?

Statins may offer an effective means of preventing or shortening the course of acute kidney injury after surgery. Statins have been reported to lengthen survival of chronic kidney disease patients with sepsis or infectious complications and to improve the course of acute kidney injury in aging rats.^13–15 These findings prompted my colleagues and I to conduct a retrospective study to evaluate whether statins may ameliorate reperfusion injury in the kidney after aortic cross-clamping.¹⁶

Promising findings from an observational review

We reviewed the records of all patients who had undergone vascular surgery at Erasmus Medical Center from January 1995 to June 2006 to examine the relation between preoperative statin use and renal function after suprarenal aortic cross-clamping.¹⁶ Of the 1,944 patients who met inclusion criteria, 515 (26.5%) were statin users. Postoperative kidney injury was defined as more than a 10% reduction in creatinine clearance on postoperative day 1 or 2 compared with baseline. Recovery of kidney function was defined as a creatinine clearance of greater than 90% of the baseline value by postoperative day 3.

The clinical characteristics of the populations with and without kidney injury after aortic cross-clamping were similar, including baseline creatinine clearance and serum creatinine.

Acute kidney injury within 2 days of surgery occurred in 664 patients (34%), of which 313 (47%) had complete recovery of kidney function at postoperative day 3. Although the incidence of postoperative kidney injury was similar among statin users and nonusers, statin use was associated with an increased chance of complete recovery of kidney function at day 3 (odds ratio = 2.0; 95% CI, 1.0–3.8).

All-cause mortality was assessed during a mean follow-up of 6.24 years. Statin use was associated with improved long-term survival, regardless of any change in kidney function (hazard ratio for death = 0.60; 95% CI, 0.48–0.75). Among the four broad patient groups, survival was highest among statin users with no postoperative kidney injury, followed by statin users who had kidney injury, then by nonusers of statins with no kidney injury, and finally by nonusers of statins who had kidney injury.

We concluded that perioperative statin use was associated with clinically significant recovery from acute kidney injury after high-risk vascular surgery and, more importantly, with improved long-term survival regardless of the presence of kidney injury. These promising findings require confirmation in prospective trials.

SUMMARY

Vascular surgery carries a high risk of perioperative mortality. Perioperative use of extended-release fluvastatin is associated with a reduced incidence of myocardial ischemia and the composite of MI and cardiovascular death at 30 days following surgery. These beneficial clinical outcomes are achieved without an increase in the incidence of side effects, including liver dysfunction and myopathy. Preoperative initiation of a long-acting statin is a reasonable strategy for reducing the risks associated with vascular surgery, and offers a bridge to postoperative statin continuation to blunt the inflammatory stress of surgery. Ischemic reperfusion injury is a major cause of renal dysfunction following vascular surgery. Statin therapy appears to help restore kidney function after aortic cross-clamping in patients undergoing high-risk vascular surgery.

DISCUSSION

Question from the audience: The majority of patients randomized in DECREASE III had relatively normal cholesterol levels. Do you believe those patients are biologically different from patients with physiologic vascular disease and elevated cholesterol levels?

Dr. Poldermans: We enrolled patients with various baseline cholesterol levels, and we found that these levels were not related to postoperative outcome. It would be a good idea to examine inflammation status just prior to surgery in patients with lower cholesterol levels to see if they have different outcomes from those with high cholesterol.

Question from the audience: If a patient is already on a short-acting statin and we know that he or she won’t be able to take a statin postoperatively, should we change to a long-acting statin just prior to surgery?

Dr. Poldermans: To be honest, this is a financial issue. If you have the opportunity, the best course would be to prescribe a statin with a prolonged half-life or an extended-release formulation. Of course, it’s not always possible to prescribe one particular statin. You have to negotiate what is feasible and hope to initiate the statin as early as possible to reduce risk.

Question from the audience: In studies conducted outside the perioperative setting, such as PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and a substudy of REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering), it took about 30 days after statin initiation for hsCRP levels to minimize, and at least that long for halting of plaque progression to be detected by intravascular ultrasonography. Given that, does it make sense to delay nonurgent surgery in a patient in whom you’re worried about a postoperative MI?

Dr. Poldermans: Rat studies show improved blood flow and reduced thrombosis within hours of statin initiation. In the perioperative setting, therefore, initiating a statin within 30 days may be appropriate, but nobody knows the exact timing for optimal effect. Since there are no data to answer this question, I would not postpone surgery for this reason.

NOTE: The individual co-authors in this debate-based article are responsible only for those views within their respective bylined subsections and those views ascribed to them in the rebuttals and discussion at the end.

 

Perioperative beta-blockade improves outcomes

By Don Poldermans, MD, PhD

It is my contention that perioperative beta-blockade improves mortality and cardiac outcomes in select high- and intermediate-risk patients undergoing noncardiac surgery. Patients on chronic beta-blocker therapy should have it continued perioperatively. For patients not already on beta-blockade who are at cardiac risk, initiation of low-dose beta-blocker therapy should be considered prior to surgery; such therapy should be started approximately 1 month before surgery, with dose titration to achieve hemodynamic stability. Reports of increased stroke rates with perioperative beta-blockade appear to be due to inappropriate acute administration of high-dose beta-blocker therapy.

THE PHYSIOLOGIC RATIONALE FOR PERIOPERATIVE BETA-BLOCKADE

Perioperative myocardial infarction (MI) can occur by one of two mechanisms, both of which can be attenuated by beta-blockade:

• The stress induced by surgery can cause an asymptomatic coronary plaque to become unstable and rupture, resulting in complete occlusion of a portion of the coronary tree. This type of perioperative MI occurs typically in patients with multiple risk factors for MI absent a critical coronary stenosis. The perioperative risk associated with unstable plaque can be reduced pharmacologically with aspirin, statins, and chronic beta-blocker therapy.
• Alternately, a fixed coronary stenosis can predispose to a mismatch of oxygen demand and supply, leading to myocardial ischemia and infarction. The patient with a fixed coronary lesion typically presents with stable angina pectoris, and the at-risk stenosis is identified through a stress echocardiogram or nuclear scan. The risk conferred by flow-limiting stable plaque can be reduced by coronary revascularization and a short course of beta-blocker therapy prior to surgery.

INITIAL SUPPORTIVE DATA

Mangano and colleagues were the first to evaluate perioperative beta-blockade in a randomized, controlled fashion.^1,2 In their study of 200 surgical patients with or at risk for coronary artery disease, oral atenolol administered perioperatively was associated with a 50% reduction (compared with placebo) in the incidence of postoperative myocardial ischemia as measured by three-lead Holter monitoring.² During 2 years of follow-up, mortality was significantly lower in the atenolol group (10%) than in the placebo group (21%) (P = .019).¹

In the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE I), my research group randomized 112 high-risk patients (as identified by dobutamine echocardiography) to standard perioperative care alone or standard perioperative care plus bisoprolol starting 30 days prior to major vascular surgery.³ The dosage of bisoprolol was titrated to achieve a target heart rate of 60 to 70 beats per minute. Thirty days after surgery, the incidence of the primary end point—a composite of death from cardiac causes or nonfatal MI—was reduced from 34% in the standard-care group to 3.4% in the bisoprolol group (P < .001). Thus, in this unblinded study in a population with proven coronary artery disease, beta-blockade clearly improved outcomes.

Additional studies of perioperative beta-blocker use have produced a wide range of outcomes, with most favoring beta-blockade, albeit usually not to a statistically significant degree.^4–13 Notably, only some of these trials were randomized, they used various beta-blocker regimens at various doses, they were conducted in patients with varying degrees of cardiac risk, and many had small sample sizes.

What emerged from these trials was the idea that perioperative beta-blockade in patients with coronary artery disease produces an effect similar to that of long-term beta-blockade in reducing the risk of cardiovascular events in post-MI patients and in those with coronary artery disease and heart failure.

THE POISE STUDY AND ITS IMPLICATIONS

Results of the Perioperative Ischemic Evaluation (POISE) were published in 2008, in which 8,351 noncardiac surgery patients with or at risk of atherosclerotic disease were randomized to placebo or extended-release metoprolol succinate started 2 to 4 hours preoperatively and continued for 30 days.¹⁴ Metoprolol was associated with a clear reduction in the primary end point, a composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest (5.8% vs 6.9% with placebo; hazard ratio [HR] = 0.84 [95% CI, 0.70–0.99]; P = .0399), but this effect was offset by significant increases in total mortality and stroke incidence in the metoprolol group. Mortality was 3.1% with metoprolol versus 2.3% with placebo (HR = 1.33 [95% CI, 1.03–1.74]; P = .0317), and stroke incidence was 1.0% with metoprolol versus 0.5% with placebo (HR = 2.17 [95% CI, 1.26–3.74]; P = .0053). Cerebral infarction, not bleeding, explained most of the excess mortality with metoprolol.

Of the 60 strokes in POISE, 49 were ischemic in origin, 3 were hemorrhagic, and 8 were of uncertain etiology. Preoperative predictors of stroke were the use of clopidogrel and a history of stroke or transient ischemic attack. Postoperative predictors of stroke included intraoperative bleeding and intraoperative hypotension. These predictors suggest a diseased cerebrovascular tree or unstable hemodynamics during the intraoperative period in the patients who suffered a stroke.

Does dosing explain the rise in mortality and strokes?

Could the fatal outcomes associated with the beta-blocker in POISE be attributed to the dosage of metoprolol? In the study, 100 mg of metoprolol was started immediately prior to surgery, and an additional 100 mg could be given, depending on the hemodynamic response. Maintenance therapy (200 mg/day) was started on the same day, making it possible that a patient could have received as much as 400 mg of metoprolol the day of surgery. The starting dose of metoprolol used in POISE was two to eight times the commonly prescribed dose.

The initial 100-mg dose of metoprolol used in POISE has a similar beta₁-receptor blockade potency compared with the 5-mg dose of bisoprolol used in DECREASE I.³ However, in DECREASE I, bisoprolol was initiated 30 days prior to surgery and was titrated, if necessary, according to heart rate. The maintenance dose of bisoprolol was half of the maintenance dose used in POISE. In the later DECREASE trials, the starting dose of bisoprolol was only 2.5 mg. Therefore, there was a huge difference in beta-blocker dosing between POISE and DECREASE.

Perioperative cardiac outcomes were similar in POISE and DECREASE I, with clear reductions in each trial among the patients randomized to the beta-blocker, as in other trials of perioperative beta-blockade. Stroke outcomes, in contrast, are inconsistent among trials of perioperative beta-blockade, with no increase in stroke observed in studies using low-dose titrated bisoprolol and an overall increase in stroke in studies of metoprolol, driven by the data from POISE^{2–5,14–17} (Figure 1). When interpreting the pooled analyses in Figure 1, it should be noted that DECREASE I³ and IV¹⁷ were open-label trials, not double-blind studies.

 

 

What about timing of beta-blocker initiation?

The POISE findings may also be explained in part by the timing of beta-blocker initiation. Whereas bisoprolol was carefully titrated for 30 days before surgery in DECREASE, metoprolol was initiated just before surgery in POISE, and the maximum recommended dose may have been prescribed during the first 24 hours, although subsequent dosing was 200 mg daily, which is 50% of the maximum daily therapeutic dose. This extremely narrow time window for titration may be important, since the beneficial effects of beta-blockade on coronary plaque stability are likely to take weeks to develop. 

To determine whether there might be a relation between timing of beta-blocker initiation and postoperative stroke, we performed an analysis (in press) plotting stroke rates according to timing of beta-blocker initiation from eight studies of perioperative beta-blockade. As illustrated in Figure 2, patients on titrated chronic beta-blocker therapy (at least 10 days) had a low (< 1%) incidence of stroke, whereas patients in whom beta-blocker therapy was started immediately before surgery had a much higher incidence of stroke. This finding suggests that ample time for titrating the beta-blocker dose may be necessary to achieve an optimal, stable hemodynamic condition and thereby prevent hemodynamic aberrations that could raise the risk of stroke.

Reassurance from a large case-control study

My colleagues and I conducted a case-control study from among more than 75,000 patients who underwent noncardiac, nonvascular surgery at our institution, Erasmus Medical Center, from 1991 to 2001.¹⁸ The cases were the 989 patients who died in the hospital postoperatively; the controls were 1,879 survivors matched with the cases for age, sex, the year the surgery was performed, and the type of surgery. The incidence of perioperative stroke was 0.5%, which is comparable to the rate found in the literature. Risk factors predictive of stroke were the presence of diabetes, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, coronary artery disease, and hypertension. Notably, no relationship was found between chronic beta-blocker use and stroke.

WHAT ABOUT PATIENTS AT INTERMEDIATE RISK?

Because the effect of perioperative beta-blockade has traditionally been ill defined in surgical patients at intermediate risk of cardiovascular events, the DECREASE study group recently completed a study (DECREASE IV) to assess perioperative bisoprolol in terms of cardiac morbidity and mortality in intermediate-risk patients undergoing elective noncardiovascular surgery.¹⁷ Enrollees had a score of 1 to 2 on the Revised Cardiac Risk Index of Lee et al,¹⁹ which corresponds to an estimated risk of between 1% and 6% for a perioperative cardiovascular event.¹⁷

DECREASE IV also aimed to assess the effect of perioperative fluvastatin, so a 2 x 2 factorial design was used in which the study’s 1,066 patients were randomized to receive bisoprolol, fluvastatin, combination treatment, or combination placebo control. Bisoprolol was initiated up to 30 days prior to surgery, and the 2.5-mg daily starting dosage was titrated according to the patient’s heart rate to achieve a target rate of 50 to 70 beats per minute. Fluvastatin was also started up to 30 days prior to surgery. Patients who received bisoprolol (with or without fluvastatin) had a significant reduction in the 30-day incidence of cardiac death and nonfatal MI compared with those who did not receive bisoprolol (2.1% vs 6.0%; HR = 0.34 [95% CI, 0.17–0.67]; P = .002). Fluvastatin was associated with a favorable trend on this end point, but statistical significance was not achieved (P = .17).¹⁷

There was no difference among treatment groups in the incidence of stroke (4 strokes in the 533 patients who received bisoprolol vs 3 strokes in the 533 patients who did not),¹⁷ which further suggests that the increased stroke rate seen with beta-blockade in POISE may have been due to dosage, timing of initiation, or both.

CONCLUSIONS

Dose-related hypotension may explain POISE findings

Our understanding of postoperative stroke is incomplete, but it appears that dosing of a beta-blocker can be a contributor, especially with respect to the potential side effect of hypotension during surgery. Keep in mind that the average age of patients in POISE was approximately 70 years and that patients were naïve to beta-blockers. Some may have had asymptomatic left ventricular dysfunction, and we know that starting a beta-blocker at a high dose in such patients may lead to hypotension. At my institution we routinely perform echocardiographic screening of all patients scheduled for surgery, and we have found that more than half of the patients with heart failure have it uncovered only through this screening.

It is not the medicine alone that can cause perioperative hypotension; other factors may induce hypotension, requiring beta-blocker titration and careful monitoring of hemodynamics during surgery.

Advice: Start early and titrate dose; continue chronic beta-blockade

My advice is as follows:

• If a patient is on chronic beta-blocker therapy, do not stop it perioperatively. We have seen devastating outcomes in the Netherlands when patients had their beta-blockers stopped immediately before surgery. Consider adjusting the dose, but do not stop it entirely. If a beta-blocker is on board and the patient develops hypotension or bradycardia during surgery, treat the symptoms and check for sepsis.
• In a patient not on a beta-blocker, consider adding one if the patient is at intermediate or high risk of a cardiac event, but start at a low dosage (ie, 2.5 mg/day for bisoprolol and 25 mg/day for metoprolol). Treatment ideally should be started 30 days preoperatively; in the Netherlands, we have the chance to start well in advance of surgery so we can titrate the dose according to hemodynamics.
• If a beta-blocker is not started because of insufficient time for titration, do not add one to treat tachycardia that develops during surgery, since tachycardia may represent a response to normal defense mechanisms.

 

 

Safety of perioperative beta-blocker use has not been adequately demonstrated

By P.J. Devereaux, MD, PhD

I contend that perioperative beta-blockade is a practice not grounded in evidence-based medicine, and its overall safety has increasingly come into question as more data from large, high-quality trials have emerged. I will begin with a historical overview of perioperative beta-blocker use, review the results of the POISE trial (for which I was the co-principal investigator), explore the major questions raised by this trial, and conclude with some take-away messages.

THE HISTORY OF PERIOPERATIVE BETA-BLOCKADE

In the 1970s, physicians were encouraged to hold beta-blockers prior to surgery out of concern that these medications may inhibit the required cardiovascular response when patients developed hypotension, and could thereby lead to serious adverse consequences.

In the 1980s, new research associated tachycardia with perioperative cardiovascular events, leading to proposals to implement perioperative beta-blocker use.

In the 1990s, two randomized trials with a total sample size of 312 patients^1,3 suggested that perioperative beta-blockers had a large treatment effect in preventing major cardiovascular events and death. These small trials had several methodological limitations:

• One trial³ was unblinded in a setting in which the vast majority of MIs are clinically silent.
• One trial³ was stopped early—after randomizing only 112 patients—for unexpected large treatment effects.
• One of the studies¹ failed to follow intention-to-treat principle.

Nevertheless, guidelines developed at the time by the American College of Cardiology and the American Heart Association (ACC/AHA) recommended the use of perioperative beta-blockers on the basis of the physiological rationale and these two small clinical trials. That recommendation was retained in the latest (2007) update of the ACC/AHA perioperative guidelines.²⁰

In 2006, two clinical trials with a total sample size of 1,417 were completed,^4,15 surpassing the total size of previous trials by more than fourfold. These two more recent trials did not suffer from the methodological limitations of earlier trials. These trials showed no benefit of perioperative beta-blocker use; in fact, there was a trend toward worse outcomes in the beta-blocker recipients.^4,15 Despite these new data, guidelines committees continued to recommend perioperative beta-blockade.²⁰

THE POISE TRIAL

Study design

This was the context into which the POISE results were released in 2008. POISE was a randomized, controlled, blinded trial of patients 45 years or older scheduled for noncardiac surgery who had, or were at high risk of, atherosclerotic disease.¹⁴ The intervention consisted of metoprolol succinate (metoprolol controlled release [CR]) or placebo started 2 to 4 hours preoperatively (if heart rate was ≥ 50 beats per minute and systolic blood pressure [SBP] was ≥ 100 mm Hg) and continued for 30 days. The target dosage of metoprolol was 200 mg once daily. No patients received the recommended maximum dosage of 400 mg over 24 hours. The main outcome measure was a 30-day composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest.

We randomized 9,298 patients in a 1:1 ratio to metoprolol or placebo. We encountered data fraud at a number of centers that prompted exclusion of data from 474 patients allocated to metoprolol and 473 allocated to placebo. Therefore, the total number of patients available for the intention-to-treat analysis was 8,351, from 190 centers in 23 countries.

Results

The risk of the primary composite outcome was reduced by 16% (relative reduction) in recipients of metoprolol CR compared with placebo recipients (P = .0399). Significantly fewer nonfatal MIs occurred in the metoprolol CR group than in the placebo group (152 [3.6%] vs 215 [5.1%]; P = .0008), leaving little doubt that perioperative beta-blockade prevents MI.

In contrast, total mortality was increased in the beta-blocker group, with 129 deaths among those assigned to metoprolol CR and 97 among those assigned to placebo (P = .0317), and the incidence of stroke was also significantly greater in the metoprolol CR group (1.0% vs. 0.5%; P = .0053).

Consistency with findings from other trials

The POISE data are consistent with those from a 2008 meta-analysis of high-quality randomized controlled trials in noncardiac surgery patients, which showed a significantly greater risk of death among patients assigned to a beta-blocker than among controls who were not (160 deaths [2.8%] vs 127 deaths [2.3%]; odds ratio [OR] = 1.27 [95% CI, 1.01–1.61]).²¹ This meta-analysis also found a significantly greater risk of nonfatal stroke in beta-blocker recipients compared with controls (38 [0.7%] vs 17 [0.3%]; OR = 2.16 [95% CI, 1.27–3.68]).

I also contend that the DECREASE IV trial supports the POISE findings in that although few strokes were encountered in DECREASE IV, the trend was in the direction of harm in the beta-blocker group, which had 4 strokes among 533 patients versus 3 strokes among 533 patients not receiving the beta-blocker.¹⁷

Predictive role of hypotension

Clinically significant hypotension (defined as systolic blood pressure < 90 mm Hg that required intervention) was common in POISE, developing in 9.7% of the placebo group and 15.0% of the metoprolol group.¹⁴ On multivariate analysis, clinically significant hypotension was an independent predictor—in fact the dominant predictor—of both death and stroke (Table 1). Hypotension was associated with a nearly fivefold increase in the risk of death and a doubling in the risk of stroke. The population-attributable risk of hypotension to death was 37.3, meaning that hypotension potentially accounted for 37.3% of deaths in the study. The population-attributable risk of hypotension to stroke was 14.7. In light of hypotension’s role as the dominant predictor of death, I take issue with Dr. Poldermans’ earlier contention that cerebral infarction explained most of the excess mortality with metoprolol in POISE.

The link between hypotension and death in POISE is consistent with findings from the largest beta-blocker trial undertaken, COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), in which 45,852 patients with acute MI were randomized to metoprolol or placebo.²² In COMMIT, metoprolol had no effect on 30-day all-cause mortality but significantly reduced the risk of arrhythmic death, a benefit that was countered by a significantly increased risk of death from shock with a beta-blocker in acute MI. Clinically significant hypotension is much more common in the perioperative setting than in acute MI, which may explain the excess number of deaths observed with metoprolol in POISE as opposed to metoprolol’s neutral effect on mortality in COMMIT.

 

 

ANSWERING THE CRITICS

Several criticisms have been raised about POISE, as detailed below.

Beta-blocker dose

Some contend that a lower dose of beta-blocker would provide benefit and minimize risk, but this assertion must be supported by evidence from a large clinical trial. The targeted dosage of metoprolol in POISE represents 50% of the maximum daily therapeutic dose. Further, the protocol called for decreasing the dosage to 100 mg/day if SBP dropped to less than 100 mm Hg or if heart rate fell to less than 45 beats per minute.

The two small trials on which guideline recommendations for perioperative beta-blockade are primarily based^1,3 had a sample size that was 4% of that in POISE, which calls into question the reliability of their results. The study by Mangano et al used atenolol at a target dosage that was 50% of the maximum daily therapeutic dose,¹ the same as with metoprolol in POISE. DECREASE initiated bisoprolol at 25% of the maximum daily therapeutic dose, and allowed for titration to 50% of the maximum daily therapeutic dose.³

As the second largest study of perioperative beta-blockade, the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial enrolled 921 patients who were assigned to placebo or controlled-release metoprolol with a target dosage that was 25% of the maximum daily therapeutic dose.⁴ The 30-day outcomes from DIPOM showed a trend toward an excess of death and stroke despite using only one-half the dosage in POISE and the same dosage as in DECREASE.

Timing of beta-blocker initiation

Another contention is that earlier beta-blocker initiation would be better. The issue with timing of initiation is not benefit, as POISE showed that starting a beta-blocker hours before surgery results in a reduction in the risk of MI. The issue is whether giving a beta-blocker earlier makes administering the drug safer. Nearly 10% of placebo recipients in POISE developed clinically significant hypotension, which suggests that the titrated dosage of a beta-blocker that appears effective preoperatively is unlikely to inform a safe dose after surgery, when hypotension is common.

The practicality of titrating the dose of beta-blocker prior to surgery also comes into play. Most patients referred to my institution for surgery are seen 1 to 2 weeks in advance, at the earliest. Real-world practice at present simply does not afford us the luxury of seeing patients three to four times before surgery in order to titrate the beta-blocker dose.

POISE did not address chronic beta-blocker therapy

It is important to remember that POISE excluded patients on chronic beta-blocker therapy and thus did not attempt to address the perioperative management of such patients who undergo noncardiac surgery. My suspicion is that perioperative continuation of beta-blockade in these patients is the best course of action, but this too has not been studied robustly, so we need a large controlled trial to confirm that this practice is indeed safe. 

CONCLUSIONS

The POISE results suggest that for every 1,000 patients treated, perioperative metoprolol would:

• Prevent 15 MIs, 3 cardiac revascularizations, and 7 new cases of atrial fibrillation
• Result in 8 excess deaths, 5 strokes, 53 cases of clinically significant hypotension, and 42 cases of clinically significant bradycardia.

The central take-away message is that patients are unlikely to want a perioperative beta-blocker if they are unwilling to accept a probable increase in mortality or if they place three times more value on avoiding a perioperative stroke than on avoiding an MI.

It has been 10 years since the recommendation to use perioperatove beta-blockers was incorporated into perioperative practice guidelines. Assuming only 10% of physicians acted on this recommendation, 100 million patients have received a perioperative beta-blocker over this time as a result. If the POISE results are applicable, a full 800,000 of these patients died and another 500,000 suffered perioperative strokes as a result of being given a beta-blocker. This issue is not to be taken lightly, given the evidence to suggest harm.

Though it is possible that an alternative beta-blocker regimen to the one used in POISE may provide benefit without substantial harm, the data suggest this is not probable. The POISE data highlight the risk of making assumptions, as well as the importance of and need for large, high-quality randomized trials in the perioperative setting.

It is time for perioperative medicine to enter the age of evidence-based practice and embrace one of its central tenets: only large trials are reliable when it comes to therapeutic questions.

 

 

Rebuttals and discussion

POLDERMANS REBUTTAL: MORE TRANSPARENCY NEEDED IN POISE DOSING DATA

Dr. Poldermans: The initial paper describing the POISE trial design did indeed indicate that it was possible for a patient to receive 400 mg of metoprolol on the first day of treatment. We need to see the actual doses of metoprolol given to all patients in POISE who had a perioperative stroke. If you show me these data, the issue will be much easier to discuss.

Our data from randomized trials are consistent in showing that a titrated dosing regimen using bisoprolol reduces the incidence of postoperative cardiac events with no increase in the number of strokes.

My take-home message is that if you want to use beta-blockers, use them sensibly, use them carefully, and act during surgery. If many of your patients are developing hypotension, then you are doing something wrong.

DEVEREAUX REBUTTAL: A SHIFT IN THINKING IS REQUIRED

Dr. Devereaux: The data from POISE are fully available, and I take issue with Dr. Poldermans’ contention that a patient could have received as much as 400 mg of metoprolol CR on the day of surgery; this was not an option according to protocol. I believe his statement is misleading in the same way that it is misleading to indicate that in the DECREASE trial patients may have received 20 mg of bisoprolol within 24 hours of surgery. It is possible that a patient in DECREASE could have gone to surgery at 2:00 pm and may have taken his or her bisoprolol at 10:00 am that morning. The following morning (in the hospital), it is possible that the patient would have received his or her bisoprolol 10 mg at 7:00 or 8:00 am (ie, 20 mg within 24 hours of surgery). Although this is possible and something similar could have happened within POISE, it does not reflect a patient receiving an effective dose of metoprolol CR 400 mg or bisoprolol 20 mg over a 24-hour period.

I worry about the distortion of reality in perioperative medicine that leads so many of us to believe that randomization is magical despite small sample sizes. Small randomized trials are at profound risk of imbalance between the randomized groups, whether we see it or not, and the results are therefore simply not reliable.

Unless we shift our thinking, we make ourselves susceptible to overconfidence in the benefits of a certain intervention before the data from large clinical trials become available. In the meantime, as we have seen from POISE, an intervention may have negative consequences that are not apparent from small clinical trials.

The reality of excess stroke with perioperative beta-blockers is consistent across all the trials. It does not mean that we cannot find another way to give beta-blockers safely, but if we want to establish safety, we need a large trial that unequivocally demonstrates safety, as opposed to simply using observational data, retrospective cohorts, or comparisons between two nonrandomized trials. Until we have large data sets, it is very difficult to say that we can give beta-blockers safely.

DISCUSSION WITH THE AUDIENCE

Moderator^*: Dr. Devereaux, was the hypotension in POISE related to the long-acting beta-blocker itself or to the large dose of if that was used? Similarly, were the strokes a result of the drug itself or of the hypotension?

Dr. Devereaux: I must take issue with your premise that the dose of metoprolol used in POISE was “large.” As I noted, Mangano’s study used its beta-blocker (atenolol) at 50% of its maximum daily therapeutic dose,¹ the same proportion used in POISE, and Dr. Poldermans’ own DECREASE trial allowed titration of bisoprolol up to 50% of the maximum daily therapeutic dose.³ The DIPOM trial used half the dose of metoprolol that we used, yet it too yielded a trend toward more death and stroke in the beta-blocker group.⁴ So it’s not that the dose we used was at some excessive level. At the same time, that does not mean that a smaller dose may not have achieved a similarly significant benefit in cardiac outcomes.

We can’t explain most of the strokes. Because most strokes were ischemic, I suspect that the explanation may lie in the threshold used to define clinically significant hypotension. We used an SBP cutoff of less than 90 mm Hg, but we did not classify large drops in SBP, such as from 180 to 95 mm Hg, as clinically significant hypotension. The high incidence of clinically significant hypotension in the placebo group—about 10%—suggests that hypotension was likely the driving factor for stroke. The beta-blocker exacerbated the hypotension, but its more important effect may have been that it made it harder for the body to overcome the hypotension. That is the exact same signal observed in the COMMIT trial in the setting of acute MI.²²

Dr. Poldermans: I’d like to see the intraoperative blood pressure data for the 60 patients who suffered strokes in POISE. We could then find out exactly when the hypotension occurred, what kind of hypotension it was, what the patient’s initial blood pressure reading was, and so on. If we had access to this information, we could determine which occurred first—the hypotension or the stroke.

Dr. Devereaux: Although trials can indicate a signal, they can’t explain with certainty the pathway through which the outcome occurred. For example, we know that beta-blockers prevent MI, but we don’t know how. What’s most impressive about the stroke issue is the consistency across all the perioperative beta-blocker trials: every one shows a direction of excess stroke with beta-blockers.

Question from the audience: The patient groups studied in DECREASE and POISE were different. DECREASE studied a very high-risk vascular surgery group with known coronary artery disease on the basis of echocardiography. POISE included patients undergoing emergency surgery and patients with sepsis. Can you describe the outcomes in POISE solely among the patients who underwent elective vascular surgery, similar to the patients studied in DECREASE?

Dr. Devereaux: In terms of the benefit to bisoprolol in very high-risk patients in DECREASE, remember that it was a study of 112 patients. That’s far too small a trial to establish safety or efficacy. The benefit of perioperative beta-blockade in preventing MI is unequivocal because it’s consistent across all trials. But the real issue is, was it safe?

Interestingly, in POISE, the groups at highest risk looked like they benefited the least, not the most. The notion of targeting high-risk people is not supported by POISE; if anything, the POISE results went in the direction of harm with beta-blockade in high-risk patients. That being said, the P value for interaction is not statistically significant, but it’s heading in the direction of harm. So I wouldn’t take comfort in believing that if we simply target high-risk patients, beta-blockers become safe.

Question from the audience: I believe that the seven or eight studies that showed higher stroke rates with beta-blockers all gave beta-blockade within 24 hours of surgery. Only in DECREASE was it given days and weeks in advance of surgery. Can you comment?

Dr. Poldermans: There’s clearly a relation between the time of beta-blocker initiation and the incidence of stroke. If you look at the randomized trials, you see an increased incidence of stroke in patients in whom beta-blockers are started just prior to surgery but not in patients who are on chronic beta-blockers. In our case-control study,¹⁸ we screened more than 185,000 patients for stroke and could not detect an increased incidence of stroke in those on chronic beta-blocker therapy. So stroke indeed has something to do with starting beta-blockers just before surgery.

Dr. Devereaux: In DECREASE IV, bisoprolol was started up to 1 month before surgery, yet there were 4 strokes in the bisoprolol group versus 3 in the control group.¹⁷

Dr. Poldermans: Yes, but that difference is not statistically meaningful.

 

Comment from the audience: I’m uncomfortable with the way Dr. Devereaux stresses the importance of significant findings from large randomized trials but then quibbles about a stroke rate of 4 versus 3, which is not statistically significant. Keep it scientific: either there is or there isn’t a P value that achieves significance.

Though I congratulate you on a great trial, any resident in my program would be fired for pursuing your strategy of perioperative care in POISE, which included using an SBP of 100 mm Hg as the threshold for stopping the beta-blocker regardless of preoperative blood pressure. An SBP of 100 mm Hg is not the definition of hypotension. Most anesthesiologists and perioperative physicians peg the beta-blockade to a reasonable level based on the preoperative blood pressure. They titrate in fluids and titrate in the beta-blocker. Certainly the timing is an issue—we don’t recommend giving it right before the operation.

Dr. Devereaux: I referred to the stroke rates in DECREASE IV because Dr. Poldermans has claimed that the excess in strokes has occurred in all trials but his, yet DECREASE IV was one of his trials and also one in which bisoprolol was started early. I’m not claiming statistical significance between the 3 versus 4 strokes in DECREASE IV, but the stroke trend is in the same direction as in the other trials, so it tells us nothing with regard to safety. My point is, has anyone proven safety? As much as we’d like to imagine that beta-blockers are safe perioperatively—and maybe they are—it has not been proven. The largest trials at present are consistent with a signal toward harm.

It’s easy to criticize the methodology after a trial is done. A number of us came together and thought we had a reasonable protocol for POISE. We found a reduction in the incidence of MI but more strokes and higher mortality with perioperative metoprolol. Does this mean there is not a safe way to give a beta-blocker and derive the benefit? Of course not. But at the moment the evidence does not support a way to give a beta-blocker safely. Do we need to find a way to give it safely? Of course we do.

For example, the design of POISE II is factorial, looking at aspirin versus placebo as well as clonidine versus placebo. There are a number of factors about clonidine that suggest we might be able to achieve the benefits we saw in POISE and avoid the risk, but until we do a large trial, we’re not going to know.

Comment from the audience: It’s important that we clearly understand the conclusion from POISE. It’s not that the administration of beta-blockers is not safe. It’s that the administration of a beta-blocker, as your methodology applied it, was not totally safe. Those are two very different conclusions.

Dr. Devereaux: I would say the conclusion is that the way that beta-blockers are being given has not been proven to be safe. The result is consistent. It’s even consistent with DECREASE IV.

Moderator: I believe in large clinical trials, but they must apply to real-life practice. POISE did not address the practices of many people in this room, particularly regarding the doses of metoprolol used. So it is hard for us to apply the findings in clinical practice. Those of you who design large trials need to think through your trial design very thoroughly, considering the millions of dollars that go into these trials. It’s not fair to clinicians to do a study that may have little clinical relevance.

Dr. Devereaux: Investigators from 190 centers in 23 countries were involved in POISE, and all of them thought we had a reasonable approach and methodology. That doesn’t mean it was perfect, yet the criticisms we are hearing now did not surface while the trial was ongoing.

Comment from the audience: My hospital in Australia contributed to the POISE study. When it started 6 or 7 years ago, the cardiologists were using beta-blockers liberally and haphazardly. It was a huge challenge to convince them that conducting the trial was justifiable—that the case for perioperative beta-blockers had not been absolutely and overwhelmingly proved. They wanted to put beta-blockers in the water supply at the doses we’re talking about.

It would be interesting to do separate analyses of the data from the various countries involved in POISE. In Australia, the percentage of the population on chronic beta-blockers—who therefore would have been ineligible for the trial—is now quite high. Most patients who need to be on beta-blockers long term are on them, whereas that was not the case 15 years ago. The population is changing even while we’re doing the trials. Australian cardiologists are no longer putting every patient on perioperative beta-blockers; they’re thinking about it first.

Dr. Devereaux: A compelling feature of POISE as an international trial is its consistency of outcomes across the planet. No matter where we looked, the outcomes were consistent: in Asia, Europe, North America, and Australia.

Moderator: Would each of you summarize your take-home message for clinicians?

Dr. Devereaux: I urge clinicians to actually read the trials themselves rather than just relying on the advice of guideline writers. It’s important not to allow ourselves to become entrenched in a practice without evidence, just because we’ve done it for so long. If you told your patients the number of MIs prevented and the potential number of excess strokes and deaths, I suspect the average patient would conclude it’s not a great trade-off.

Remember that two-thirds of MIs in the perioperative setting are clinically silent. That doesn’t mean they’re not important, but the strokes, in contrast, are profoundly devastating. One-third of patients with stroke in POISE were dead within 30 days, and of those who survived, 60% were incapacitated, needing help with everyday activities.

I encourage clinicians to read the POISE manuscript with a fresh perspective, regardless of how you’ve practiced until now. Then ask yourself whether you really are comfortable with the safety of perioperative beta-blockers at this time. Of course, that doesn’t mean the evidence won’t change in the future.

Dr. Poldermans: The main imperative is to improve postoperative care. We strongly believe that perioperative beta-blockers work in the general population. If you have a patient who needs to be on a beta-blocker after surgery, why not start it preoperatively? I believe that dosing and timing of initiation are important. If you have the opportunity to start the beta-blocker prior to surgery, do so at a reasonable dose and start early. Patients in whom beta-blockers are started immediately prior to surgery may be worse off, with a higher incidence of stroke.

*Amir K. Jaffer, MD, University of Miami Miller School of Medicine, served as moderator of the debate and the discussion period.

NOTE: The individual co-authors in this debate-based article are responsible only for those views within their respective bylined subsections and those views ascribed to them in the rebuttals and discussion at the end.

 

Perioperative beta-blockade improves outcomes

By Don Poldermans, MD, PhD

It is my contention that perioperative beta-blockade improves mortality and cardiac outcomes in select high- and intermediate-risk patients undergoing noncardiac surgery. Patients on chronic beta-blocker therapy should have it continued perioperatively. For patients not already on beta-blockade who are at cardiac risk, initiation of low-dose beta-blocker therapy should be considered prior to surgery; such therapy should be started approximately 1 month before surgery, with dose titration to achieve hemodynamic stability. Reports of increased stroke rates with perioperative beta-blockade appear to be due to inappropriate acute administration of high-dose beta-blocker therapy.

THE PHYSIOLOGIC RATIONALE FOR PERIOPERATIVE BETA-BLOCKADE

Perioperative myocardial infarction (MI) can occur by one of two mechanisms, both of which can be attenuated by beta-blockade:

• The stress induced by surgery can cause an asymptomatic coronary plaque to become unstable and rupture, resulting in complete occlusion of a portion of the coronary tree. This type of perioperative MI occurs typically in patients with multiple risk factors for MI absent a critical coronary stenosis. The perioperative risk associated with unstable plaque can be reduced pharmacologically with aspirin, statins, and chronic beta-blocker therapy.
• Alternately, a fixed coronary stenosis can predispose to a mismatch of oxygen demand and supply, leading to myocardial ischemia and infarction. The patient with a fixed coronary lesion typically presents with stable angina pectoris, and the at-risk stenosis is identified through a stress echocardiogram or nuclear scan. The risk conferred by flow-limiting stable plaque can be reduced by coronary revascularization and a short course of beta-blocker therapy prior to surgery.

INITIAL SUPPORTIVE DATA

Mangano and colleagues were the first to evaluate perioperative beta-blockade in a randomized, controlled fashion.^1,2 In their study of 200 surgical patients with or at risk for coronary artery disease, oral atenolol administered perioperatively was associated with a 50% reduction (compared with placebo) in the incidence of postoperative myocardial ischemia as measured by three-lead Holter monitoring.² During 2 years of follow-up, mortality was significantly lower in the atenolol group (10%) than in the placebo group (21%) (P = .019).¹

In the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE I), my research group randomized 112 high-risk patients (as identified by dobutamine echocardiography) to standard perioperative care alone or standard perioperative care plus bisoprolol starting 30 days prior to major vascular surgery.³ The dosage of bisoprolol was titrated to achieve a target heart rate of 60 to 70 beats per minute. Thirty days after surgery, the incidence of the primary end point—a composite of death from cardiac causes or nonfatal MI—was reduced from 34% in the standard-care group to 3.4% in the bisoprolol group (P < .001). Thus, in this unblinded study in a population with proven coronary artery disease, beta-blockade clearly improved outcomes.

Additional studies of perioperative beta-blocker use have produced a wide range of outcomes, with most favoring beta-blockade, albeit usually not to a statistically significant degree.^4–13 Notably, only some of these trials were randomized, they used various beta-blocker regimens at various doses, they were conducted in patients with varying degrees of cardiac risk, and many had small sample sizes.

What emerged from these trials was the idea that perioperative beta-blockade in patients with coronary artery disease produces an effect similar to that of long-term beta-blockade in reducing the risk of cardiovascular events in post-MI patients and in those with coronary artery disease and heart failure.

THE POISE STUDY AND ITS IMPLICATIONS

Results of the Perioperative Ischemic Evaluation (POISE) were published in 2008, in which 8,351 noncardiac surgery patients with or at risk of atherosclerotic disease were randomized to placebo or extended-release metoprolol succinate started 2 to 4 hours preoperatively and continued for 30 days.¹⁴ Metoprolol was associated with a clear reduction in the primary end point, a composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest (5.8% vs 6.9% with placebo; hazard ratio [HR] = 0.84 [95% CI, 0.70–0.99]; P = .0399), but this effect was offset by significant increases in total mortality and stroke incidence in the metoprolol group. Mortality was 3.1% with metoprolol versus 2.3% with placebo (HR = 1.33 [95% CI, 1.03–1.74]; P = .0317), and stroke incidence was 1.0% with metoprolol versus 0.5% with placebo (HR = 2.17 [95% CI, 1.26–3.74]; P = .0053). Cerebral infarction, not bleeding, explained most of the excess mortality with metoprolol.

Of the 60 strokes in POISE, 49 were ischemic in origin, 3 were hemorrhagic, and 8 were of uncertain etiology. Preoperative predictors of stroke were the use of clopidogrel and a history of stroke or transient ischemic attack. Postoperative predictors of stroke included intraoperative bleeding and intraoperative hypotension. These predictors suggest a diseased cerebrovascular tree or unstable hemodynamics during the intraoperative period in the patients who suffered a stroke.

Does dosing explain the rise in mortality and strokes?

Could the fatal outcomes associated with the beta-blocker in POISE be attributed to the dosage of metoprolol? In the study, 100 mg of metoprolol was started immediately prior to surgery, and an additional 100 mg could be given, depending on the hemodynamic response. Maintenance therapy (200 mg/day) was started on the same day, making it possible that a patient could have received as much as 400 mg of metoprolol the day of surgery. The starting dose of metoprolol used in POISE was two to eight times the commonly prescribed dose.

The initial 100-mg dose of metoprolol used in POISE has a similar beta₁-receptor blockade potency compared with the 5-mg dose of bisoprolol used in DECREASE I.³ However, in DECREASE I, bisoprolol was initiated 30 days prior to surgery and was titrated, if necessary, according to heart rate. The maintenance dose of bisoprolol was half of the maintenance dose used in POISE. In the later DECREASE trials, the starting dose of bisoprolol was only 2.5 mg. Therefore, there was a huge difference in beta-blocker dosing between POISE and DECREASE.

Perioperative cardiac outcomes were similar in POISE and DECREASE I, with clear reductions in each trial among the patients randomized to the beta-blocker, as in other trials of perioperative beta-blockade. Stroke outcomes, in contrast, are inconsistent among trials of perioperative beta-blockade, with no increase in stroke observed in studies using low-dose titrated bisoprolol and an overall increase in stroke in studies of metoprolol, driven by the data from POISE^{2–5,14–17} (Figure 1). When interpreting the pooled analyses in Figure 1, it should be noted that DECREASE I³ and IV¹⁷ were open-label trials, not double-blind studies.

 

 

What about timing of beta-blocker initiation?

The POISE findings may also be explained in part by the timing of beta-blocker initiation. Whereas bisoprolol was carefully titrated for 30 days before surgery in DECREASE, metoprolol was initiated just before surgery in POISE, and the maximum recommended dose may have been prescribed during the first 24 hours, although subsequent dosing was 200 mg daily, which is 50% of the maximum daily therapeutic dose. This extremely narrow time window for titration may be important, since the beneficial effects of beta-blockade on coronary plaque stability are likely to take weeks to develop. 

To determine whether there might be a relation between timing of beta-blocker initiation and postoperative stroke, we performed an analysis (in press) plotting stroke rates according to timing of beta-blocker initiation from eight studies of perioperative beta-blockade. As illustrated in Figure 2, patients on titrated chronic beta-blocker therapy (at least 10 days) had a low (< 1%) incidence of stroke, whereas patients in whom beta-blocker therapy was started immediately before surgery had a much higher incidence of stroke. This finding suggests that ample time for titrating the beta-blocker dose may be necessary to achieve an optimal, stable hemodynamic condition and thereby prevent hemodynamic aberrations that could raise the risk of stroke.

Reassurance from a large case-control study

My colleagues and I conducted a case-control study from among more than 75,000 patients who underwent noncardiac, nonvascular surgery at our institution, Erasmus Medical Center, from 1991 to 2001.¹⁸ The cases were the 989 patients who died in the hospital postoperatively; the controls were 1,879 survivors matched with the cases for age, sex, the year the surgery was performed, and the type of surgery. The incidence of perioperative stroke was 0.5%, which is comparable to the rate found in the literature. Risk factors predictive of stroke were the presence of diabetes, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, coronary artery disease, and hypertension. Notably, no relationship was found between chronic beta-blocker use and stroke.

WHAT ABOUT PATIENTS AT INTERMEDIATE RISK?

Because the effect of perioperative beta-blockade has traditionally been ill defined in surgical patients at intermediate risk of cardiovascular events, the DECREASE study group recently completed a study (DECREASE IV) to assess perioperative bisoprolol in terms of cardiac morbidity and mortality in intermediate-risk patients undergoing elective noncardiovascular surgery.¹⁷ Enrollees had a score of 1 to 2 on the Revised Cardiac Risk Index of Lee et al,¹⁹ which corresponds to an estimated risk of between 1% and 6% for a perioperative cardiovascular event.¹⁷

DECREASE IV also aimed to assess the effect of perioperative fluvastatin, so a 2 x 2 factorial design was used in which the study’s 1,066 patients were randomized to receive bisoprolol, fluvastatin, combination treatment, or combination placebo control. Bisoprolol was initiated up to 30 days prior to surgery, and the 2.5-mg daily starting dosage was titrated according to the patient’s heart rate to achieve a target rate of 50 to 70 beats per minute. Fluvastatin was also started up to 30 days prior to surgery. Patients who received bisoprolol (with or without fluvastatin) had a significant reduction in the 30-day incidence of cardiac death and nonfatal MI compared with those who did not receive bisoprolol (2.1% vs 6.0%; HR = 0.34 [95% CI, 0.17–0.67]; P = .002). Fluvastatin was associated with a favorable trend on this end point, but statistical significance was not achieved (P = .17).¹⁷

There was no difference among treatment groups in the incidence of stroke (4 strokes in the 533 patients who received bisoprolol vs 3 strokes in the 533 patients who did not),¹⁷ which further suggests that the increased stroke rate seen with beta-blockade in POISE may have been due to dosage, timing of initiation, or both.

CONCLUSIONS

Dose-related hypotension may explain POISE findings

Our understanding of postoperative stroke is incomplete, but it appears that dosing of a beta-blocker can be a contributor, especially with respect to the potential side effect of hypotension during surgery. Keep in mind that the average age of patients in POISE was approximately 70 years and that patients were naïve to beta-blockers. Some may have had asymptomatic left ventricular dysfunction, and we know that starting a beta-blocker at a high dose in such patients may lead to hypotension. At my institution we routinely perform echocardiographic screening of all patients scheduled for surgery, and we have found that more than half of the patients with heart failure have it uncovered only through this screening.

It is not the medicine alone that can cause perioperative hypotension; other factors may induce hypotension, requiring beta-blocker titration and careful monitoring of hemodynamics during surgery.

Advice: Start early and titrate dose; continue chronic beta-blockade

My advice is as follows:

• If a patient is on chronic beta-blocker therapy, do not stop it perioperatively. We have seen devastating outcomes in the Netherlands when patients had their beta-blockers stopped immediately before surgery. Consider adjusting the dose, but do not stop it entirely. If a beta-blocker is on board and the patient develops hypotension or bradycardia during surgery, treat the symptoms and check for sepsis.
• In a patient not on a beta-blocker, consider adding one if the patient is at intermediate or high risk of a cardiac event, but start at a low dosage (ie, 2.5 mg/day for bisoprolol and 25 mg/day for metoprolol). Treatment ideally should be started 30 days preoperatively; in the Netherlands, we have the chance to start well in advance of surgery so we can titrate the dose according to hemodynamics.
• If a beta-blocker is not started because of insufficient time for titration, do not add one to treat tachycardia that develops during surgery, since tachycardia may represent a response to normal defense mechanisms.

 

 

Safety of perioperative beta-blocker use has not been adequately demonstrated

By P.J. Devereaux, MD, PhD

I contend that perioperative beta-blockade is a practice not grounded in evidence-based medicine, and its overall safety has increasingly come into question as more data from large, high-quality trials have emerged. I will begin with a historical overview of perioperative beta-blocker use, review the results of the POISE trial (for which I was the co-principal investigator), explore the major questions raised by this trial, and conclude with some take-away messages.

THE HISTORY OF PERIOPERATIVE BETA-BLOCKADE

In the 1970s, physicians were encouraged to hold beta-blockers prior to surgery out of concern that these medications may inhibit the required cardiovascular response when patients developed hypotension, and could thereby lead to serious adverse consequences.

In the 1980s, new research associated tachycardia with perioperative cardiovascular events, leading to proposals to implement perioperative beta-blocker use.

In the 1990s, two randomized trials with a total sample size of 312 patients^1,3 suggested that perioperative beta-blockers had a large treatment effect in preventing major cardiovascular events and death. These small trials had several methodological limitations:

• One trial³ was unblinded in a setting in which the vast majority of MIs are clinically silent.
• One trial³ was stopped early—after randomizing only 112 patients—for unexpected large treatment effects.
• One of the studies¹ failed to follow intention-to-treat principle.

Nevertheless, guidelines developed at the time by the American College of Cardiology and the American Heart Association (ACC/AHA) recommended the use of perioperative beta-blockers on the basis of the physiological rationale and these two small clinical trials. That recommendation was retained in the latest (2007) update of the ACC/AHA perioperative guidelines.²⁰

In 2006, two clinical trials with a total sample size of 1,417 were completed,^4,15 surpassing the total size of previous trials by more than fourfold. These two more recent trials did not suffer from the methodological limitations of earlier trials. These trials showed no benefit of perioperative beta-blocker use; in fact, there was a trend toward worse outcomes in the beta-blocker recipients.^4,15 Despite these new data, guidelines committees continued to recommend perioperative beta-blockade.²⁰

THE POISE TRIAL

Study design

This was the context into which the POISE results were released in 2008. POISE was a randomized, controlled, blinded trial of patients 45 years or older scheduled for noncardiac surgery who had, or were at high risk of, atherosclerotic disease.¹⁴ The intervention consisted of metoprolol succinate (metoprolol controlled release [CR]) or placebo started 2 to 4 hours preoperatively (if heart rate was ≥ 50 beats per minute and systolic blood pressure [SBP] was ≥ 100 mm Hg) and continued for 30 days. The target dosage of metoprolol was 200 mg once daily. No patients received the recommended maximum dosage of 400 mg over 24 hours. The main outcome measure was a 30-day composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest.

We randomized 9,298 patients in a 1:1 ratio to metoprolol or placebo. We encountered data fraud at a number of centers that prompted exclusion of data from 474 patients allocated to metoprolol and 473 allocated to placebo. Therefore, the total number of patients available for the intention-to-treat analysis was 8,351, from 190 centers in 23 countries.

Results

The risk of the primary composite outcome was reduced by 16% (relative reduction) in recipients of metoprolol CR compared with placebo recipients (P = .0399). Significantly fewer nonfatal MIs occurred in the metoprolol CR group than in the placebo group (152 [3.6%] vs 215 [5.1%]; P = .0008), leaving little doubt that perioperative beta-blockade prevents MI.

In contrast, total mortality was increased in the beta-blocker group, with 129 deaths among those assigned to metoprolol CR and 97 among those assigned to placebo (P = .0317), and the incidence of stroke was also significantly greater in the metoprolol CR group (1.0% vs. 0.5%; P = .0053).

Consistency with findings from other trials

The POISE data are consistent with those from a 2008 meta-analysis of high-quality randomized controlled trials in noncardiac surgery patients, which showed a significantly greater risk of death among patients assigned to a beta-blocker than among controls who were not (160 deaths [2.8%] vs 127 deaths [2.3%]; odds ratio [OR] = 1.27 [95% CI, 1.01–1.61]).²¹ This meta-analysis also found a significantly greater risk of nonfatal stroke in beta-blocker recipients compared with controls (38 [0.7%] vs 17 [0.3%]; OR = 2.16 [95% CI, 1.27–3.68]).

I also contend that the DECREASE IV trial supports the POISE findings in that although few strokes were encountered in DECREASE IV, the trend was in the direction of harm in the beta-blocker group, which had 4 strokes among 533 patients versus 3 strokes among 533 patients not receiving the beta-blocker.¹⁷

Predictive role of hypotension

Clinically significant hypotension (defined as systolic blood pressure < 90 mm Hg that required intervention) was common in POISE, developing in 9.7% of the placebo group and 15.0% of the metoprolol group.¹⁴ On multivariate analysis, clinically significant hypotension was an independent predictor—in fact the dominant predictor—of both death and stroke (Table 1). Hypotension was associated with a nearly fivefold increase in the risk of death and a doubling in the risk of stroke. The population-attributable risk of hypotension to death was 37.3, meaning that hypotension potentially accounted for 37.3% of deaths in the study. The population-attributable risk of hypotension to stroke was 14.7. In light of hypotension’s role as the dominant predictor of death, I take issue with Dr. Poldermans’ earlier contention that cerebral infarction explained most of the excess mortality with metoprolol in POISE.

The link between hypotension and death in POISE is consistent with findings from the largest beta-blocker trial undertaken, COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), in which 45,852 patients with acute MI were randomized to metoprolol or placebo.²² In COMMIT, metoprolol had no effect on 30-day all-cause mortality but significantly reduced the risk of arrhythmic death, a benefit that was countered by a significantly increased risk of death from shock with a beta-blocker in acute MI. Clinically significant hypotension is much more common in the perioperative setting than in acute MI, which may explain the excess number of deaths observed with metoprolol in POISE as opposed to metoprolol’s neutral effect on mortality in COMMIT.

 

 

ANSWERING THE CRITICS

Several criticisms have been raised about POISE, as detailed below.

Beta-blocker dose

Some contend that a lower dose of beta-blocker would provide benefit and minimize risk, but this assertion must be supported by evidence from a large clinical trial. The targeted dosage of metoprolol in POISE represents 50% of the maximum daily therapeutic dose. Further, the protocol called for decreasing the dosage to 100 mg/day if SBP dropped to less than 100 mm Hg or if heart rate fell to less than 45 beats per minute.

The two small trials on which guideline recommendations for perioperative beta-blockade are primarily based^1,3 had a sample size that was 4% of that in POISE, which calls into question the reliability of their results. The study by Mangano et al used atenolol at a target dosage that was 50% of the maximum daily therapeutic dose,¹ the same as with metoprolol in POISE. DECREASE initiated bisoprolol at 25% of the maximum daily therapeutic dose, and allowed for titration to 50% of the maximum daily therapeutic dose.³

As the second largest study of perioperative beta-blockade, the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial enrolled 921 patients who were assigned to placebo or controlled-release metoprolol with a target dosage that was 25% of the maximum daily therapeutic dose.⁴ The 30-day outcomes from DIPOM showed a trend toward an excess of death and stroke despite using only one-half the dosage in POISE and the same dosage as in DECREASE.

Timing of beta-blocker initiation

Another contention is that earlier beta-blocker initiation would be better. The issue with timing of initiation is not benefit, as POISE showed that starting a beta-blocker hours before surgery results in a reduction in the risk of MI. The issue is whether giving a beta-blocker earlier makes administering the drug safer. Nearly 10% of placebo recipients in POISE developed clinically significant hypotension, which suggests that the titrated dosage of a beta-blocker that appears effective preoperatively is unlikely to inform a safe dose after surgery, when hypotension is common.

The practicality of titrating the dose of beta-blocker prior to surgery also comes into play. Most patients referred to my institution for surgery are seen 1 to 2 weeks in advance, at the earliest. Real-world practice at present simply does not afford us the luxury of seeing patients three to four times before surgery in order to titrate the beta-blocker dose.

POISE did not address chronic beta-blocker therapy

It is important to remember that POISE excluded patients on chronic beta-blocker therapy and thus did not attempt to address the perioperative management of such patients who undergo noncardiac surgery. My suspicion is that perioperative continuation of beta-blockade in these patients is the best course of action, but this too has not been studied robustly, so we need a large controlled trial to confirm that this practice is indeed safe. 

CONCLUSIONS

The POISE results suggest that for every 1,000 patients treated, perioperative metoprolol would:

• Prevent 15 MIs, 3 cardiac revascularizations, and 7 new cases of atrial fibrillation
• Result in 8 excess deaths, 5 strokes, 53 cases of clinically significant hypotension, and 42 cases of clinically significant bradycardia.

The central take-away message is that patients are unlikely to want a perioperative beta-blocker if they are unwilling to accept a probable increase in mortality or if they place three times more value on avoiding a perioperative stroke than on avoiding an MI.

It has been 10 years since the recommendation to use perioperatove beta-blockers was incorporated into perioperative practice guidelines. Assuming only 10% of physicians acted on this recommendation, 100 million patients have received a perioperative beta-blocker over this time as a result. If the POISE results are applicable, a full 800,000 of these patients died and another 500,000 suffered perioperative strokes as a result of being given a beta-blocker. This issue is not to be taken lightly, given the evidence to suggest harm.

Though it is possible that an alternative beta-blocker regimen to the one used in POISE may provide benefit without substantial harm, the data suggest this is not probable. The POISE data highlight the risk of making assumptions, as well as the importance of and need for large, high-quality randomized trials in the perioperative setting.

It is time for perioperative medicine to enter the age of evidence-based practice and embrace one of its central tenets: only large trials are reliable when it comes to therapeutic questions.

 

 

Rebuttals and discussion

POLDERMANS REBUTTAL: MORE TRANSPARENCY NEEDED IN POISE DOSING DATA

Dr. Poldermans: The initial paper describing the POISE trial design did indeed indicate that it was possible for a patient to receive 400 mg of metoprolol on the first day of treatment. We need to see the actual doses of metoprolol given to all patients in POISE who had a perioperative stroke. If you show me these data, the issue will be much easier to discuss.

Our data from randomized trials are consistent in showing that a titrated dosing regimen using bisoprolol reduces the incidence of postoperative cardiac events with no increase in the number of strokes.

My take-home message is that if you want to use beta-blockers, use them sensibly, use them carefully, and act during surgery. If many of your patients are developing hypotension, then you are doing something wrong.

DEVEREAUX REBUTTAL: A SHIFT IN THINKING IS REQUIRED

Dr. Devereaux: The data from POISE are fully available, and I take issue with Dr. Poldermans’ contention that a patient could have received as much as 400 mg of metoprolol CR on the day of surgery; this was not an option according to protocol. I believe his statement is misleading in the same way that it is misleading to indicate that in the DECREASE trial patients may have received 20 mg of bisoprolol within 24 hours of surgery. It is possible that a patient in DECREASE could have gone to surgery at 2:00 pm and may have taken his or her bisoprolol at 10:00 am that morning. The following morning (in the hospital), it is possible that the patient would have received his or her bisoprolol 10 mg at 7:00 or 8:00 am (ie, 20 mg within 24 hours of surgery). Although this is possible and something similar could have happened within POISE, it does not reflect a patient receiving an effective dose of metoprolol CR 400 mg or bisoprolol 20 mg over a 24-hour period.

I worry about the distortion of reality in perioperative medicine that leads so many of us to believe that randomization is magical despite small sample sizes. Small randomized trials are at profound risk of imbalance between the randomized groups, whether we see it or not, and the results are therefore simply not reliable.

Unless we shift our thinking, we make ourselves susceptible to overconfidence in the benefits of a certain intervention before the data from large clinical trials become available. In the meantime, as we have seen from POISE, an intervention may have negative consequences that are not apparent from small clinical trials.

The reality of excess stroke with perioperative beta-blockers is consistent across all the trials. It does not mean that we cannot find another way to give beta-blockers safely, but if we want to establish safety, we need a large trial that unequivocally demonstrates safety, as opposed to simply using observational data, retrospective cohorts, or comparisons between two nonrandomized trials. Until we have large data sets, it is very difficult to say that we can give beta-blockers safely.

DISCUSSION WITH THE AUDIENCE

Moderator^*: Dr. Devereaux, was the hypotension in POISE related to the long-acting beta-blocker itself or to the large dose of if that was used? Similarly, were the strokes a result of the drug itself or of the hypotension?

Dr. Devereaux: I must take issue with your premise that the dose of metoprolol used in POISE was “large.” As I noted, Mangano’s study used its beta-blocker (atenolol) at 50% of its maximum daily therapeutic dose,¹ the same proportion used in POISE, and Dr. Poldermans’ own DECREASE trial allowed titration of bisoprolol up to 50% of the maximum daily therapeutic dose.³ The DIPOM trial used half the dose of metoprolol that we used, yet it too yielded a trend toward more death and stroke in the beta-blocker group.⁴ So it’s not that the dose we used was at some excessive level. At the same time, that does not mean that a smaller dose may not have achieved a similarly significant benefit in cardiac outcomes.

We can’t explain most of the strokes. Because most strokes were ischemic, I suspect that the explanation may lie in the threshold used to define clinically significant hypotension. We used an SBP cutoff of less than 90 mm Hg, but we did not classify large drops in SBP, such as from 180 to 95 mm Hg, as clinically significant hypotension. The high incidence of clinically significant hypotension in the placebo group—about 10%—suggests that hypotension was likely the driving factor for stroke. The beta-blocker exacerbated the hypotension, but its more important effect may have been that it made it harder for the body to overcome the hypotension. That is the exact same signal observed in the COMMIT trial in the setting of acute MI.²²

Dr. Poldermans: I’d like to see the intraoperative blood pressure data for the 60 patients who suffered strokes in POISE. We could then find out exactly when the hypotension occurred, what kind of hypotension it was, what the patient’s initial blood pressure reading was, and so on. If we had access to this information, we could determine which occurred first—the hypotension or the stroke.

Dr. Devereaux: Although trials can indicate a signal, they can’t explain with certainty the pathway through which the outcome occurred. For example, we know that beta-blockers prevent MI, but we don’t know how. What’s most impressive about the stroke issue is the consistency across all the perioperative beta-blocker trials: every one shows a direction of excess stroke with beta-blockers.

Question from the audience: The patient groups studied in DECREASE and POISE were different. DECREASE studied a very high-risk vascular surgery group with known coronary artery disease on the basis of echocardiography. POISE included patients undergoing emergency surgery and patients with sepsis. Can you describe the outcomes in POISE solely among the patients who underwent elective vascular surgery, similar to the patients studied in DECREASE?

Dr. Devereaux: In terms of the benefit to bisoprolol in very high-risk patients in DECREASE, remember that it was a study of 112 patients. That’s far too small a trial to establish safety or efficacy. The benefit of perioperative beta-blockade in preventing MI is unequivocal because it’s consistent across all trials. But the real issue is, was it safe?

Interestingly, in POISE, the groups at highest risk looked like they benefited the least, not the most. The notion of targeting high-risk people is not supported by POISE; if anything, the POISE results went in the direction of harm with beta-blockade in high-risk patients. That being said, the P value for interaction is not statistically significant, but it’s heading in the direction of harm. So I wouldn’t take comfort in believing that if we simply target high-risk patients, beta-blockers become safe.

Question from the audience: I believe that the seven or eight studies that showed higher stroke rates with beta-blockers all gave beta-blockade within 24 hours of surgery. Only in DECREASE was it given days and weeks in advance of surgery. Can you comment?

Dr. Poldermans: There’s clearly a relation between the time of beta-blocker initiation and the incidence of stroke. If you look at the randomized trials, you see an increased incidence of stroke in patients in whom beta-blockers are started just prior to surgery but not in patients who are on chronic beta-blockers. In our case-control study,¹⁸ we screened more than 185,000 patients for stroke and could not detect an increased incidence of stroke in those on chronic beta-blocker therapy. So stroke indeed has something to do with starting beta-blockers just before surgery.

Dr. Devereaux: In DECREASE IV, bisoprolol was started up to 1 month before surgery, yet there were 4 strokes in the bisoprolol group versus 3 in the control group.¹⁷

Dr. Poldermans: Yes, but that difference is not statistically meaningful.

 

Comment from the audience: I’m uncomfortable with the way Dr. Devereaux stresses the importance of significant findings from large randomized trials but then quibbles about a stroke rate of 4 versus 3, which is not statistically significant. Keep it scientific: either there is or there isn’t a P value that achieves significance.

Though I congratulate you on a great trial, any resident in my program would be fired for pursuing your strategy of perioperative care in POISE, which included using an SBP of 100 mm Hg as the threshold for stopping the beta-blocker regardless of preoperative blood pressure. An SBP of 100 mm Hg is not the definition of hypotension. Most anesthesiologists and perioperative physicians peg the beta-blockade to a reasonable level based on the preoperative blood pressure. They titrate in fluids and titrate in the beta-blocker. Certainly the timing is an issue—we don’t recommend giving it right before the operation.

Dr. Devereaux: I referred to the stroke rates in DECREASE IV because Dr. Poldermans has claimed that the excess in strokes has occurred in all trials but his, yet DECREASE IV was one of his trials and also one in which bisoprolol was started early. I’m not claiming statistical significance between the 3 versus 4 strokes in DECREASE IV, but the stroke trend is in the same direction as in the other trials, so it tells us nothing with regard to safety. My point is, has anyone proven safety? As much as we’d like to imagine that beta-blockers are safe perioperatively—and maybe they are—it has not been proven. The largest trials at present are consistent with a signal toward harm.

It’s easy to criticize the methodology after a trial is done. A number of us came together and thought we had a reasonable protocol for POISE. We found a reduction in the incidence of MI but more strokes and higher mortality with perioperative metoprolol. Does this mean there is not a safe way to give a beta-blocker and derive the benefit? Of course not. But at the moment the evidence does not support a way to give a beta-blocker safely. Do we need to find a way to give it safely? Of course we do.

For example, the design of POISE II is factorial, looking at aspirin versus placebo as well as clonidine versus placebo. There are a number of factors about clonidine that suggest we might be able to achieve the benefits we saw in POISE and avoid the risk, but until we do a large trial, we’re not going to know.

Comment from the audience: It’s important that we clearly understand the conclusion from POISE. It’s not that the administration of beta-blockers is not safe. It’s that the administration of a beta-blocker, as your methodology applied it, was not totally safe. Those are two very different conclusions.

Dr. Devereaux: I would say the conclusion is that the way that beta-blockers are being given has not been proven to be safe. The result is consistent. It’s even consistent with DECREASE IV.

Moderator: I believe in large clinical trials, but they must apply to real-life practice. POISE did not address the practices of many people in this room, particularly regarding the doses of metoprolol used. So it is hard for us to apply the findings in clinical practice. Those of you who design large trials need to think through your trial design very thoroughly, considering the millions of dollars that go into these trials. It’s not fair to clinicians to do a study that may have little clinical relevance.

Dr. Devereaux: Investigators from 190 centers in 23 countries were involved in POISE, and all of them thought we had a reasonable approach and methodology. That doesn’t mean it was perfect, yet the criticisms we are hearing now did not surface while the trial was ongoing.

Comment from the audience: My hospital in Australia contributed to the POISE study. When it started 6 or 7 years ago, the cardiologists were using beta-blockers liberally and haphazardly. It was a huge challenge to convince them that conducting the trial was justifiable—that the case for perioperative beta-blockers had not been absolutely and overwhelmingly proved. They wanted to put beta-blockers in the water supply at the doses we’re talking about.

It would be interesting to do separate analyses of the data from the various countries involved in POISE. In Australia, the percentage of the population on chronic beta-blockers—who therefore would have been ineligible for the trial—is now quite high. Most patients who need to be on beta-blockers long term are on them, whereas that was not the case 15 years ago. The population is changing even while we’re doing the trials. Australian cardiologists are no longer putting every patient on perioperative beta-blockers; they’re thinking about it first.

Dr. Devereaux: A compelling feature of POISE as an international trial is its consistency of outcomes across the planet. No matter where we looked, the outcomes were consistent: in Asia, Europe, North America, and Australia.

Moderator: Would each of you summarize your take-home message for clinicians?

Dr. Devereaux: I urge clinicians to actually read the trials themselves rather than just relying on the advice of guideline writers. It’s important not to allow ourselves to become entrenched in a practice without evidence, just because we’ve done it for so long. If you told your patients the number of MIs prevented and the potential number of excess strokes and deaths, I suspect the average patient would conclude it’s not a great trade-off.

Remember that two-thirds of MIs in the perioperative setting are clinically silent. That doesn’t mean they’re not important, but the strokes, in contrast, are profoundly devastating. One-third of patients with stroke in POISE were dead within 30 days, and of those who survived, 60% were incapacitated, needing help with everyday activities.

I encourage clinicians to read the POISE manuscript with a fresh perspective, regardless of how you’ve practiced until now. Then ask yourself whether you really are comfortable with the safety of perioperative beta-blockers at this time. Of course, that doesn’t mean the evidence won’t change in the future.

Dr. Poldermans: The main imperative is to improve postoperative care. We strongly believe that perioperative beta-blockers work in the general population. If you have a patient who needs to be on a beta-blocker after surgery, why not start it preoperatively? I believe that dosing and timing of initiation are important. If you have the opportunity to start the beta-blocker prior to surgery, do so at a reasonable dose and start early. Patients in whom beta-blockers are started immediately prior to surgery may be worse off, with a higher incidence of stroke.

*Amir K. Jaffer, MD, University of Miami Miller School of Medicine, served as moderator of the debate and the discussion period.

NOTE: The individual co-authors in this debate-based article are responsible only for those views within their respective bylined subsections and those views ascribed to them in the rebuttals and discussion at the end.

 

Perioperative beta-blockade improves outcomes

By Don Poldermans, MD, PhD

It is my contention that perioperative beta-blockade improves mortality and cardiac outcomes in select high- and intermediate-risk patients undergoing noncardiac surgery. Patients on chronic beta-blocker therapy should have it continued perioperatively. For patients not already on beta-blockade who are at cardiac risk, initiation of low-dose beta-blocker therapy should be considered prior to surgery; such therapy should be started approximately 1 month before surgery, with dose titration to achieve hemodynamic stability. Reports of increased stroke rates with perioperative beta-blockade appear to be due to inappropriate acute administration of high-dose beta-blocker therapy.

THE PHYSIOLOGIC RATIONALE FOR PERIOPERATIVE BETA-BLOCKADE

Perioperative myocardial infarction (MI) can occur by one of two mechanisms, both of which can be attenuated by beta-blockade:

• The stress induced by surgery can cause an asymptomatic coronary plaque to become unstable and rupture, resulting in complete occlusion of a portion of the coronary tree. This type of perioperative MI occurs typically in patients with multiple risk factors for MI absent a critical coronary stenosis. The perioperative risk associated with unstable plaque can be reduced pharmacologically with aspirin, statins, and chronic beta-blocker therapy.
• Alternately, a fixed coronary stenosis can predispose to a mismatch of oxygen demand and supply, leading to myocardial ischemia and infarction. The patient with a fixed coronary lesion typically presents with stable angina pectoris, and the at-risk stenosis is identified through a stress echocardiogram or nuclear scan. The risk conferred by flow-limiting stable plaque can be reduced by coronary revascularization and a short course of beta-blocker therapy prior to surgery.

INITIAL SUPPORTIVE DATA

Mangano and colleagues were the first to evaluate perioperative beta-blockade in a randomized, controlled fashion.^1,2 In their study of 200 surgical patients with or at risk for coronary artery disease, oral atenolol administered perioperatively was associated with a 50% reduction (compared with placebo) in the incidence of postoperative myocardial ischemia as measured by three-lead Holter monitoring.² During 2 years of follow-up, mortality was significantly lower in the atenolol group (10%) than in the placebo group (21%) (P = .019).¹

In the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE I), my research group randomized 112 high-risk patients (as identified by dobutamine echocardiography) to standard perioperative care alone or standard perioperative care plus bisoprolol starting 30 days prior to major vascular surgery.³ The dosage of bisoprolol was titrated to achieve a target heart rate of 60 to 70 beats per minute. Thirty days after surgery, the incidence of the primary end point—a composite of death from cardiac causes or nonfatal MI—was reduced from 34% in the standard-care group to 3.4% in the bisoprolol group (P < .001). Thus, in this unblinded study in a population with proven coronary artery disease, beta-blockade clearly improved outcomes.

Additional studies of perioperative beta-blocker use have produced a wide range of outcomes, with most favoring beta-blockade, albeit usually not to a statistically significant degree.^4–13 Notably, only some of these trials were randomized, they used various beta-blocker regimens at various doses, they were conducted in patients with varying degrees of cardiac risk, and many had small sample sizes.

What emerged from these trials was the idea that perioperative beta-blockade in patients with coronary artery disease produces an effect similar to that of long-term beta-blockade in reducing the risk of cardiovascular events in post-MI patients and in those with coronary artery disease and heart failure.

THE POISE STUDY AND ITS IMPLICATIONS

Results of the Perioperative Ischemic Evaluation (POISE) were published in 2008, in which 8,351 noncardiac surgery patients with or at risk of atherosclerotic disease were randomized to placebo or extended-release metoprolol succinate started 2 to 4 hours preoperatively and continued for 30 days.¹⁴ Metoprolol was associated with a clear reduction in the primary end point, a composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest (5.8% vs 6.9% with placebo; hazard ratio [HR] = 0.84 [95% CI, 0.70–0.99]; P = .0399), but this effect was offset by significant increases in total mortality and stroke incidence in the metoprolol group. Mortality was 3.1% with metoprolol versus 2.3% with placebo (HR = 1.33 [95% CI, 1.03–1.74]; P = .0317), and stroke incidence was 1.0% with metoprolol versus 0.5% with placebo (HR = 2.17 [95% CI, 1.26–3.74]; P = .0053). Cerebral infarction, not bleeding, explained most of the excess mortality with metoprolol.

Of the 60 strokes in POISE, 49 were ischemic in origin, 3 were hemorrhagic, and 8 were of uncertain etiology. Preoperative predictors of stroke were the use of clopidogrel and a history of stroke or transient ischemic attack. Postoperative predictors of stroke included intraoperative bleeding and intraoperative hypotension. These predictors suggest a diseased cerebrovascular tree or unstable hemodynamics during the intraoperative period in the patients who suffered a stroke.

Does dosing explain the rise in mortality and strokes?

Could the fatal outcomes associated with the beta-blocker in POISE be attributed to the dosage of metoprolol? In the study, 100 mg of metoprolol was started immediately prior to surgery, and an additional 100 mg could be given, depending on the hemodynamic response. Maintenance therapy (200 mg/day) was started on the same day, making it possible that a patient could have received as much as 400 mg of metoprolol the day of surgery. The starting dose of metoprolol used in POISE was two to eight times the commonly prescribed dose.

The initial 100-mg dose of metoprolol used in POISE has a similar beta₁-receptor blockade potency compared with the 5-mg dose of bisoprolol used in DECREASE I.³ However, in DECREASE I, bisoprolol was initiated 30 days prior to surgery and was titrated, if necessary, according to heart rate. The maintenance dose of bisoprolol was half of the maintenance dose used in POISE. In the later DECREASE trials, the starting dose of bisoprolol was only 2.5 mg. Therefore, there was a huge difference in beta-blocker dosing between POISE and DECREASE.

Perioperative cardiac outcomes were similar in POISE and DECREASE I, with clear reductions in each trial among the patients randomized to the beta-blocker, as in other trials of perioperative beta-blockade. Stroke outcomes, in contrast, are inconsistent among trials of perioperative beta-blockade, with no increase in stroke observed in studies using low-dose titrated bisoprolol and an overall increase in stroke in studies of metoprolol, driven by the data from POISE^{2–5,14–17} (Figure 1). When interpreting the pooled analyses in Figure 1, it should be noted that DECREASE I³ and IV¹⁷ were open-label trials, not double-blind studies.

 

 

What about timing of beta-blocker initiation?

The POISE findings may also be explained in part by the timing of beta-blocker initiation. Whereas bisoprolol was carefully titrated for 30 days before surgery in DECREASE, metoprolol was initiated just before surgery in POISE, and the maximum recommended dose may have been prescribed during the first 24 hours, although subsequent dosing was 200 mg daily, which is 50% of the maximum daily therapeutic dose. This extremely narrow time window for titration may be important, since the beneficial effects of beta-blockade on coronary plaque stability are likely to take weeks to develop. 

To determine whether there might be a relation between timing of beta-blocker initiation and postoperative stroke, we performed an analysis (in press) plotting stroke rates according to timing of beta-blocker initiation from eight studies of perioperative beta-blockade. As illustrated in Figure 2, patients on titrated chronic beta-blocker therapy (at least 10 days) had a low (< 1%) incidence of stroke, whereas patients in whom beta-blocker therapy was started immediately before surgery had a much higher incidence of stroke. This finding suggests that ample time for titrating the beta-blocker dose may be necessary to achieve an optimal, stable hemodynamic condition and thereby prevent hemodynamic aberrations that could raise the risk of stroke.

Reassurance from a large case-control study

My colleagues and I conducted a case-control study from among more than 75,000 patients who underwent noncardiac, nonvascular surgery at our institution, Erasmus Medical Center, from 1991 to 2001.¹⁸ The cases were the 989 patients who died in the hospital postoperatively; the controls were 1,879 survivors matched with the cases for age, sex, the year the surgery was performed, and the type of surgery. The incidence of perioperative stroke was 0.5%, which is comparable to the rate found in the literature. Risk factors predictive of stroke were the presence of diabetes, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, coronary artery disease, and hypertension. Notably, no relationship was found between chronic beta-blocker use and stroke.

WHAT ABOUT PATIENTS AT INTERMEDIATE RISK?

Because the effect of perioperative beta-blockade has traditionally been ill defined in surgical patients at intermediate risk of cardiovascular events, the DECREASE study group recently completed a study (DECREASE IV) to assess perioperative bisoprolol in terms of cardiac morbidity and mortality in intermediate-risk patients undergoing elective noncardiovascular surgery.¹⁷ Enrollees had a score of 1 to 2 on the Revised Cardiac Risk Index of Lee et al,¹⁹ which corresponds to an estimated risk of between 1% and 6% for a perioperative cardiovascular event.¹⁷

DECREASE IV also aimed to assess the effect of perioperative fluvastatin, so a 2 x 2 factorial design was used in which the study’s 1,066 patients were randomized to receive bisoprolol, fluvastatin, combination treatment, or combination placebo control. Bisoprolol was initiated up to 30 days prior to surgery, and the 2.5-mg daily starting dosage was titrated according to the patient’s heart rate to achieve a target rate of 50 to 70 beats per minute. Fluvastatin was also started up to 30 days prior to surgery. Patients who received bisoprolol (with or without fluvastatin) had a significant reduction in the 30-day incidence of cardiac death and nonfatal MI compared with those who did not receive bisoprolol (2.1% vs 6.0%; HR = 0.34 [95% CI, 0.17–0.67]; P = .002). Fluvastatin was associated with a favorable trend on this end point, but statistical significance was not achieved (P = .17).¹⁷

There was no difference among treatment groups in the incidence of stroke (4 strokes in the 533 patients who received bisoprolol vs 3 strokes in the 533 patients who did not),¹⁷ which further suggests that the increased stroke rate seen with beta-blockade in POISE may have been due to dosage, timing of initiation, or both.

CONCLUSIONS

Dose-related hypotension may explain POISE findings

Our understanding of postoperative stroke is incomplete, but it appears that dosing of a beta-blocker can be a contributor, especially with respect to the potential side effect of hypotension during surgery. Keep in mind that the average age of patients in POISE was approximately 70 years and that patients were naïve to beta-blockers. Some may have had asymptomatic left ventricular dysfunction, and we know that starting a beta-blocker at a high dose in such patients may lead to hypotension. At my institution we routinely perform echocardiographic screening of all patients scheduled for surgery, and we have found that more than half of the patients with heart failure have it uncovered only through this screening.

It is not the medicine alone that can cause perioperative hypotension; other factors may induce hypotension, requiring beta-blocker titration and careful monitoring of hemodynamics during surgery.

Advice: Start early and titrate dose; continue chronic beta-blockade

My advice is as follows:

• If a patient is on chronic beta-blocker therapy, do not stop it perioperatively. We have seen devastating outcomes in the Netherlands when patients had their beta-blockers stopped immediately before surgery. Consider adjusting the dose, but do not stop it entirely. If a beta-blocker is on board and the patient develops hypotension or bradycardia during surgery, treat the symptoms and check for sepsis.
• In a patient not on a beta-blocker, consider adding one if the patient is at intermediate or high risk of a cardiac event, but start at a low dosage (ie, 2.5 mg/day for bisoprolol and 25 mg/day for metoprolol). Treatment ideally should be started 30 days preoperatively; in the Netherlands, we have the chance to start well in advance of surgery so we can titrate the dose according to hemodynamics.
• If a beta-blocker is not started because of insufficient time for titration, do not add one to treat tachycardia that develops during surgery, since tachycardia may represent a response to normal defense mechanisms.

 

 

Safety of perioperative beta-blocker use has not been adequately demonstrated

By P.J. Devereaux, MD, PhD

I contend that perioperative beta-blockade is a practice not grounded in evidence-based medicine, and its overall safety has increasingly come into question as more data from large, high-quality trials have emerged. I will begin with a historical overview of perioperative beta-blocker use, review the results of the POISE trial (for which I was the co-principal investigator), explore the major questions raised by this trial, and conclude with some take-away messages.

THE HISTORY OF PERIOPERATIVE BETA-BLOCKADE

In the 1970s, physicians were encouraged to hold beta-blockers prior to surgery out of concern that these medications may inhibit the required cardiovascular response when patients developed hypotension, and could thereby lead to serious adverse consequences.

In the 1980s, new research associated tachycardia with perioperative cardiovascular events, leading to proposals to implement perioperative beta-blocker use.

In the 1990s, two randomized trials with a total sample size of 312 patients^1,3 suggested that perioperative beta-blockers had a large treatment effect in preventing major cardiovascular events and death. These small trials had several methodological limitations:

• One trial³ was unblinded in a setting in which the vast majority of MIs are clinically silent.
• One trial³ was stopped early—after randomizing only 112 patients—for unexpected large treatment effects.
• One of the studies¹ failed to follow intention-to-treat principle.

Nevertheless, guidelines developed at the time by the American College of Cardiology and the American Heart Association (ACC/AHA) recommended the use of perioperative beta-blockers on the basis of the physiological rationale and these two small clinical trials. That recommendation was retained in the latest (2007) update of the ACC/AHA perioperative guidelines.²⁰

In 2006, two clinical trials with a total sample size of 1,417 were completed,^4,15 surpassing the total size of previous trials by more than fourfold. These two more recent trials did not suffer from the methodological limitations of earlier trials. These trials showed no benefit of perioperative beta-blocker use; in fact, there was a trend toward worse outcomes in the beta-blocker recipients.^4,15 Despite these new data, guidelines committees continued to recommend perioperative beta-blockade.²⁰

THE POISE TRIAL

Study design

This was the context into which the POISE results were released in 2008. POISE was a randomized, controlled, blinded trial of patients 45 years or older scheduled for noncardiac surgery who had, or were at high risk of, atherosclerotic disease.¹⁴ The intervention consisted of metoprolol succinate (metoprolol controlled release [CR]) or placebo started 2 to 4 hours preoperatively (if heart rate was ≥ 50 beats per minute and systolic blood pressure [SBP] was ≥ 100 mm Hg) and continued for 30 days. The target dosage of metoprolol was 200 mg once daily. No patients received the recommended maximum dosage of 400 mg over 24 hours. The main outcome measure was a 30-day composite of cardiovascular death, nonfatal MI, or nonfatal cardiac arrest.

We randomized 9,298 patients in a 1:1 ratio to metoprolol or placebo. We encountered data fraud at a number of centers that prompted exclusion of data from 474 patients allocated to metoprolol and 473 allocated to placebo. Therefore, the total number of patients available for the intention-to-treat analysis was 8,351, from 190 centers in 23 countries.

Results

The risk of the primary composite outcome was reduced by 16% (relative reduction) in recipients of metoprolol CR compared with placebo recipients (P = .0399). Significantly fewer nonfatal MIs occurred in the metoprolol CR group than in the placebo group (152 [3.6%] vs 215 [5.1%]; P = .0008), leaving little doubt that perioperative beta-blockade prevents MI.

In contrast, total mortality was increased in the beta-blocker group, with 129 deaths among those assigned to metoprolol CR and 97 among those assigned to placebo (P = .0317), and the incidence of stroke was also significantly greater in the metoprolol CR group (1.0% vs. 0.5%; P = .0053).

Consistency with findings from other trials

The POISE data are consistent with those from a 2008 meta-analysis of high-quality randomized controlled trials in noncardiac surgery patients, which showed a significantly greater risk of death among patients assigned to a beta-blocker than among controls who were not (160 deaths [2.8%] vs 127 deaths [2.3%]; odds ratio [OR] = 1.27 [95% CI, 1.01–1.61]).²¹ This meta-analysis also found a significantly greater risk of nonfatal stroke in beta-blocker recipients compared with controls (38 [0.7%] vs 17 [0.3%]; OR = 2.16 [95% CI, 1.27–3.68]).

I also contend that the DECREASE IV trial supports the POISE findings in that although few strokes were encountered in DECREASE IV, the trend was in the direction of harm in the beta-blocker group, which had 4 strokes among 533 patients versus 3 strokes among 533 patients not receiving the beta-blocker.¹⁷

Predictive role of hypotension

Clinically significant hypotension (defined as systolic blood pressure < 90 mm Hg that required intervention) was common in POISE, developing in 9.7% of the placebo group and 15.0% of the metoprolol group.¹⁴ On multivariate analysis, clinically significant hypotension was an independent predictor—in fact the dominant predictor—of both death and stroke (Table 1). Hypotension was associated with a nearly fivefold increase in the risk of death and a doubling in the risk of stroke. The population-attributable risk of hypotension to death was 37.3, meaning that hypotension potentially accounted for 37.3% of deaths in the study. The population-attributable risk of hypotension to stroke was 14.7. In light of hypotension’s role as the dominant predictor of death, I take issue with Dr. Poldermans’ earlier contention that cerebral infarction explained most of the excess mortality with metoprolol in POISE.

The link between hypotension and death in POISE is consistent with findings from the largest beta-blocker trial undertaken, COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), in which 45,852 patients with acute MI were randomized to metoprolol or placebo.²² In COMMIT, metoprolol had no effect on 30-day all-cause mortality but significantly reduced the risk of arrhythmic death, a benefit that was countered by a significantly increased risk of death from shock with a beta-blocker in acute MI. Clinically significant hypotension is much more common in the perioperative setting than in acute MI, which may explain the excess number of deaths observed with metoprolol in POISE as opposed to metoprolol’s neutral effect on mortality in COMMIT.

 

 

ANSWERING THE CRITICS

Several criticisms have been raised about POISE, as detailed below.

Beta-blocker dose

Some contend that a lower dose of beta-blocker would provide benefit and minimize risk, but this assertion must be supported by evidence from a large clinical trial. The targeted dosage of metoprolol in POISE represents 50% of the maximum daily therapeutic dose. Further, the protocol called for decreasing the dosage to 100 mg/day if SBP dropped to less than 100 mm Hg or if heart rate fell to less than 45 beats per minute.

The two small trials on which guideline recommendations for perioperative beta-blockade are primarily based^1,3 had a sample size that was 4% of that in POISE, which calls into question the reliability of their results. The study by Mangano et al used atenolol at a target dosage that was 50% of the maximum daily therapeutic dose,¹ the same as with metoprolol in POISE. DECREASE initiated bisoprolol at 25% of the maximum daily therapeutic dose, and allowed for titration to 50% of the maximum daily therapeutic dose.³

As the second largest study of perioperative beta-blockade, the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial enrolled 921 patients who were assigned to placebo or controlled-release metoprolol with a target dosage that was 25% of the maximum daily therapeutic dose.⁴ The 30-day outcomes from DIPOM showed a trend toward an excess of death and stroke despite using only one-half the dosage in POISE and the same dosage as in DECREASE.

Timing of beta-blocker initiation

Another contention is that earlier beta-blocker initiation would be better. The issue with timing of initiation is not benefit, as POISE showed that starting a beta-blocker hours before surgery results in a reduction in the risk of MI. The issue is whether giving a beta-blocker earlier makes administering the drug safer. Nearly 10% of placebo recipients in POISE developed clinically significant hypotension, which suggests that the titrated dosage of a beta-blocker that appears effective preoperatively is unlikely to inform a safe dose after surgery, when hypotension is common.

The practicality of titrating the dose of beta-blocker prior to surgery also comes into play. Most patients referred to my institution for surgery are seen 1 to 2 weeks in advance, at the earliest. Real-world practice at present simply does not afford us the luxury of seeing patients three to four times before surgery in order to titrate the beta-blocker dose.

POISE did not address chronic beta-blocker therapy

It is important to remember that POISE excluded patients on chronic beta-blocker therapy and thus did not attempt to address the perioperative management of such patients who undergo noncardiac surgery. My suspicion is that perioperative continuation of beta-blockade in these patients is the best course of action, but this too has not been studied robustly, so we need a large controlled trial to confirm that this practice is indeed safe. 

CONCLUSIONS

The POISE results suggest that for every 1,000 patients treated, perioperative metoprolol would:

• Prevent 15 MIs, 3 cardiac revascularizations, and 7 new cases of atrial fibrillation
• Result in 8 excess deaths, 5 strokes, 53 cases of clinically significant hypotension, and 42 cases of clinically significant bradycardia.

The central take-away message is that patients are unlikely to want a perioperative beta-blocker if they are unwilling to accept a probable increase in mortality or if they place three times more value on avoiding a perioperative stroke than on avoiding an MI.

It has been 10 years since the recommendation to use perioperatove beta-blockers was incorporated into perioperative practice guidelines. Assuming only 10% of physicians acted on this recommendation, 100 million patients have received a perioperative beta-blocker over this time as a result. If the POISE results are applicable, a full 800,000 of these patients died and another 500,000 suffered perioperative strokes as a result of being given a beta-blocker. This issue is not to be taken lightly, given the evidence to suggest harm.

Though it is possible that an alternative beta-blocker regimen to the one used in POISE may provide benefit without substantial harm, the data suggest this is not probable. The POISE data highlight the risk of making assumptions, as well as the importance of and need for large, high-quality randomized trials in the perioperative setting.

It is time for perioperative medicine to enter the age of evidence-based practice and embrace one of its central tenets: only large trials are reliable when it comes to therapeutic questions.

 

 

Rebuttals and discussion

POLDERMANS REBUTTAL: MORE TRANSPARENCY NEEDED IN POISE DOSING DATA

Dr. Poldermans: The initial paper describing the POISE trial design did indeed indicate that it was possible for a patient to receive 400 mg of metoprolol on the first day of treatment. We need to see the actual doses of metoprolol given to all patients in POISE who had a perioperative stroke. If you show me these data, the issue will be much easier to discuss.

Our data from randomized trials are consistent in showing that a titrated dosing regimen using bisoprolol reduces the incidence of postoperative cardiac events with no increase in the number of strokes.

My take-home message is that if you want to use beta-blockers, use them sensibly, use them carefully, and act during surgery. If many of your patients are developing hypotension, then you are doing something wrong.

DEVEREAUX REBUTTAL: A SHIFT IN THINKING IS REQUIRED

Dr. Devereaux: The data from POISE are fully available, and I take issue with Dr. Poldermans’ contention that a patient could have received as much as 400 mg of metoprolol CR on the day of surgery; this was not an option according to protocol. I believe his statement is misleading in the same way that it is misleading to indicate that in the DECREASE trial patients may have received 20 mg of bisoprolol within 24 hours of surgery. It is possible that a patient in DECREASE could have gone to surgery at 2:00 pm and may have taken his or her bisoprolol at 10:00 am that morning. The following morning (in the hospital), it is possible that the patient would have received his or her bisoprolol 10 mg at 7:00 or 8:00 am (ie, 20 mg within 24 hours of surgery). Although this is possible and something similar could have happened within POISE, it does not reflect a patient receiving an effective dose of metoprolol CR 400 mg or bisoprolol 20 mg over a 24-hour period.

I worry about the distortion of reality in perioperative medicine that leads so many of us to believe that randomization is magical despite small sample sizes. Small randomized trials are at profound risk of imbalance between the randomized groups, whether we see it or not, and the results are therefore simply not reliable.

Unless we shift our thinking, we make ourselves susceptible to overconfidence in the benefits of a certain intervention before the data from large clinical trials become available. In the meantime, as we have seen from POISE, an intervention may have negative consequences that are not apparent from small clinical trials.

The reality of excess stroke with perioperative beta-blockers is consistent across all the trials. It does not mean that we cannot find another way to give beta-blockers safely, but if we want to establish safety, we need a large trial that unequivocally demonstrates safety, as opposed to simply using observational data, retrospective cohorts, or comparisons between two nonrandomized trials. Until we have large data sets, it is very difficult to say that we can give beta-blockers safely.

DISCUSSION WITH THE AUDIENCE

Moderator^*: Dr. Devereaux, was the hypotension in POISE related to the long-acting beta-blocker itself or to the large dose of if that was used? Similarly, were the strokes a result of the drug itself or of the hypotension?

Dr. Devereaux: I must take issue with your premise that the dose of metoprolol used in POISE was “large.” As I noted, Mangano’s study used its beta-blocker (atenolol) at 50% of its maximum daily therapeutic dose,¹ the same proportion used in POISE, and Dr. Poldermans’ own DECREASE trial allowed titration of bisoprolol up to 50% of the maximum daily therapeutic dose.³ The DIPOM trial used half the dose of metoprolol that we used, yet it too yielded a trend toward more death and stroke in the beta-blocker group.⁴ So it’s not that the dose we used was at some excessive level. At the same time, that does not mean that a smaller dose may not have achieved a similarly significant benefit in cardiac outcomes.

We can’t explain most of the strokes. Because most strokes were ischemic, I suspect that the explanation may lie in the threshold used to define clinically significant hypotension. We used an SBP cutoff of less than 90 mm Hg, but we did not classify large drops in SBP, such as from 180 to 95 mm Hg, as clinically significant hypotension. The high incidence of clinically significant hypotension in the placebo group—about 10%—suggests that hypotension was likely the driving factor for stroke. The beta-blocker exacerbated the hypotension, but its more important effect may have been that it made it harder for the body to overcome the hypotension. That is the exact same signal observed in the COMMIT trial in the setting of acute MI.²²

Dr. Poldermans: I’d like to see the intraoperative blood pressure data for the 60 patients who suffered strokes in POISE. We could then find out exactly when the hypotension occurred, what kind of hypotension it was, what the patient’s initial blood pressure reading was, and so on. If we had access to this information, we could determine which occurred first—the hypotension or the stroke.

Dr. Devereaux: Although trials can indicate a signal, they can’t explain with certainty the pathway through which the outcome occurred. For example, we know that beta-blockers prevent MI, but we don’t know how. What’s most impressive about the stroke issue is the consistency across all the perioperative beta-blocker trials: every one shows a direction of excess stroke with beta-blockers.

Question from the audience: The patient groups studied in DECREASE and POISE were different. DECREASE studied a very high-risk vascular surgery group with known coronary artery disease on the basis of echocardiography. POISE included patients undergoing emergency surgery and patients with sepsis. Can you describe the outcomes in POISE solely among the patients who underwent elective vascular surgery, similar to the patients studied in DECREASE?

Dr. Devereaux: In terms of the benefit to bisoprolol in very high-risk patients in DECREASE, remember that it was a study of 112 patients. That’s far too small a trial to establish safety or efficacy. The benefit of perioperative beta-blockade in preventing MI is unequivocal because it’s consistent across all trials. But the real issue is, was it safe?

Interestingly, in POISE, the groups at highest risk looked like they benefited the least, not the most. The notion of targeting high-risk people is not supported by POISE; if anything, the POISE results went in the direction of harm with beta-blockade in high-risk patients. That being said, the P value for interaction is not statistically significant, but it’s heading in the direction of harm. So I wouldn’t take comfort in believing that if we simply target high-risk patients, beta-blockers become safe.

Question from the audience: I believe that the seven or eight studies that showed higher stroke rates with beta-blockers all gave beta-blockade within 24 hours of surgery. Only in DECREASE was it given days and weeks in advance of surgery. Can you comment?

Dr. Poldermans: There’s clearly a relation between the time of beta-blocker initiation and the incidence of stroke. If you look at the randomized trials, you see an increased incidence of stroke in patients in whom beta-blockers are started just prior to surgery but not in patients who are on chronic beta-blockers. In our case-control study,¹⁸ we screened more than 185,000 patients for stroke and could not detect an increased incidence of stroke in those on chronic beta-blocker therapy. So stroke indeed has something to do with starting beta-blockers just before surgery.

Dr. Devereaux: In DECREASE IV, bisoprolol was started up to 1 month before surgery, yet there were 4 strokes in the bisoprolol group versus 3 in the control group.¹⁷

Dr. Poldermans: Yes, but that difference is not statistically meaningful.

 

Comment from the audience: I’m uncomfortable with the way Dr. Devereaux stresses the importance of significant findings from large randomized trials but then quibbles about a stroke rate of 4 versus 3, which is not statistically significant. Keep it scientific: either there is or there isn’t a P value that achieves significance.

Though I congratulate you on a great trial, any resident in my program would be fired for pursuing your strategy of perioperative care in POISE, which included using an SBP of 100 mm Hg as the threshold for stopping the beta-blocker regardless of preoperative blood pressure. An SBP of 100 mm Hg is not the definition of hypotension. Most anesthesiologists and perioperative physicians peg the beta-blockade to a reasonable level based on the preoperative blood pressure. They titrate in fluids and titrate in the beta-blocker. Certainly the timing is an issue—we don’t recommend giving it right before the operation.

Dr. Devereaux: I referred to the stroke rates in DECREASE IV because Dr. Poldermans has claimed that the excess in strokes has occurred in all trials but his, yet DECREASE IV was one of his trials and also one in which bisoprolol was started early. I’m not claiming statistical significance between the 3 versus 4 strokes in DECREASE IV, but the stroke trend is in the same direction as in the other trials, so it tells us nothing with regard to safety. My point is, has anyone proven safety? As much as we’d like to imagine that beta-blockers are safe perioperatively—and maybe they are—it has not been proven. The largest trials at present are consistent with a signal toward harm.

It’s easy to criticize the methodology after a trial is done. A number of us came together and thought we had a reasonable protocol for POISE. We found a reduction in the incidence of MI but more strokes and higher mortality with perioperative metoprolol. Does this mean there is not a safe way to give a beta-blocker and derive the benefit? Of course not. But at the moment the evidence does not support a way to give a beta-blocker safely. Do we need to find a way to give it safely? Of course we do.

For example, the design of POISE II is factorial, looking at aspirin versus placebo as well as clonidine versus placebo. There are a number of factors about clonidine that suggest we might be able to achieve the benefits we saw in POISE and avoid the risk, but until we do a large trial, we’re not going to know.

Comment from the audience: It’s important that we clearly understand the conclusion from POISE. It’s not that the administration of beta-blockers is not safe. It’s that the administration of a beta-blocker, as your methodology applied it, was not totally safe. Those are two very different conclusions.

Dr. Devereaux: I would say the conclusion is that the way that beta-blockers are being given has not been proven to be safe. The result is consistent. It’s even consistent with DECREASE IV.

Moderator: I believe in large clinical trials, but they must apply to real-life practice. POISE did not address the practices of many people in this room, particularly regarding the doses of metoprolol used. So it is hard for us to apply the findings in clinical practice. Those of you who design large trials need to think through your trial design very thoroughly, considering the millions of dollars that go into these trials. It’s not fair to clinicians to do a study that may have little clinical relevance.

Dr. Devereaux: Investigators from 190 centers in 23 countries were involved in POISE, and all of them thought we had a reasonable approach and methodology. That doesn’t mean it was perfect, yet the criticisms we are hearing now did not surface while the trial was ongoing.

Comment from the audience: My hospital in Australia contributed to the POISE study. When it started 6 or 7 years ago, the cardiologists were using beta-blockers liberally and haphazardly. It was a huge challenge to convince them that conducting the trial was justifiable—that the case for perioperative beta-blockers had not been absolutely and overwhelmingly proved. They wanted to put beta-blockers in the water supply at the doses we’re talking about.

It would be interesting to do separate analyses of the data from the various countries involved in POISE. In Australia, the percentage of the population on chronic beta-blockers—who therefore would have been ineligible for the trial—is now quite high. Most patients who need to be on beta-blockers long term are on them, whereas that was not the case 15 years ago. The population is changing even while we’re doing the trials. Australian cardiologists are no longer putting every patient on perioperative beta-blockers; they’re thinking about it first.

Dr. Devereaux: A compelling feature of POISE as an international trial is its consistency of outcomes across the planet. No matter where we looked, the outcomes were consistent: in Asia, Europe, North America, and Australia.

Moderator: Would each of you summarize your take-home message for clinicians?

Dr. Devereaux: I urge clinicians to actually read the trials themselves rather than just relying on the advice of guideline writers. It’s important not to allow ourselves to become entrenched in a practice without evidence, just because we’ve done it for so long. If you told your patients the number of MIs prevented and the potential number of excess strokes and deaths, I suspect the average patient would conclude it’s not a great trade-off.

Remember that two-thirds of MIs in the perioperative setting are clinically silent. That doesn’t mean they’re not important, but the strokes, in contrast, are profoundly devastating. One-third of patients with stroke in POISE were dead within 30 days, and of those who survived, 60% were incapacitated, needing help with everyday activities.

I encourage clinicians to read the POISE manuscript with a fresh perspective, regardless of how you’ve practiced until now. Then ask yourself whether you really are comfortable with the safety of perioperative beta-blockers at this time. Of course, that doesn’t mean the evidence won’t change in the future.

Dr. Poldermans: The main imperative is to improve postoperative care. We strongly believe that perioperative beta-blockers work in the general population. If you have a patient who needs to be on a beta-blocker after surgery, why not start it preoperatively? I believe that dosing and timing of initiation are important. If you have the opportunity to start the beta-blocker prior to surgery, do so at a reasonable dose and start early. Patients in whom beta-blockers are started immediately prior to surgery may be worse off, with a higher incidence of stroke.

*Amir K. Jaffer, MD, University of Miami Miller School of Medicine, served as moderator of the debate and the discussion period.

Assessing patients with liver disease for surgery is one of the most common reasons for hepatology consultation in the hospital. This review focuses on practical aspects of evaluating patients with known or suspected liver disease and provides guidance for determining whether it is safe to proceed with surgery in such patients. I begin with a case study to introduce some common clinical challenges and then revisit the case—with relevant teaching points—at the end.

CASE: A MIDDLE-AGED MAN WITH LIVER DISEASE SCHEDULED FOR CARDIAC SURGERY

A 57-year-old man with a history of liver disease is referred for preoperative assessment. It is 6:30 pm, and the patient has just arrived in the hospital; he is scheduled for coronary artery bypass graft surgery (CABG) early tomorrow morning for ischemic heart disease. Ten years ago, he was diagnosed with hepatitis C virus infection; 2 years later, he had a cholecystectomy. He has a remote history of intravenous drug use.

The sub-intern asks for an assessment of operative risk as well as advice on the type of anesthesia to be used.

HEPATIC EFFECTS OF ANESTHESIA

Anesthesiologists are keenly aware of the hepatic effects of anesthesia and that they must carefully choose anesthetics for patients with liver disease. There are a number of at least theoretical concerns about using particular anesthetics:

• Inhaled anesthetics, such as isoflurane, cause systemic vasodilation and depress cardiac output. These effects are of concern since many patients with advanced liver disease already have a hyperdynamic circulation because of peripheral vasodilation.
• Spinal or epidural anesthetics may reduce mean arterial pressure, which is of concern for similar reasons.
• Nitrous oxide has less of a depressive effect unless the patient has concomitant hypercapnia.

Another consideration is the hepatic metabolism of anesthetic agents. Use of halothane, which is 20% metabolized by the liver, is now uncommon, particularly if there is any concern about liver disease. In contrast, enflurane is only 4% metabolized by the liver. Numerous other anesthetics—including isoflurane, desflurane, and sevoflurane—have only minimal hepatic metabolism (< 0.2%), which makes them, along with nitrous oxide, the best anesthetic choices for patients with liver disease.

ASSESSING OPERATIVE RISK

The more important issue in the consultation for our patient is the degree of operative risk associated with his underlying liver disease. A number of factors are pertinent, including the etiology and severity of the liver disease and the type of surgery planned.

Acute liver disease has higher operative risk

Literature dating back 40 years has associated acute viral and alcoholic hepatitis with poor outcomes in surgical patients. Major elective surgery for a patient with suspected acute hepatitis A, for example, should be deferred until the patient has recovered, barring some compelling reason for greater urgency, such as a perforated viscus.

In chronic liver disease, hepatocellular function predicts outcome

For patients with chronic liver disease, outcomes correlate with underlying hepatocellular function. Chronic liver disease tends to run a predictable course (Figure 1). Patients with well-compensated cirrhosis may enjoy good health for many years. But once an index complication—such as variceal hemorrhage, ascites, hepatic encephalopathy, or jaundice—develops, prognosis rapidly worsens.¹

When a patient with liver disease is evaluated for surgery, evidence should be sought to determine whether an index complication has already occurred. Because the patient in our case study had a cholecystectomy several years before, I would also ask, “What did the surgeon say your liver looked like? Did you have any bleeding problems afterwards? Did you develop ascites?”

It is also important to determine whether portal hypertension is present. For a patient with liver disease, otherwise unexplained thrombocytopenia is a useful indicator of portal hypertension.

Systems for scoring liver disease severity

Even a surgical patient with well-compensated liver disease is at risk for developing complications postoperatively, particularly if abdominal surgery is planned. Risk should be assessed in all patients with liver disease using either the Child-Pugh scoring system or the Model for End-Stage Liver Disease (MELD) scoring system.

The Child-Pugh score, which assigns 1 to 3 points according to the presence/absence and levels of each of five simple factors (bilirubin, albumin, prothrombin time/international normalized ratio [INR], ascites, and encephalopathy stage), has been used for decades to assess the severity of liver disease. Patients with Child-Pugh class A disease (score of 5–6) have well-compensated cirrhosis and good synthetic function, and therefore have essentially no restrictions for undergoing surgery. For patients in Child-Pugh class B (score of 7–9), the risk of perioperative complications and mortality is higher and any major hepatic surgery (such as hepatic resection) should be avoided. Patients with class C cirrhosis (score of 10–15) are not candidates for any major elective surgery and should be considered for liver transplantation referral.

The MELD scoring system was developed more recently and is used to prioritize eligibility for liver transplantation. Calculated using a mathematical formula that incorporates three objective patient variables—
creatinine, bilirubin, and INR—the MELD score correlates very well with prognosis. The score can be calculated by an online MELD calculator such as the one at www.unos.org/resources.² A patient with a high MELD score is unlikely to survive for more than a few months without liver transplantation; a patient with a low MELD score is likely to survive for at least 12 months. Calculating the MELD score is now one of the first assessments in any patient suspected of having cirrhosis.

Risk factors for complications and death

In a retrospective study to identify factors associated with complications and mortality in surgical patients with cirrhosis, Ziser et al reviewed the records of 733 patients with cirrhosis who underwent surgical procedures (except liver transplantation) at the Mayo Clinic over an 11-year period (1980–1991).³ The mortality rate within 30 days of surgery was 11.6%. Long-term follow-up showed that most deaths occurred within the first few months after surgery, when many patients succumbed to pneumonia or renal insufficiency.

Univariate analysis of the results identified many patient- and procedure-related factors that were predictive of complications and short- and long-term mortality. Table 1 lists those factors that were found by multivariate analysis to be independently predictive of perioperative complications and of postoperative mortality.³

 

 

Risk factors have strong cumulative power

The study by Ziser et al also underscored the cumulative effect of risk factors, as the probability of developing a perioperative complication increased dramatically with the number of risk factors (as identified by multiavariate analysis) that a patient had, as follows³:

• 9.3% risk of complications with 1 risk factor
• 14.5% risk with 2 factors
• 33.5% risk with 3 factors
• 63.0% risk with 4 or 5 factors
• 73.3% risk with 6 factors
• 100% risk with 7 or 8 factors.

Postoperative complications: Beware hepatorenal syndrome

The most common postoperative complications in the study by Ziser et al were pneumonia, other infections, ventilation dependency, and ascites.³

Possibly the most ominous perioperative complication in a patient with liver disease is the onset of renal insufficiency, which may be precipitated by a number of factors, including nephrotoxic drugs and intraoperative hypotension. Renal insufficiency is usually a predictor of markedly reduced survival and a sign that hepatorenal syndrome may have developed.

Hepatorenal syndrome, which occurred in 3.3% of patients in the analysis by Ziser et al,³ is the presence of renal failure in a patient with cirrhosis. It is characterized by advanced liver failure and severe sinusoidal portal hypertension. The renal failure is said to be “functional” because significant histological changes are absent on kidney biopsy. Marked arteriolar vasodilation occurs in the extrarenal circulation with renal vasoconstriction leading to reduced glomerular filtration.

IMPORTANCE OF SURGICAL PROCEDURE TYPE

In addition to the patient-specific risk factors discussed above, certain surgical procedures deserve special consideration in patients with liver disease.

Cholecystectomy: Open vs closed

Patients with liver disease have the same indication for cholecystectomy as anyone else does: symptomatic gallstone disease. Patients with cirrhosis who are found to have incidental gallstones on ultrasonography should not undergo cholecystectomy unless the gallstones are symptomatic, as liver function may deteriorate after surgery.

For a patient with liver disease undergoing cholecystectomy, a common concern is whether an open or closed procedure should be done. Conventional wisdom had been that a patient with underlying liver disease (particularly cirrhosis) should have an open procedure so that the surgeon could more easily control bleeding, but that notion has changed in recent years with evidence supporting the safety of a laparoscopic approach in patients with liver disease.

One study supporting this new strategy is a retrospective review of 50 patients who had undergone cholecystectomy for symptomatic gallstone disease at the Mayo Clinic between 1990 and 1997.⁴ The procedure was open in half of the patients and laparoscopic in the other half. All patients had Child-Pugh class A or B cirrhosis. The indications for surgery were acute cholecystitis, biliary colic, or pancreatitis, and the number of patients with each of these indications was comparable between the open-surgery and laparoscopy groups. Three patients who initially underwent laparoscopy were converted to open cholecystectomy: two for bleeding and one for poor access. The study found that laparoscopic cholecystectomy was associated with statistically significant reductions in operating room time, blood loss, and length of hospital stay. No deaths occurred in either group. The authors concluded that laparoscopic cholecystectomy is safe in patients with cirrhosis and offers several advantages over an open surgical approach.

In light of these findings and other recent evidence, laparoscopic cholecystectomy should be recommended for patients with liver disease unless they have ascites or other evidence of overt hepatic decompensation, in which case cholecystectomy itself is contraindicated.

Cardiac surgery with bypass poses extra risk

Patients with liver disease undergoing open heart surgery with cardiopulmonary bypass are at especially high risk because of the effect on hepatic hemodynamics. This risk was demonstrated in a retrospective review of all patients with cirrhosis who underwent cardiac surgery with cardiopulmonary bypass at the Cleveland Clinic from 1992 to 2002.⁵ Of the 44 patients identified, 12 (27%) developed hepatic decompensation and 7 (16%) died. Hepatic decompensation was a major factor in all the deaths.

The MELD and Child-Pugh scores correlated well with one another in this study and were highly associated with hepatic decompensation and death. The best cutoff values for predicting mortality and hepatic decompensation were found to be a score greater than 7 in the Child-Pugh system and a score greater than 13 in the MELD system. (For context, receipt of a donor liver via a transplant list in the United States requires a MELD score of at least 15.) The study confirmed that the Child-Pugh score, which is easy to determine at the bedside, remains a reliable predictor of poor outcomes.⁵

CASE REVISITED: POSTOPERATIVE LIVER FUNCTION DECLINE―HOW SERIOUS IS IT?

Our patient undergoes the CABG procedure, and 3 days later you are asked to see him. According to the sub-intern, although the surgery was successful, the patient is now “in liver failure.” After hearing this news, the family is anxious to discuss liver transplantation.

On examination, the patient is alert and extubated, so he is clearly not encephalopathic. His wound is clean and shows no sign of infection. He appears to be mildly icteric, and he may have some ascites, based on mild flank dullness.

His laboratory test results are as follows:

• Bilirubin, 3.1 mg/dL (normal range, 0.3–1.2)
• INR, 1.2 (0.9–1.2)
• Alanine aminotransferase (ALT), 300 U/L (10–40)
• Creatinine, 0.9 mg/dL (0.6–1.2).

Although the bilirubin and ALT are elevated, it is notable that the creatinine is normal. This pattern is not uncommon after elective surgery in a patient with underlying cirrhosis. Renal dysfunction is the biggest concern in the perioperative management of a patient with liver disease, as it is an indicator that the patient may develop overt hepatic decompensation. Likely reasons for the patient’s ALT elevation are the effects of cardiopulmonary bypass and possible intraoperative hypotension.

The family needs to be told that the patient is not in liver failure and that it is best to wait with the expectation that he will do fine unless other complications supervene.

You advise cautious diuresis, and the ALT falls over the next few days. The bilirubin declines to 2.0 mg/dL. At this point, you advise discharge planning.

One need not wait for the bilirubin to return to normal: after an acute hepatic insult such as ischemic hepatitis or intraoperative hypotension, bilirubin is the last indicator to improve. Bilirubin is in part albumin-bound, and the half-life of albumin is 18 days, so a patient can remain icteric for some time after the rest of the liver function tests have returned to normal.

 

 

DISCUSSION

Question from the audience: What are your recommendations regarding platelet transfusion if the platelet count is less than 50,000 in a patient with liver disease?

Dr. Martin: For patients with thrombocytopenia, it is prudent to get the platelet count above 60,000 before any procedure. We will not even do a blind liver biopsy in a patient with a platelet count of less than 60,000.

Question from the audience: A study from the Annals of Surgery concludes that patients with liver disease do poorly with a hemoglobin of less than 10 g/dL. Would you transfuse aggressively before surgery?

Dr. Martin: For a patient with anemia, I don’t like to use aggressive transfusion if cirrhosis is present because the portal pressure may go up and increase the risk of variceal hemorrhage. If there is adequate time for a work-up, one can screen for varices by endoscopy. If there is evidence of overt hepatic decompensation and portal hypertension (esophageal varices, a palpable spleen, and thrombocytopenia), I wouldn’t try to get the hemoglobin much above 10 g/dL.

Question from the audience: How would you modify prophylaxis for deep vein thrombosis following hip or knee replacement surgery in patients with liver disease?

Dr. Martin: I would base it on the INR. Patients who are already mildly coagulopathic tend to be very sensitive to warfarin in the long term. For immediate perioperative prophylaxis, I would not administer anything if the patient had a platelet count below 60,000; otherwise I would probably proceed as usual.

Question from the audience: You said that we shouldn’t operate on patients with acute hepatitis, but we frequently encounter patients with drug-induced hepatitis, such as from anticholesterol drugs. These patients’ ALT and aspartate aminotransferase (AST) levels can remain elevated for 2 or 3 months. How long should we delay surgery? For example, is it dangerous to proceed with a mastectomy a month after discontinuing the drug if the liver enzymes are still around 100 U/L?

Dr. Martin: It’s worth noting that much of the literature on surgery in patients with acute viral hepatitis is 30 or 40 years old. If such a patient had a compelling reason to have surgery, you might wait until the liver enzymes were trending downward and you were confident that the patient was recovering.

Question from the audience: How do you manage patients who have varices or have had variceal bleeding in the past? Many of them are on beta-blockers, such as propranolol, which can cause hypotension intraoperatively.

Dr. Martin: The standard of care is to prescribe beta-blockers for a patient with large varices, or to ablate the varices by endoscopy, which is my practice. In general, I would discontinue propranolol on the morning of surgery. If possible, however, I would have the patient undergo endoscopy before surgery to assess the likelihood of short-term variceal bleeding. If the varices look to be at low risk of bleeding, the beta-blocker can safely be stopped. If they look to be at high risk of bleeding, the surgery should be delayed for a few weeks, if possible, so that the varices can be ablated, which usually takes two or three sessions.

Question from the audience: I deal with many referrals, and I struggle with how aggressive a work-up I should do for patients undergoing elective surgery when a new abnormality is found in one of their liver function tests.

Dr. Martin: I would try to establish whether the abnormality is a chronic problem. Has the patient been told about an abnormal liver test in the past? Ask if the patient has been a blood donor, as measurement of ALT and some hepatitis serologies would have been required. Also ask if he or she has ever taken out a big life insurance policy, which also would have required liver function testing. If the abnormality is chronic, you may proceed with surgery if the bilirubin and INR are normal. In the absence of chronicity, surgery should be delayed for further work-up only in patients with indicators of significant liver disease—either markedly abnormal liver tests, thrombocytopenia, or coagulopathy.

Follow-up question: But patients rarely know whether they’ve had elevated liver enzymes in the past. You said not to worry about enzyme abnormalities unless they are markedly elevated, but how high is that?

Dr. Martin: AST and ALT are indicators of liver injury rather than of synthetic function. The true liver function tests are really albumin, bilirubin, and prothrombin time. Paradoxically, one of the best liver function tests is the platelet count. For me, a red flag for a patient with newly recognized liver disease is any degree of thrombocytopenia or coagulopathy or an elevation of bilirubin above the upper limit of normal. A patient with a platelet count of 90,000 and an INR above 1.2 has significant underlying liver disease, and I would be very concerned. Unless it’s a dire emergency, such a patient would need further evaluation before proceeding with surgery. In contrast, a patient with an ALT of 89, an AST of 65, and normal prothrombin time and platelet count should be safe to proceed to surgery. But such a patient needs an evaluation for liver disease afterward.

Question from the audience: My institution performs many liver resections for metastases or primary liver cancers. Our liver surgeons routinely discontinue statins 2 to 3 weeks before liver surgery, but it has been said at this summit that is not necessary. What’s your opinion?

Dr. Martin: I think that statins get a very bad rap in terms of hepatotoxity. Most patients with metabolic syndrome have hyperlipidemia, which can cause fatty liver disease and hepatic dysfunction. Statins help bring the lipid levels down. Hepatologists do not regard statins as major culprits in causing liver problems. I don’t believe there’s any particular indication to stop them before a patient undergoes hepatic surgery.

Question from the audience: I assess patients 1 or 2 weeks before surgery. For a patient with coagulopathy whom you suspect has underlying liver disease, is there any value in trying to treat the coagulopathy with vitamin K?

Dr. Martin: It can be worthwhile to try 10 mg subcutaneously for 3 days to see whether the situation improves, but if the patient has severe parenchymal liver disease, the vitamin K won’t help much.

Assessing patients with liver disease for surgery is one of the most common reasons for hepatology consultation in the hospital. This review focuses on practical aspects of evaluating patients with known or suspected liver disease and provides guidance for determining whether it is safe to proceed with surgery in such patients. I begin with a case study to introduce some common clinical challenges and then revisit the case—with relevant teaching points—at the end.

CASE: A MIDDLE-AGED MAN WITH LIVER DISEASE SCHEDULED FOR CARDIAC SURGERY

A 57-year-old man with a history of liver disease is referred for preoperative assessment. It is 6:30 pm, and the patient has just arrived in the hospital; he is scheduled for coronary artery bypass graft surgery (CABG) early tomorrow morning for ischemic heart disease. Ten years ago, he was diagnosed with hepatitis C virus infection; 2 years later, he had a cholecystectomy. He has a remote history of intravenous drug use.

The sub-intern asks for an assessment of operative risk as well as advice on the type of anesthesia to be used.

HEPATIC EFFECTS OF ANESTHESIA

Anesthesiologists are keenly aware of the hepatic effects of anesthesia and that they must carefully choose anesthetics for patients with liver disease. There are a number of at least theoretical concerns about using particular anesthetics:

• Inhaled anesthetics, such as isoflurane, cause systemic vasodilation and depress cardiac output. These effects are of concern since many patients with advanced liver disease already have a hyperdynamic circulation because of peripheral vasodilation.
• Spinal or epidural anesthetics may reduce mean arterial pressure, which is of concern for similar reasons.
• Nitrous oxide has less of a depressive effect unless the patient has concomitant hypercapnia.

Another consideration is the hepatic metabolism of anesthetic agents. Use of halothane, which is 20% metabolized by the liver, is now uncommon, particularly if there is any concern about liver disease. In contrast, enflurane is only 4% metabolized by the liver. Numerous other anesthetics—including isoflurane, desflurane, and sevoflurane—have only minimal hepatic metabolism (< 0.2%), which makes them, along with nitrous oxide, the best anesthetic choices for patients with liver disease.

ASSESSING OPERATIVE RISK

The more important issue in the consultation for our patient is the degree of operative risk associated with his underlying liver disease. A number of factors are pertinent, including the etiology and severity of the liver disease and the type of surgery planned.

Acute liver disease has higher operative risk

Literature dating back 40 years has associated acute viral and alcoholic hepatitis with poor outcomes in surgical patients. Major elective surgery for a patient with suspected acute hepatitis A, for example, should be deferred until the patient has recovered, barring some compelling reason for greater urgency, such as a perforated viscus.

In chronic liver disease, hepatocellular function predicts outcome

For patients with chronic liver disease, outcomes correlate with underlying hepatocellular function. Chronic liver disease tends to run a predictable course (Figure 1). Patients with well-compensated cirrhosis may enjoy good health for many years. But once an index complication—such as variceal hemorrhage, ascites, hepatic encephalopathy, or jaundice—develops, prognosis rapidly worsens.¹

When a patient with liver disease is evaluated for surgery, evidence should be sought to determine whether an index complication has already occurred. Because the patient in our case study had a cholecystectomy several years before, I would also ask, “What did the surgeon say your liver looked like? Did you have any bleeding problems afterwards? Did you develop ascites?”

It is also important to determine whether portal hypertension is present. For a patient with liver disease, otherwise unexplained thrombocytopenia is a useful indicator of portal hypertension.

Systems for scoring liver disease severity

Even a surgical patient with well-compensated liver disease is at risk for developing complications postoperatively, particularly if abdominal surgery is planned. Risk should be assessed in all patients with liver disease using either the Child-Pugh scoring system or the Model for End-Stage Liver Disease (MELD) scoring system.

The Child-Pugh score, which assigns 1 to 3 points according to the presence/absence and levels of each of five simple factors (bilirubin, albumin, prothrombin time/international normalized ratio [INR], ascites, and encephalopathy stage), has been used for decades to assess the severity of liver disease. Patients with Child-Pugh class A disease (score of 5–6) have well-compensated cirrhosis and good synthetic function, and therefore have essentially no restrictions for undergoing surgery. For patients in Child-Pugh class B (score of 7–9), the risk of perioperative complications and mortality is higher and any major hepatic surgery (such as hepatic resection) should be avoided. Patients with class C cirrhosis (score of 10–15) are not candidates for any major elective surgery and should be considered for liver transplantation referral.

The MELD scoring system was developed more recently and is used to prioritize eligibility for liver transplantation. Calculated using a mathematical formula that incorporates three objective patient variables—
creatinine, bilirubin, and INR—the MELD score correlates very well with prognosis. The score can be calculated by an online MELD calculator such as the one at www.unos.org/resources.² A patient with a high MELD score is unlikely to survive for more than a few months without liver transplantation; a patient with a low MELD score is likely to survive for at least 12 months. Calculating the MELD score is now one of the first assessments in any patient suspected of having cirrhosis.

Risk factors for complications and death

In a retrospective study to identify factors associated with complications and mortality in surgical patients with cirrhosis, Ziser et al reviewed the records of 733 patients with cirrhosis who underwent surgical procedures (except liver transplantation) at the Mayo Clinic over an 11-year period (1980–1991).³ The mortality rate within 30 days of surgery was 11.6%. Long-term follow-up showed that most deaths occurred within the first few months after surgery, when many patients succumbed to pneumonia or renal insufficiency.

Univariate analysis of the results identified many patient- and procedure-related factors that were predictive of complications and short- and long-term mortality. Table 1 lists those factors that were found by multivariate analysis to be independently predictive of perioperative complications and of postoperative mortality.³

 

 

Risk factors have strong cumulative power

The study by Ziser et al also underscored the cumulative effect of risk factors, as the probability of developing a perioperative complication increased dramatically with the number of risk factors (as identified by multiavariate analysis) that a patient had, as follows³:

• 9.3% risk of complications with 1 risk factor
• 14.5% risk with 2 factors
• 33.5% risk with 3 factors
• 63.0% risk with 4 or 5 factors
• 73.3% risk with 6 factors
• 100% risk with 7 or 8 factors.

Postoperative complications: Beware hepatorenal syndrome

The most common postoperative complications in the study by Ziser et al were pneumonia, other infections, ventilation dependency, and ascites.³

Possibly the most ominous perioperative complication in a patient with liver disease is the onset of renal insufficiency, which may be precipitated by a number of factors, including nephrotoxic drugs and intraoperative hypotension. Renal insufficiency is usually a predictor of markedly reduced survival and a sign that hepatorenal syndrome may have developed.

Hepatorenal syndrome, which occurred in 3.3% of patients in the analysis by Ziser et al,³ is the presence of renal failure in a patient with cirrhosis. It is characterized by advanced liver failure and severe sinusoidal portal hypertension. The renal failure is said to be “functional” because significant histological changes are absent on kidney biopsy. Marked arteriolar vasodilation occurs in the extrarenal circulation with renal vasoconstriction leading to reduced glomerular filtration.

IMPORTANCE OF SURGICAL PROCEDURE TYPE

In addition to the patient-specific risk factors discussed above, certain surgical procedures deserve special consideration in patients with liver disease.

Cholecystectomy: Open vs closed

Patients with liver disease have the same indication for cholecystectomy as anyone else does: symptomatic gallstone disease. Patients with cirrhosis who are found to have incidental gallstones on ultrasonography should not undergo cholecystectomy unless the gallstones are symptomatic, as liver function may deteriorate after surgery.

For a patient with liver disease undergoing cholecystectomy, a common concern is whether an open or closed procedure should be done. Conventional wisdom had been that a patient with underlying liver disease (particularly cirrhosis) should have an open procedure so that the surgeon could more easily control bleeding, but that notion has changed in recent years with evidence supporting the safety of a laparoscopic approach in patients with liver disease.

One study supporting this new strategy is a retrospective review of 50 patients who had undergone cholecystectomy for symptomatic gallstone disease at the Mayo Clinic between 1990 and 1997.⁴ The procedure was open in half of the patients and laparoscopic in the other half. All patients had Child-Pugh class A or B cirrhosis. The indications for surgery were acute cholecystitis, biliary colic, or pancreatitis, and the number of patients with each of these indications was comparable between the open-surgery and laparoscopy groups. Three patients who initially underwent laparoscopy were converted to open cholecystectomy: two for bleeding and one for poor access. The study found that laparoscopic cholecystectomy was associated with statistically significant reductions in operating room time, blood loss, and length of hospital stay. No deaths occurred in either group. The authors concluded that laparoscopic cholecystectomy is safe in patients with cirrhosis and offers several advantages over an open surgical approach.

In light of these findings and other recent evidence, laparoscopic cholecystectomy should be recommended for patients with liver disease unless they have ascites or other evidence of overt hepatic decompensation, in which case cholecystectomy itself is contraindicated.

Cardiac surgery with bypass poses extra risk

Patients with liver disease undergoing open heart surgery with cardiopulmonary bypass are at especially high risk because of the effect on hepatic hemodynamics. This risk was demonstrated in a retrospective review of all patients with cirrhosis who underwent cardiac surgery with cardiopulmonary bypass at the Cleveland Clinic from 1992 to 2002.⁵ Of the 44 patients identified, 12 (27%) developed hepatic decompensation and 7 (16%) died. Hepatic decompensation was a major factor in all the deaths.

The MELD and Child-Pugh scores correlated well with one another in this study and were highly associated with hepatic decompensation and death. The best cutoff values for predicting mortality and hepatic decompensation were found to be a score greater than 7 in the Child-Pugh system and a score greater than 13 in the MELD system. (For context, receipt of a donor liver via a transplant list in the United States requires a MELD score of at least 15.) The study confirmed that the Child-Pugh score, which is easy to determine at the bedside, remains a reliable predictor of poor outcomes.⁵

CASE REVISITED: POSTOPERATIVE LIVER FUNCTION DECLINE―HOW SERIOUS IS IT?

Our patient undergoes the CABG procedure, and 3 days later you are asked to see him. According to the sub-intern, although the surgery was successful, the patient is now “in liver failure.” After hearing this news, the family is anxious to discuss liver transplantation.

On examination, the patient is alert and extubated, so he is clearly not encephalopathic. His wound is clean and shows no sign of infection. He appears to be mildly icteric, and he may have some ascites, based on mild flank dullness.

His laboratory test results are as follows:

• Bilirubin, 3.1 mg/dL (normal range, 0.3–1.2)
• INR, 1.2 (0.9–1.2)
• Alanine aminotransferase (ALT), 300 U/L (10–40)
• Creatinine, 0.9 mg/dL (0.6–1.2).

Although the bilirubin and ALT are elevated, it is notable that the creatinine is normal. This pattern is not uncommon after elective surgery in a patient with underlying cirrhosis. Renal dysfunction is the biggest concern in the perioperative management of a patient with liver disease, as it is an indicator that the patient may develop overt hepatic decompensation. Likely reasons for the patient’s ALT elevation are the effects of cardiopulmonary bypass and possible intraoperative hypotension.

The family needs to be told that the patient is not in liver failure and that it is best to wait with the expectation that he will do fine unless other complications supervene.

You advise cautious diuresis, and the ALT falls over the next few days. The bilirubin declines to 2.0 mg/dL. At this point, you advise discharge planning.

One need not wait for the bilirubin to return to normal: after an acute hepatic insult such as ischemic hepatitis or intraoperative hypotension, bilirubin is the last indicator to improve. Bilirubin is in part albumin-bound, and the half-life of albumin is 18 days, so a patient can remain icteric for some time after the rest of the liver function tests have returned to normal.

 

 

DISCUSSION

Question from the audience: What are your recommendations regarding platelet transfusion if the platelet count is less than 50,000 in a patient with liver disease?

Dr. Martin: For patients with thrombocytopenia, it is prudent to get the platelet count above 60,000 before any procedure. We will not even do a blind liver biopsy in a patient with a platelet count of less than 60,000.

Question from the audience: A study from the Annals of Surgery concludes that patients with liver disease do poorly with a hemoglobin of less than 10 g/dL. Would you transfuse aggressively before surgery?

Dr. Martin: For a patient with anemia, I don’t like to use aggressive transfusion if cirrhosis is present because the portal pressure may go up and increase the risk of variceal hemorrhage. If there is adequate time for a work-up, one can screen for varices by endoscopy. If there is evidence of overt hepatic decompensation and portal hypertension (esophageal varices, a palpable spleen, and thrombocytopenia), I wouldn’t try to get the hemoglobin much above 10 g/dL.

Question from the audience: How would you modify prophylaxis for deep vein thrombosis following hip or knee replacement surgery in patients with liver disease?

Dr. Martin: I would base it on the INR. Patients who are already mildly coagulopathic tend to be very sensitive to warfarin in the long term. For immediate perioperative prophylaxis, I would not administer anything if the patient had a platelet count below 60,000; otherwise I would probably proceed as usual.

Question from the audience: You said that we shouldn’t operate on patients with acute hepatitis, but we frequently encounter patients with drug-induced hepatitis, such as from anticholesterol drugs. These patients’ ALT and aspartate aminotransferase (AST) levels can remain elevated for 2 or 3 months. How long should we delay surgery? For example, is it dangerous to proceed with a mastectomy a month after discontinuing the drug if the liver enzymes are still around 100 U/L?

Dr. Martin: It’s worth noting that much of the literature on surgery in patients with acute viral hepatitis is 30 or 40 years old. If such a patient had a compelling reason to have surgery, you might wait until the liver enzymes were trending downward and you were confident that the patient was recovering.

Question from the audience: How do you manage patients who have varices or have had variceal bleeding in the past? Many of them are on beta-blockers, such as propranolol, which can cause hypotension intraoperatively.

Dr. Martin: The standard of care is to prescribe beta-blockers for a patient with large varices, or to ablate the varices by endoscopy, which is my practice. In general, I would discontinue propranolol on the morning of surgery. If possible, however, I would have the patient undergo endoscopy before surgery to assess the likelihood of short-term variceal bleeding. If the varices look to be at low risk of bleeding, the beta-blocker can safely be stopped. If they look to be at high risk of bleeding, the surgery should be delayed for a few weeks, if possible, so that the varices can be ablated, which usually takes two or three sessions.

Question from the audience: I deal with many referrals, and I struggle with how aggressive a work-up I should do for patients undergoing elective surgery when a new abnormality is found in one of their liver function tests.

Dr. Martin: I would try to establish whether the abnormality is a chronic problem. Has the patient been told about an abnormal liver test in the past? Ask if the patient has been a blood donor, as measurement of ALT and some hepatitis serologies would have been required. Also ask if he or she has ever taken out a big life insurance policy, which also would have required liver function testing. If the abnormality is chronic, you may proceed with surgery if the bilirubin and INR are normal. In the absence of chronicity, surgery should be delayed for further work-up only in patients with indicators of significant liver disease—either markedly abnormal liver tests, thrombocytopenia, or coagulopathy.

Follow-up question: But patients rarely know whether they’ve had elevated liver enzymes in the past. You said not to worry about enzyme abnormalities unless they are markedly elevated, but how high is that?

Dr. Martin: AST and ALT are indicators of liver injury rather than of synthetic function. The true liver function tests are really albumin, bilirubin, and prothrombin time. Paradoxically, one of the best liver function tests is the platelet count. For me, a red flag for a patient with newly recognized liver disease is any degree of thrombocytopenia or coagulopathy or an elevation of bilirubin above the upper limit of normal. A patient with a platelet count of 90,000 and an INR above 1.2 has significant underlying liver disease, and I would be very concerned. Unless it’s a dire emergency, such a patient would need further evaluation before proceeding with surgery. In contrast, a patient with an ALT of 89, an AST of 65, and normal prothrombin time and platelet count should be safe to proceed to surgery. But such a patient needs an evaluation for liver disease afterward.

Question from the audience: My institution performs many liver resections for metastases or primary liver cancers. Our liver surgeons routinely discontinue statins 2 to 3 weeks before liver surgery, but it has been said at this summit that is not necessary. What’s your opinion?

Dr. Martin: I think that statins get a very bad rap in terms of hepatotoxity. Most patients with metabolic syndrome have hyperlipidemia, which can cause fatty liver disease and hepatic dysfunction. Statins help bring the lipid levels down. Hepatologists do not regard statins as major culprits in causing liver problems. I don’t believe there’s any particular indication to stop them before a patient undergoes hepatic surgery.

Question from the audience: I assess patients 1 or 2 weeks before surgery. For a patient with coagulopathy whom you suspect has underlying liver disease, is there any value in trying to treat the coagulopathy with vitamin K?

Dr. Martin: It can be worthwhile to try 10 mg subcutaneously for 3 days to see whether the situation improves, but if the patient has severe parenchymal liver disease, the vitamin K won’t help much.

Assessing patients with liver disease for surgery is one of the most common reasons for hepatology consultation in the hospital. This review focuses on practical aspects of evaluating patients with known or suspected liver disease and provides guidance for determining whether it is safe to proceed with surgery in such patients. I begin with a case study to introduce some common clinical challenges and then revisit the case—with relevant teaching points—at the end.

CASE: A MIDDLE-AGED MAN WITH LIVER DISEASE SCHEDULED FOR CARDIAC SURGERY

A 57-year-old man with a history of liver disease is referred for preoperative assessment. It is 6:30 pm, and the patient has just arrived in the hospital; he is scheduled for coronary artery bypass graft surgery (CABG) early tomorrow morning for ischemic heart disease. Ten years ago, he was diagnosed with hepatitis C virus infection; 2 years later, he had a cholecystectomy. He has a remote history of intravenous drug use.

The sub-intern asks for an assessment of operative risk as well as advice on the type of anesthesia to be used.

HEPATIC EFFECTS OF ANESTHESIA

Anesthesiologists are keenly aware of the hepatic effects of anesthesia and that they must carefully choose anesthetics for patients with liver disease. There are a number of at least theoretical concerns about using particular anesthetics:

• Inhaled anesthetics, such as isoflurane, cause systemic vasodilation and depress cardiac output. These effects are of concern since many patients with advanced liver disease already have a hyperdynamic circulation because of peripheral vasodilation.
• Spinal or epidural anesthetics may reduce mean arterial pressure, which is of concern for similar reasons.
• Nitrous oxide has less of a depressive effect unless the patient has concomitant hypercapnia.

Another consideration is the hepatic metabolism of anesthetic agents. Use of halothane, which is 20% metabolized by the liver, is now uncommon, particularly if there is any concern about liver disease. In contrast, enflurane is only 4% metabolized by the liver. Numerous other anesthetics—including isoflurane, desflurane, and sevoflurane—have only minimal hepatic metabolism (< 0.2%), which makes them, along with nitrous oxide, the best anesthetic choices for patients with liver disease.

ASSESSING OPERATIVE RISK

The more important issue in the consultation for our patient is the degree of operative risk associated with his underlying liver disease. A number of factors are pertinent, including the etiology and severity of the liver disease and the type of surgery planned.

Acute liver disease has higher operative risk

Literature dating back 40 years has associated acute viral and alcoholic hepatitis with poor outcomes in surgical patients. Major elective surgery for a patient with suspected acute hepatitis A, for example, should be deferred until the patient has recovered, barring some compelling reason for greater urgency, such as a perforated viscus.

In chronic liver disease, hepatocellular function predicts outcome

For patients with chronic liver disease, outcomes correlate with underlying hepatocellular function. Chronic liver disease tends to run a predictable course (Figure 1). Patients with well-compensated cirrhosis may enjoy good health for many years. But once an index complication—such as variceal hemorrhage, ascites, hepatic encephalopathy, or jaundice—develops, prognosis rapidly worsens.¹

When a patient with liver disease is evaluated for surgery, evidence should be sought to determine whether an index complication has already occurred. Because the patient in our case study had a cholecystectomy several years before, I would also ask, “What did the surgeon say your liver looked like? Did you have any bleeding problems afterwards? Did you develop ascites?”

It is also important to determine whether portal hypertension is present. For a patient with liver disease, otherwise unexplained thrombocytopenia is a useful indicator of portal hypertension.

Systems for scoring liver disease severity

Even a surgical patient with well-compensated liver disease is at risk for developing complications postoperatively, particularly if abdominal surgery is planned. Risk should be assessed in all patients with liver disease using either the Child-Pugh scoring system or the Model for End-Stage Liver Disease (MELD) scoring system.

The Child-Pugh score, which assigns 1 to 3 points according to the presence/absence and levels of each of five simple factors (bilirubin, albumin, prothrombin time/international normalized ratio [INR], ascites, and encephalopathy stage), has been used for decades to assess the severity of liver disease. Patients with Child-Pugh class A disease (score of 5–6) have well-compensated cirrhosis and good synthetic function, and therefore have essentially no restrictions for undergoing surgery. For patients in Child-Pugh class B (score of 7–9), the risk of perioperative complications and mortality is higher and any major hepatic surgery (such as hepatic resection) should be avoided. Patients with class C cirrhosis (score of 10–15) are not candidates for any major elective surgery and should be considered for liver transplantation referral.

The MELD scoring system was developed more recently and is used to prioritize eligibility for liver transplantation. Calculated using a mathematical formula that incorporates three objective patient variables—
creatinine, bilirubin, and INR—the MELD score correlates very well with prognosis. The score can be calculated by an online MELD calculator such as the one at www.unos.org/resources.² A patient with a high MELD score is unlikely to survive for more than a few months without liver transplantation; a patient with a low MELD score is likely to survive for at least 12 months. Calculating the MELD score is now one of the first assessments in any patient suspected of having cirrhosis.

Risk factors for complications and death

In a retrospective study to identify factors associated with complications and mortality in surgical patients with cirrhosis, Ziser et al reviewed the records of 733 patients with cirrhosis who underwent surgical procedures (except liver transplantation) at the Mayo Clinic over an 11-year period (1980–1991).³ The mortality rate within 30 days of surgery was 11.6%. Long-term follow-up showed that most deaths occurred within the first few months after surgery, when many patients succumbed to pneumonia or renal insufficiency.

Univariate analysis of the results identified many patient- and procedure-related factors that were predictive of complications and short- and long-term mortality. Table 1 lists those factors that were found by multivariate analysis to be independently predictive of perioperative complications and of postoperative mortality.³

 

 

Risk factors have strong cumulative power

The study by Ziser et al also underscored the cumulative effect of risk factors, as the probability of developing a perioperative complication increased dramatically with the number of risk factors (as identified by multiavariate analysis) that a patient had, as follows³:

• 9.3% risk of complications with 1 risk factor
• 14.5% risk with 2 factors
• 33.5% risk with 3 factors
• 63.0% risk with 4 or 5 factors
• 73.3% risk with 6 factors
• 100% risk with 7 or 8 factors.

Postoperative complications: Beware hepatorenal syndrome

The most common postoperative complications in the study by Ziser et al were pneumonia, other infections, ventilation dependency, and ascites.³

Possibly the most ominous perioperative complication in a patient with liver disease is the onset of renal insufficiency, which may be precipitated by a number of factors, including nephrotoxic drugs and intraoperative hypotension. Renal insufficiency is usually a predictor of markedly reduced survival and a sign that hepatorenal syndrome may have developed.

Hepatorenal syndrome, which occurred in 3.3% of patients in the analysis by Ziser et al,³ is the presence of renal failure in a patient with cirrhosis. It is characterized by advanced liver failure and severe sinusoidal portal hypertension. The renal failure is said to be “functional” because significant histological changes are absent on kidney biopsy. Marked arteriolar vasodilation occurs in the extrarenal circulation with renal vasoconstriction leading to reduced glomerular filtration.

IMPORTANCE OF SURGICAL PROCEDURE TYPE

In addition to the patient-specific risk factors discussed above, certain surgical procedures deserve special consideration in patients with liver disease.

Cholecystectomy: Open vs closed

Patients with liver disease have the same indication for cholecystectomy as anyone else does: symptomatic gallstone disease. Patients with cirrhosis who are found to have incidental gallstones on ultrasonography should not undergo cholecystectomy unless the gallstones are symptomatic, as liver function may deteriorate after surgery.

For a patient with liver disease undergoing cholecystectomy, a common concern is whether an open or closed procedure should be done. Conventional wisdom had been that a patient with underlying liver disease (particularly cirrhosis) should have an open procedure so that the surgeon could more easily control bleeding, but that notion has changed in recent years with evidence supporting the safety of a laparoscopic approach in patients with liver disease.

One study supporting this new strategy is a retrospective review of 50 patients who had undergone cholecystectomy for symptomatic gallstone disease at the Mayo Clinic between 1990 and 1997.⁴ The procedure was open in half of the patients and laparoscopic in the other half. All patients had Child-Pugh class A or B cirrhosis. The indications for surgery were acute cholecystitis, biliary colic, or pancreatitis, and the number of patients with each of these indications was comparable between the open-surgery and laparoscopy groups. Three patients who initially underwent laparoscopy were converted to open cholecystectomy: two for bleeding and one for poor access. The study found that laparoscopic cholecystectomy was associated with statistically significant reductions in operating room time, blood loss, and length of hospital stay. No deaths occurred in either group. The authors concluded that laparoscopic cholecystectomy is safe in patients with cirrhosis and offers several advantages over an open surgical approach.

In light of these findings and other recent evidence, laparoscopic cholecystectomy should be recommended for patients with liver disease unless they have ascites or other evidence of overt hepatic decompensation, in which case cholecystectomy itself is contraindicated.

Cardiac surgery with bypass poses extra risk

Patients with liver disease undergoing open heart surgery with cardiopulmonary bypass are at especially high risk because of the effect on hepatic hemodynamics. This risk was demonstrated in a retrospective review of all patients with cirrhosis who underwent cardiac surgery with cardiopulmonary bypass at the Cleveland Clinic from 1992 to 2002.⁵ Of the 44 patients identified, 12 (27%) developed hepatic decompensation and 7 (16%) died. Hepatic decompensation was a major factor in all the deaths.

The MELD and Child-Pugh scores correlated well with one another in this study and were highly associated with hepatic decompensation and death. The best cutoff values for predicting mortality and hepatic decompensation were found to be a score greater than 7 in the Child-Pugh system and a score greater than 13 in the MELD system. (For context, receipt of a donor liver via a transplant list in the United States requires a MELD score of at least 15.) The study confirmed that the Child-Pugh score, which is easy to determine at the bedside, remains a reliable predictor of poor outcomes.⁵

CASE REVISITED: POSTOPERATIVE LIVER FUNCTION DECLINE―HOW SERIOUS IS IT?

Our patient undergoes the CABG procedure, and 3 days later you are asked to see him. According to the sub-intern, although the surgery was successful, the patient is now “in liver failure.” After hearing this news, the family is anxious to discuss liver transplantation.

On examination, the patient is alert and extubated, so he is clearly not encephalopathic. His wound is clean and shows no sign of infection. He appears to be mildly icteric, and he may have some ascites, based on mild flank dullness.

His laboratory test results are as follows:

• Bilirubin, 3.1 mg/dL (normal range, 0.3–1.2)
• INR, 1.2 (0.9–1.2)
• Alanine aminotransferase (ALT), 300 U/L (10–40)
• Creatinine, 0.9 mg/dL (0.6–1.2).

Although the bilirubin and ALT are elevated, it is notable that the creatinine is normal. This pattern is not uncommon after elective surgery in a patient with underlying cirrhosis. Renal dysfunction is the biggest concern in the perioperative management of a patient with liver disease, as it is an indicator that the patient may develop overt hepatic decompensation. Likely reasons for the patient’s ALT elevation are the effects of cardiopulmonary bypass and possible intraoperative hypotension.

The family needs to be told that the patient is not in liver failure and that it is best to wait with the expectation that he will do fine unless other complications supervene.

You advise cautious diuresis, and the ALT falls over the next few days. The bilirubin declines to 2.0 mg/dL. At this point, you advise discharge planning.

One need not wait for the bilirubin to return to normal: after an acute hepatic insult such as ischemic hepatitis or intraoperative hypotension, bilirubin is the last indicator to improve. Bilirubin is in part albumin-bound, and the half-life of albumin is 18 days, so a patient can remain icteric for some time after the rest of the liver function tests have returned to normal.

 

 

DISCUSSION

Question from the audience: What are your recommendations regarding platelet transfusion if the platelet count is less than 50,000 in a patient with liver disease?

Dr. Martin: For patients with thrombocytopenia, it is prudent to get the platelet count above 60,000 before any procedure. We will not even do a blind liver biopsy in a patient with a platelet count of less than 60,000.

Question from the audience: A study from the Annals of Surgery concludes that patients with liver disease do poorly with a hemoglobin of less than 10 g/dL. Would you transfuse aggressively before surgery?

Dr. Martin: For a patient with anemia, I don’t like to use aggressive transfusion if cirrhosis is present because the portal pressure may go up and increase the risk of variceal hemorrhage. If there is adequate time for a work-up, one can screen for varices by endoscopy. If there is evidence of overt hepatic decompensation and portal hypertension (esophageal varices, a palpable spleen, and thrombocytopenia), I wouldn’t try to get the hemoglobin much above 10 g/dL.

Question from the audience: How would you modify prophylaxis for deep vein thrombosis following hip or knee replacement surgery in patients with liver disease?

Dr. Martin: I would base it on the INR. Patients who are already mildly coagulopathic tend to be very sensitive to warfarin in the long term. For immediate perioperative prophylaxis, I would not administer anything if the patient had a platelet count below 60,000; otherwise I would probably proceed as usual.

Question from the audience: You said that we shouldn’t operate on patients with acute hepatitis, but we frequently encounter patients with drug-induced hepatitis, such as from anticholesterol drugs. These patients’ ALT and aspartate aminotransferase (AST) levels can remain elevated for 2 or 3 months. How long should we delay surgery? For example, is it dangerous to proceed with a mastectomy a month after discontinuing the drug if the liver enzymes are still around 100 U/L?

Dr. Martin: It’s worth noting that much of the literature on surgery in patients with acute viral hepatitis is 30 or 40 years old. If such a patient had a compelling reason to have surgery, you might wait until the liver enzymes were trending downward and you were confident that the patient was recovering.

Question from the audience: How do you manage patients who have varices or have had variceal bleeding in the past? Many of them are on beta-blockers, such as propranolol, which can cause hypotension intraoperatively.

Dr. Martin: The standard of care is to prescribe beta-blockers for a patient with large varices, or to ablate the varices by endoscopy, which is my practice. In general, I would discontinue propranolol on the morning of surgery. If possible, however, I would have the patient undergo endoscopy before surgery to assess the likelihood of short-term variceal bleeding. If the varices look to be at low risk of bleeding, the beta-blocker can safely be stopped. If they look to be at high risk of bleeding, the surgery should be delayed for a few weeks, if possible, so that the varices can be ablated, which usually takes two or three sessions.

Question from the audience: I deal with many referrals, and I struggle with how aggressive a work-up I should do for patients undergoing elective surgery when a new abnormality is found in one of their liver function tests.

Dr. Martin: I would try to establish whether the abnormality is a chronic problem. Has the patient been told about an abnormal liver test in the past? Ask if the patient has been a blood donor, as measurement of ALT and some hepatitis serologies would have been required. Also ask if he or she has ever taken out a big life insurance policy, which also would have required liver function testing. If the abnormality is chronic, you may proceed with surgery if the bilirubin and INR are normal. In the absence of chronicity, surgery should be delayed for further work-up only in patients with indicators of significant liver disease—either markedly abnormal liver tests, thrombocytopenia, or coagulopathy.

Follow-up question: But patients rarely know whether they’ve had elevated liver enzymes in the past. You said not to worry about enzyme abnormalities unless they are markedly elevated, but how high is that?

Dr. Martin: AST and ALT are indicators of liver injury rather than of synthetic function. The true liver function tests are really albumin, bilirubin, and prothrombin time. Paradoxically, one of the best liver function tests is the platelet count. For me, a red flag for a patient with newly recognized liver disease is any degree of thrombocytopenia or coagulopathy or an elevation of bilirubin above the upper limit of normal. A patient with a platelet count of 90,000 and an INR above 1.2 has significant underlying liver disease, and I would be very concerned. Unless it’s a dire emergency, such a patient would need further evaluation before proceeding with surgery. In contrast, a patient with an ALT of 89, an AST of 65, and normal prothrombin time and platelet count should be safe to proceed to surgery. But such a patient needs an evaluation for liver disease afterward.

Question from the audience: My institution performs many liver resections for metastases or primary liver cancers. Our liver surgeons routinely discontinue statins 2 to 3 weeks before liver surgery, but it has been said at this summit that is not necessary. What’s your opinion?

Dr. Martin: I think that statins get a very bad rap in terms of hepatotoxity. Most patients with metabolic syndrome have hyperlipidemia, which can cause fatty liver disease and hepatic dysfunction. Statins help bring the lipid levels down. Hepatologists do not regard statins as major culprits in causing liver problems. I don’t believe there’s any particular indication to stop them before a patient undergoes hepatic surgery.

Question from the audience: I assess patients 1 or 2 weeks before surgery. For a patient with coagulopathy whom you suspect has underlying liver disease, is there any value in trying to treat the coagulopathy with vitamin K?

Dr. Martin: It can be worthwhile to try 10 mg subcutaneously for 3 days to see whether the situation improves, but if the patient has severe parenchymal liver disease, the vitamin K won’t help much.

Obstructive sleep apnea (OSA) is characterized by repeated complete or partial collapse of the pharyngeal airway during sleep, causing cessation of airflow (apnea) or shallow breathing (hypopnea). Persons with OSA may have repeated arousals from sleep (to reestablish breathing) with each episode of apnea or hypopnea. The resulting sleep disruption often leads to daytime somnolence and compromised neurocognitive function.

This pattern of sleep arousal, coupled with intermittent hypoxemia, is associated with serious adverse cardiovascular outcomes, including stroke. Among surgical patients, OSA is associated with postoperative complications and the need for increased medical intervention. This review discusses why OSA is important in the perioperative setting, preoperative screening for OSA risk, and perioperative management of patients with likely or confirmed OSA.

OSA AT A GLANCE

Prevalence in the general population

Four percent of middle-aged men and 2% of middle-aged women meet minimal diagnostic criteria for OSA, according to a landmark cohort study from the 1990s.¹ This makes OSA more common than asthma among adults. Risk increases with age, as 24% of persons older than 65 years have OSA and up to 50% of nursing home residents have clinically significant OSA.²

Prevalence in the surgical population

The prevalence of OSA in the surgical population is higher than that in the general population, and it can vary widely according to the underlying medical condition. A study of 433 patients undergoing general surgery reported a 3.2% prevalence of OSA,³ but this study excluded patients undergoing cardiac surgery, in whom the risk of OSA is higher. In contrast, the prevalence of OSA among obese bariatric surgery patients has been reported at greater than 70%.⁴ Notably, the patients in the general surgery study³ who appeared to be at risk for OSA based on screening questions were invited to participate in a sleep study, whereas all patients in the bariatric surgery study⁴ were evaluated through sleep studies. It is likely that the prevalence of OSA among the general surgery study patients would have been higher if all patients had been evaluated with polysomnography.

Pathophysiology

OSA can occur when any part of the upper airway does not function normally. Upper airway patency is determined by muscle activity, craniofacial and soft tissue structure, and sleep state. During sleep, upper airway muscles are relaxed, which reduces airway patency. Sleep is associated with pharyngeal narrowing and substantially increased inspiratory resistance even among persons without sleep apnea. A person who is awake can compensate for abnormal pharyngeal function through increased muscle activity. During sleep this muscle compensation fails, resulting in partial collapse and subsequent snoring, and sometimes prolonged obstructive hypoventilation. Complete closure results in apnea.

WHY OSA MATTERS

Health consequences of OSA

OSA is associated with serious health consequences, such as increased risk of motor vehicle accidents, stroke, and a number of cardiovascular conditions—hypertension, coronary artery disease, and atrial fibrillation.

Accidents. The daytime hypersomnolence resulting from OSA contributes to reduced vigilance and is likely responsible for an increased incidence of motor vehicle accidents. One study found that among a sample of men and women with unrecognized OSA undergoing polysomnography studies, the likelihood of motor vehicle accidents during the prior 5 years was significantly correlated with the subjects’ apnea-hypopnea index (AHI) score, which reflects the number of apnea or hypopnea episodes per hour of sleep.⁵ Other studies have demonstrated similar associations.

Stroke. Numerous observational studies have demonstrated an elevated prevalence of OSA among patients with stroke as compared with the general population, but these studies did not adjust for other cerebrovascular risk factors. A recent observational cohort study aimed to address this evidence gap by using proportional hazards analysis to determine the independent effect of OSA on the incidence of stroke or death from any cause among persons with no history of stroke or myocardial infarction.⁶ Study participants were 1,022 consecutive patients who underwent polysomnography for evaluation of sleep-disordered breathing. OSA was identified in 68% of patients. During the 3.4-year follow-up period, 22 strokes and 50 deaths occurred among the 697 patients with OSA compared with 2 strokes and 14 deaths among the 325 patients without OSA. The probability of survival was significantly lower for patients with OSA compared with their counterparts without OSA (P < .003). After adjustment for other risk factors, OSA was significantly associated with stroke or death (hazard ratio = 1.97; 95% CI, 1.12–3.48).⁶

Hypertension. Four large studies involving a total of 10,708 patients evaluated for sleep-disordered breathing have established an association between OSA and hypertension risk.^7–10 In each study, the risk of hypertension rose linearly with AHI scores. Clinically significant OSA, defined as an AHI score greater than 15, roughly doubled the risk of hypertension compared with the absence of apnea/hypopnea episodes, with odds ratios ranging from 1.37 to 2.89 across the four studies.^7–10 Each apnea event per hour of sleep was estimated to increase the odds of developing hypertension by approximately 1%.⁸ Notably, the effects of OSA on blood pressure are most pronounced in patients younger than age 50.⁷

Coronary artery disease. The Sleep Heart Health Study evaluated the association between sleep-disordered breathing and cardiovascular disease in 6,424 community-dwelling adults undergoing home polysomnography.¹¹ The population’s median AHI score was 4.4. At least one cardiovascular event was reported by 16% of partici­pants. Sleep-disordered breathing was associated with self-reported heart failure, stroke, and, more modestly, coronary artery disease. A linear relationship was noted between AHI and cardiovascular risk.

Snoring, which is often an indicator for OSA, has also been associated with cardiovascular risk. The Nurses’ Health Study evaluated 71,000 women who completed medical questionnaires that included questions about snoring. Over 8 years of follow-up, the relative risks for cardiovascular disease were 1.46 among occasional snorers (95% CI, 1.23–1.74) and 2.02 among regular snorers (95% CI, 1.62–2.53) in comparison with nonsnorers. Snoring, even without a diagnosis of OSA, emerged as an independent risk factor for cardiovascular disease.¹²

Atrial fibrillation. OSA has been identified as a predictor of new-onset atrial fibrillation in a retrospective cohort study (hazard ratio = 2.18; 95% CI, 1.34–3.54).¹³ In a prospective study, patients with atrial fibrillation but normal left ventricular function were found to have significantly higher AHI scores than matched normal controls.¹⁴ After adjustment for relevant covariates, the odds ratio for an association between atrial fibrillation and significant sleep-disordered breathing (AHI score > 15) was 3.04 (95% CI, 1.24–7.46).¹⁴ In another prospective trial, patients with atrial fibrillation and OSA who underwent cardioversion were at increased risk for a recurrence of atrial fibrillation if OSA was untreated (82% for untreated vs 42% for treated OSA; P = .013).¹⁵

 

 

An association with postoperative complications

OSA also has been shown to increase postoperative complication rates, increase the need for intensive care intervention, and prolong hospital stays. 

Representative evidence. One of the first studies to characterize the postoperative risks of OSA was conducted by Mayo Clinic researchers who retrospectively reviewed 4 years of data for 101 patients with OSA who had had hip or knee replacement surgery within 3 years before (n = 36) or any time after (n = 65) their OSA diagnosis.¹⁶ Outcomes were compared with those of 101 matched controls without OSA who underwent the same operations. Only half the patients with diagnosed OSA prior to their operation used continuous positive airway pressure (CPAP) therapy at home prior to hospitalization. Complications occurred among 39% of patients with OSA and among 18% of control patients (P = .001). Serious complications requiring intensive care unit transfer for cardiac ischemia or respiratory failure occurred in 24% of patients with OSA versus only 9% of controls (P = .004), and hospital stays were longer for patients with OSA compared with controls (P < .007). Most complications occurred during the first day after surgery, but a small number occurred as late as postoperative days 4 and 5.

In a separate study designed to evaluate OSA screening tools, postoperative complication rates were assessed in 211 patients who underwent polysomnography to determine the presence or absence of OSA prior to elective surgery.¹⁷ Patients undergoing various elective procedures were included, but none were undergoing cardiac or bariatric procedures. The overall rate of postoperative complications was more than twice as high among patients with OSA compared with those without OSA (27.4% vs 12.3%; P = .02). The most common complication was oxygen desaturation (ie, level ≤ 90%), which occurred among 20.6% of patients with OSA versus 9.2% of patients without OSA (P < .04). There were no deaths or serious complications.

Potential causes of complications. In the immediate postoperative period, OSA-associated complications may be attributable to lingering effects of sedatives, which can often lead to respiratory problems. Later in the postoperative course, so-called REM rebound is more likely to be implicated in complications. Patients often experience sleep deprivation in the hospital due to constant interruptions. Once a patient does sleep, the amount of REM sleep increases to compensate for this deprivation. The REM stage is when most apneas and hypopneas occur, so the risk of hypoxemia is greatest in the REM stage. As a result, respiratory and cardiovascular complications such as arrhythmias can increase.

OSA AND THE PREOPERATIVE EVALUATION

Risk factors for OSA

The top portion of Table 1 lists factors that reduce upper airway size or predispose to upper airway collapse and thereby increase risk for OSA. Fortunately, anesthesiologists are frequently aware of the craniofacial abnormalities listed in the table because they affect ease of intubation. The inclusion of menopausal status reflects the fact that women tend to catch up with men in their risk for OSA by the time they reach menopause.

Additionally, certain aspects of perioperative management can increase the risk of OSA in the perioperative setting. For example, general anesthesia can mimic the effects of sleep on the airway, reducing muscle tone and potentially leading to pharyngeal collapse. Normal response to hypercapnia is also diminished under general anesthesia and while patients remain sedated postoperatively, which subdues normal protective arousal mechanisms. This does not pose a problem while the patient remains intubated but highlights the need for respiratory monitoring in the extubated patient who is recovering from the residual effects of sedation.

History and physical examination

What to look for. A number of physical characteristics reveal potential risks for OSA. Obesity and hypertension are well established, as noted above. Large neck circumference (≥ 17 inches in men and ≥ 16 inches in women) is another characteristic associated with OSA. Examination of the upper airway can reveal obstruction due to tonsil enlargement, nasal obstruction, an elongated uvula, or macroglossia. Since retrognathia or micrognathia can produce a narrowed oropharynx, attention to mandible size and position is advised. 

Ask about sleep habits. Assessment of OSA risk in the preoperative evaluation need not be lengthy, but patients should be asked about snoring and waking habits, especially frequency of night wakening, to identify possible OSA. Patients generally do not volunteer information about sleep, so it is important to explicitly ask. Responses that suggest OSA include reports of tiredness or sleepiness during the day, or comments by a partner about the patient’s snoring. A patient who reports having a dry mouth in the morning may have nasal congestion or obstruction that leads to mouth breathing. Severe sleep disruption can lead to sleep deprivation, causing personality changes, confusion, intellectual impairment, impotence, or morning headaches (Table 1).

Preoperative screening tools. Screening tools can assist in identifying relevant questions about sleep. Three such tools for OSA have been validated for use in surgical patients: the Berlin questionnaire, the American Society of Anesthesiologists (ASA) checklist, and the STOP questionnaire.^17–20 The performance of these tools was evaluated in 177 surgical patients with OSA identified using polysomnography.¹⁷ Each tool’s sensitivity, specificity, and positive and negative predictive values were calculated according to polysomnography-based AHI severity. All three tools demonstrated moderately high sensitivity for detecting OSA.¹⁷

Use of any of these screening tools improves the likelihood of identifying OSA preoperatively. The quickest and simplest to use is the STOP questionnaire, which was recently modified to include questions about additional risk factors for OSA—body mass index, age, neck circumference, and gender; the modified tool is called the STOP-BANG questionnaire (Table 2).²⁰ In a validation study, the addition of the “BANG” questions about these risk factors increased the questionnaire’s specificity for moderate to severe OSA.²⁰ It is important to ask the questions as they are written (Table 2) to elicit the most complete response. For example, the question “Do you feel tired, fatigued, or sleepy?” may seem redundant, but all three terms should be included because men often complain of feeling sleepy while women are more likely to report feeling tired or fatigued.

Identifying levels of OSA severity. Physical examination and screening questions may be adequate to identify patients at risk for OSA prior to surgery. Mild OSA (AHI score of 5–15) can generally be managed after surgery, at the patient’s leisure. In contrast, moderate OSA (AHI score of 15–30) and severe OSA (AHI score > 30) can affect perioperative management (see next section). If moderate to severe OSA is suspected, and if there is enough time before surgery to consult a sleep lab, polysomnography can provide a more complete diagnosis.

 

 

PERIOPERATIVE MANAGEMENT OF OSA

When in doubt, proceed as if patient has OSA

Evidence of OSA’s association with postoperative complications is emerging, as noted above, but more specific information about risks is needed to develop effective management procedures. For surgical patients who are deemed to be at high risk for OSA, and for whom surgery cannot be delayed for diagnostic tests and OSA treatment, the most prudent course is to proceed with surgery but assume the patient has moderate to severe OSA. Anesthesiologists should be informed when patients are likely to have OSA, as they may choose a different strategy for managing anesthesia during surgery for patients at high risk. 

Management recommendations

The ASA published practice guidelines in 2006 for the perioperative management of patients with OSA.¹⁹ In view of the paucity of data on the best management strate­gies, the guidelines were based mostly on expert opinion. Their key recommendations include the following:

• Surgical patients should be screened clinically to determine their OSA risk. Any of the aforementioned screening tools is effective for this purpose. 
• For patients with a diagnosis of OSA or who are clinically determined to be at high risk, close attention to airway management is required, extubation should be done when the patient is fully awake (to reduce residual effects of anesthesia and sedatives), and regional anesthesia should be used whenever possible.
• Postoperative pain management in patients with confirmed or suspected OSA should minimize the use of opioids and other sedatives. Such patients also should undergo close pulse oximetry monitoring in a step-down setting after surgery and receive postoperative CPAP therapy as soon as possible.

These ASA recommendations are broadly echoed by a 2003 clinical practice review report of the American Academy of Sleep Medicine, which recommends careful attention during the first 24 hours after surgery in patients with presumed OSA and also cautions that patient-controlled analgesia may not be appropriate.²¹

Future research questions

Even with the insights reviewed above, many questions about perioperative management of OSA remain, including the following:

• Will the early diagnosis and treatment of OSA—usually with CPAP—improve perioperative and postoperative outcomes?
• What are the costs associated with observed complications of OSA, and will immediate and continued use of CPAP postoperatively prove cost-effective?
• Where should patients with OSA be monitored postoperatively, and for how long?
• Which pain-control strategies are best for patients with OSA?

DISCUSSION

Question from the audience: Have studies of OSA-associated postoperative complications stratified results on the basis of AHI score? 

Dr. Shafazand: Yes. In most studies, postoperative complications are more likely to occur among patients with AHI scores that indicate moderate to severe OSA. However, although the AHI is used extensively as a measure of OSA severity, it may not be the best measure. The degree and duration of oxygen desaturation are probably more relevant to the physiologic changes that occur than is the actual apnea or hypopnea event. The more severe the hypoxemia, the greater the risk of complications.

Comment from the audience: I want to reiterate the point from earlier in this summit that consultant physicians should avoid recommending a type of anesthetic in a preoperative consult. Despite the recommendations of the 2006 ASA guidelines,¹⁹ many anesthesiologists prefer to use a minimal opioid technique or a general anesthetic for patients with OSA rather than risk losing the airway during the operation and having to perform an emergent intubation.

Dr. Shafazand: I agree. In my own consultations I never presume to make recommendations about the type of anesthesia to be used. The important thing is to have a discussion with the anesthesiologist about the best way to manage patients with OSA, but not in the intraoperative context because the patient is going to be intubated and the airway will be protected. The discussion is really more about how to manage patients once they are extubated.

Question from the audience: Should patients with OSA undergo surgery in outpatient facilities?

Dr. Shafazand: It depends on the type and duration of the procedure. If it is a quick procedure, which is likely for an outpatient facility, with minimal sedation and a period of respiratory observation to ensure that the patient is fully awake, the outpatient setting is probably acceptable, especially if the patient is using CPAP at home. It also depends on the severity of OSA. For patients with more severe OSA, an outpatient facility is not recommended. Unfortunately, data about OSA complications in outpatient facilities are sparse.

Question from the audience: What is the role of overnight pulse oximetry versus a sleep study?

Dr. Shafazand: That is the Achilles’ heel of managing patients with OSA. Sleep labs are overbooked, so it is often not possible to order a sleep study for patients prior to surgery. Some studies have evaluated overnight pulse oximetry, noting the percentage of desaturation or the total time spent at less than 90% saturation during the night or per hour. This approach is probably adequate for screening for suspected severe OSA, but not all patients with OSA will have desaturations. Overnight pulse oximetry is at best a “poor man’s” screening tool—if it is negative, OSA cannot be ruled out.

Question from the audience: What is your opinion of surgical treatments for sleep apnea such as uvulopalatopharyngoplasty (UPPP)?

Dr. Shafazand: For patients with an AHI score below 15 and no comorbidities, some surgical correction may be advisable. For patients with an AHI score above 15, surgery can be recommended in some circumstances—for example, if there is a clear blockage of the nasal passage. But patients with moderate to severe OSA usually continue to require CPAP therapy after surgery. CPAP is still the recommended treatment for moderate to severe OSA, though surgery might help the patient tolerate CPAP better in certain instances by lowering the pressure requirements.

Question from the audience: A minimal number of hospitals actually screen patients for OSA and treat them differently. Do you know why the Joint Commission dropped a proposed safety goal to screen patients for OSA upon admission and treat based on the results?

Dr. Shafazand: I think the biggest problem is that results from the literature are so variable in terms of risks that it’s difficult to draw conclusions. Patients with desaturation are given oxygen to address the immediate problem, but there is no focus on complications. Depending on the study, there are true complications that affect patient safety but also add to the costs of care. Until there are more definitive results in the literature, there is not enough evidence to make and enforce recommendations.

Obstructive sleep apnea (OSA) is characterized by repeated complete or partial collapse of the pharyngeal airway during sleep, causing cessation of airflow (apnea) or shallow breathing (hypopnea). Persons with OSA may have repeated arousals from sleep (to reestablish breathing) with each episode of apnea or hypopnea. The resulting sleep disruption often leads to daytime somnolence and compromised neurocognitive function.

This pattern of sleep arousal, coupled with intermittent hypoxemia, is associated with serious adverse cardiovascular outcomes, including stroke. Among surgical patients, OSA is associated with postoperative complications and the need for increased medical intervention. This review discusses why OSA is important in the perioperative setting, preoperative screening for OSA risk, and perioperative management of patients with likely or confirmed OSA.

OSA AT A GLANCE

Prevalence in the general population

Four percent of middle-aged men and 2% of middle-aged women meet minimal diagnostic criteria for OSA, according to a landmark cohort study from the 1990s.¹ This makes OSA more common than asthma among adults. Risk increases with age, as 24% of persons older than 65 years have OSA and up to 50% of nursing home residents have clinically significant OSA.²

Prevalence in the surgical population

The prevalence of OSA in the surgical population is higher than that in the general population, and it can vary widely according to the underlying medical condition. A study of 433 patients undergoing general surgery reported a 3.2% prevalence of OSA,³ but this study excluded patients undergoing cardiac surgery, in whom the risk of OSA is higher. In contrast, the prevalence of OSA among obese bariatric surgery patients has been reported at greater than 70%.⁴ Notably, the patients in the general surgery study³ who appeared to be at risk for OSA based on screening questions were invited to participate in a sleep study, whereas all patients in the bariatric surgery study⁴ were evaluated through sleep studies. It is likely that the prevalence of OSA among the general surgery study patients would have been higher if all patients had been evaluated with polysomnography.

Pathophysiology

OSA can occur when any part of the upper airway does not function normally. Upper airway patency is determined by muscle activity, craniofacial and soft tissue structure, and sleep state. During sleep, upper airway muscles are relaxed, which reduces airway patency. Sleep is associated with pharyngeal narrowing and substantially increased inspiratory resistance even among persons without sleep apnea. A person who is awake can compensate for abnormal pharyngeal function through increased muscle activity. During sleep this muscle compensation fails, resulting in partial collapse and subsequent snoring, and sometimes prolonged obstructive hypoventilation. Complete closure results in apnea.

WHY OSA MATTERS

Health consequences of OSA

OSA is associated with serious health consequences, such as increased risk of motor vehicle accidents, stroke, and a number of cardiovascular conditions—hypertension, coronary artery disease, and atrial fibrillation.

Accidents. The daytime hypersomnolence resulting from OSA contributes to reduced vigilance and is likely responsible for an increased incidence of motor vehicle accidents. One study found that among a sample of men and women with unrecognized OSA undergoing polysomnography studies, the likelihood of motor vehicle accidents during the prior 5 years was significantly correlated with the subjects’ apnea-hypopnea index (AHI) score, which reflects the number of apnea or hypopnea episodes per hour of sleep.⁵ Other studies have demonstrated similar associations.

Stroke. Numerous observational studies have demonstrated an elevated prevalence of OSA among patients with stroke as compared with the general population, but these studies did not adjust for other cerebrovascular risk factors. A recent observational cohort study aimed to address this evidence gap by using proportional hazards analysis to determine the independent effect of OSA on the incidence of stroke or death from any cause among persons with no history of stroke or myocardial infarction.⁶ Study participants were 1,022 consecutive patients who underwent polysomnography for evaluation of sleep-disordered breathing. OSA was identified in 68% of patients. During the 3.4-year follow-up period, 22 strokes and 50 deaths occurred among the 697 patients with OSA compared with 2 strokes and 14 deaths among the 325 patients without OSA. The probability of survival was significantly lower for patients with OSA compared with their counterparts without OSA (P < .003). After adjustment for other risk factors, OSA was significantly associated with stroke or death (hazard ratio = 1.97; 95% CI, 1.12–3.48).⁶

Hypertension. Four large studies involving a total of 10,708 patients evaluated for sleep-disordered breathing have established an association between OSA and hypertension risk.^7–10 In each study, the risk of hypertension rose linearly with AHI scores. Clinically significant OSA, defined as an AHI score greater than 15, roughly doubled the risk of hypertension compared with the absence of apnea/hypopnea episodes, with odds ratios ranging from 1.37 to 2.89 across the four studies.^7–10 Each apnea event per hour of sleep was estimated to increase the odds of developing hypertension by approximately 1%.⁸ Notably, the effects of OSA on blood pressure are most pronounced in patients younger than age 50.⁷

Coronary artery disease. The Sleep Heart Health Study evaluated the association between sleep-disordered breathing and cardiovascular disease in 6,424 community-dwelling adults undergoing home polysomnography.¹¹ The population’s median AHI score was 4.4. At least one cardiovascular event was reported by 16% of partici­pants. Sleep-disordered breathing was associated with self-reported heart failure, stroke, and, more modestly, coronary artery disease. A linear relationship was noted between AHI and cardiovascular risk.

Snoring, which is often an indicator for OSA, has also been associated with cardiovascular risk. The Nurses’ Health Study evaluated 71,000 women who completed medical questionnaires that included questions about snoring. Over 8 years of follow-up, the relative risks for cardiovascular disease were 1.46 among occasional snorers (95% CI, 1.23–1.74) and 2.02 among regular snorers (95% CI, 1.62–2.53) in comparison with nonsnorers. Snoring, even without a diagnosis of OSA, emerged as an independent risk factor for cardiovascular disease.¹²

Atrial fibrillation. OSA has been identified as a predictor of new-onset atrial fibrillation in a retrospective cohort study (hazard ratio = 2.18; 95% CI, 1.34–3.54).¹³ In a prospective study, patients with atrial fibrillation but normal left ventricular function were found to have significantly higher AHI scores than matched normal controls.¹⁴ After adjustment for relevant covariates, the odds ratio for an association between atrial fibrillation and significant sleep-disordered breathing (AHI score > 15) was 3.04 (95% CI, 1.24–7.46).¹⁴ In another prospective trial, patients with atrial fibrillation and OSA who underwent cardioversion were at increased risk for a recurrence of atrial fibrillation if OSA was untreated (82% for untreated vs 42% for treated OSA; P = .013).¹⁵

 

 

An association with postoperative complications

OSA also has been shown to increase postoperative complication rates, increase the need for intensive care intervention, and prolong hospital stays. 

Representative evidence. One of the first studies to characterize the postoperative risks of OSA was conducted by Mayo Clinic researchers who retrospectively reviewed 4 years of data for 101 patients with OSA who had had hip or knee replacement surgery within 3 years before (n = 36) or any time after (n = 65) their OSA diagnosis.¹⁶ Outcomes were compared with those of 101 matched controls without OSA who underwent the same operations. Only half the patients with diagnosed OSA prior to their operation used continuous positive airway pressure (CPAP) therapy at home prior to hospitalization. Complications occurred among 39% of patients with OSA and among 18% of control patients (P = .001). Serious complications requiring intensive care unit transfer for cardiac ischemia or respiratory failure occurred in 24% of patients with OSA versus only 9% of controls (P = .004), and hospital stays were longer for patients with OSA compared with controls (P < .007). Most complications occurred during the first day after surgery, but a small number occurred as late as postoperative days 4 and 5.

In a separate study designed to evaluate OSA screening tools, postoperative complication rates were assessed in 211 patients who underwent polysomnography to determine the presence or absence of OSA prior to elective surgery.¹⁷ Patients undergoing various elective procedures were included, but none were undergoing cardiac or bariatric procedures. The overall rate of postoperative complications was more than twice as high among patients with OSA compared with those without OSA (27.4% vs 12.3%; P = .02). The most common complication was oxygen desaturation (ie, level ≤ 90%), which occurred among 20.6% of patients with OSA versus 9.2% of patients without OSA (P < .04). There were no deaths or serious complications.

Potential causes of complications. In the immediate postoperative period, OSA-associated complications may be attributable to lingering effects of sedatives, which can often lead to respiratory problems. Later in the postoperative course, so-called REM rebound is more likely to be implicated in complications. Patients often experience sleep deprivation in the hospital due to constant interruptions. Once a patient does sleep, the amount of REM sleep increases to compensate for this deprivation. The REM stage is when most apneas and hypopneas occur, so the risk of hypoxemia is greatest in the REM stage. As a result, respiratory and cardiovascular complications such as arrhythmias can increase.

OSA AND THE PREOPERATIVE EVALUATION

Risk factors for OSA

The top portion of Table 1 lists factors that reduce upper airway size or predispose to upper airway collapse and thereby increase risk for OSA. Fortunately, anesthesiologists are frequently aware of the craniofacial abnormalities listed in the table because they affect ease of intubation. The inclusion of menopausal status reflects the fact that women tend to catch up with men in their risk for OSA by the time they reach menopause.

Additionally, certain aspects of perioperative management can increase the risk of OSA in the perioperative setting. For example, general anesthesia can mimic the effects of sleep on the airway, reducing muscle tone and potentially leading to pharyngeal collapse. Normal response to hypercapnia is also diminished under general anesthesia and while patients remain sedated postoperatively, which subdues normal protective arousal mechanisms. This does not pose a problem while the patient remains intubated but highlights the need for respiratory monitoring in the extubated patient who is recovering from the residual effects of sedation.

History and physical examination

What to look for. A number of physical characteristics reveal potential risks for OSA. Obesity and hypertension are well established, as noted above. Large neck circumference (≥ 17 inches in men and ≥ 16 inches in women) is another characteristic associated with OSA. Examination of the upper airway can reveal obstruction due to tonsil enlargement, nasal obstruction, an elongated uvula, or macroglossia. Since retrognathia or micrognathia can produce a narrowed oropharynx, attention to mandible size and position is advised. 

Ask about sleep habits. Assessment of OSA risk in the preoperative evaluation need not be lengthy, but patients should be asked about snoring and waking habits, especially frequency of night wakening, to identify possible OSA. Patients generally do not volunteer information about sleep, so it is important to explicitly ask. Responses that suggest OSA include reports of tiredness or sleepiness during the day, or comments by a partner about the patient’s snoring. A patient who reports having a dry mouth in the morning may have nasal congestion or obstruction that leads to mouth breathing. Severe sleep disruption can lead to sleep deprivation, causing personality changes, confusion, intellectual impairment, impotence, or morning headaches (Table 1).

Preoperative screening tools. Screening tools can assist in identifying relevant questions about sleep. Three such tools for OSA have been validated for use in surgical patients: the Berlin questionnaire, the American Society of Anesthesiologists (ASA) checklist, and the STOP questionnaire.^17–20 The performance of these tools was evaluated in 177 surgical patients with OSA identified using polysomnography.¹⁷ Each tool’s sensitivity, specificity, and positive and negative predictive values were calculated according to polysomnography-based AHI severity. All three tools demonstrated moderately high sensitivity for detecting OSA.¹⁷

Use of any of these screening tools improves the likelihood of identifying OSA preoperatively. The quickest and simplest to use is the STOP questionnaire, which was recently modified to include questions about additional risk factors for OSA—body mass index, age, neck circumference, and gender; the modified tool is called the STOP-BANG questionnaire (Table 2).²⁰ In a validation study, the addition of the “BANG” questions about these risk factors increased the questionnaire’s specificity for moderate to severe OSA.²⁰ It is important to ask the questions as they are written (Table 2) to elicit the most complete response. For example, the question “Do you feel tired, fatigued, or sleepy?” may seem redundant, but all three terms should be included because men often complain of feeling sleepy while women are more likely to report feeling tired or fatigued.

Identifying levels of OSA severity. Physical examination and screening questions may be adequate to identify patients at risk for OSA prior to surgery. Mild OSA (AHI score of 5–15) can generally be managed after surgery, at the patient’s leisure. In contrast, moderate OSA (AHI score of 15–30) and severe OSA (AHI score > 30) can affect perioperative management (see next section). If moderate to severe OSA is suspected, and if there is enough time before surgery to consult a sleep lab, polysomnography can provide a more complete diagnosis.

 

 

PERIOPERATIVE MANAGEMENT OF OSA

When in doubt, proceed as if patient has OSA

Evidence of OSA’s association with postoperative complications is emerging, as noted above, but more specific information about risks is needed to develop effective management procedures. For surgical patients who are deemed to be at high risk for OSA, and for whom surgery cannot be delayed for diagnostic tests and OSA treatment, the most prudent course is to proceed with surgery but assume the patient has moderate to severe OSA. Anesthesiologists should be informed when patients are likely to have OSA, as they may choose a different strategy for managing anesthesia during surgery for patients at high risk. 

Management recommendations

The ASA published practice guidelines in 2006 for the perioperative management of patients with OSA.¹⁹ In view of the paucity of data on the best management strate­gies, the guidelines were based mostly on expert opinion. Their key recommendations include the following:

• Surgical patients should be screened clinically to determine their OSA risk. Any of the aforementioned screening tools is effective for this purpose. 
• For patients with a diagnosis of OSA or who are clinically determined to be at high risk, close attention to airway management is required, extubation should be done when the patient is fully awake (to reduce residual effects of anesthesia and sedatives), and regional anesthesia should be used whenever possible.
• Postoperative pain management in patients with confirmed or suspected OSA should minimize the use of opioids and other sedatives. Such patients also should undergo close pulse oximetry monitoring in a step-down setting after surgery and receive postoperative CPAP therapy as soon as possible.

These ASA recommendations are broadly echoed by a 2003 clinical practice review report of the American Academy of Sleep Medicine, which recommends careful attention during the first 24 hours after surgery in patients with presumed OSA and also cautions that patient-controlled analgesia may not be appropriate.²¹

Future research questions

Even with the insights reviewed above, many questions about perioperative management of OSA remain, including the following:

• Will the early diagnosis and treatment of OSA—usually with CPAP—improve perioperative and postoperative outcomes?
• What are the costs associated with observed complications of OSA, and will immediate and continued use of CPAP postoperatively prove cost-effective?
• Where should patients with OSA be monitored postoperatively, and for how long?
• Which pain-control strategies are best for patients with OSA?

DISCUSSION

Question from the audience: Have studies of OSA-associated postoperative complications stratified results on the basis of AHI score? 

Dr. Shafazand: Yes. In most studies, postoperative complications are more likely to occur among patients with AHI scores that indicate moderate to severe OSA. However, although the AHI is used extensively as a measure of OSA severity, it may not be the best measure. The degree and duration of oxygen desaturation are probably more relevant to the physiologic changes that occur than is the actual apnea or hypopnea event. The more severe the hypoxemia, the greater the risk of complications.

Comment from the audience: I want to reiterate the point from earlier in this summit that consultant physicians should avoid recommending a type of anesthetic in a preoperative consult. Despite the recommendations of the 2006 ASA guidelines,¹⁹ many anesthesiologists prefer to use a minimal opioid technique or a general anesthetic for patients with OSA rather than risk losing the airway during the operation and having to perform an emergent intubation.

Dr. Shafazand: I agree. In my own consultations I never presume to make recommendations about the type of anesthesia to be used. The important thing is to have a discussion with the anesthesiologist about the best way to manage patients with OSA, but not in the intraoperative context because the patient is going to be intubated and the airway will be protected. The discussion is really more about how to manage patients once they are extubated.

Question from the audience: Should patients with OSA undergo surgery in outpatient facilities?

Dr. Shafazand: It depends on the type and duration of the procedure. If it is a quick procedure, which is likely for an outpatient facility, with minimal sedation and a period of respiratory observation to ensure that the patient is fully awake, the outpatient setting is probably acceptable, especially if the patient is using CPAP at home. It also depends on the severity of OSA. For patients with more severe OSA, an outpatient facility is not recommended. Unfortunately, data about OSA complications in outpatient facilities are sparse.

Question from the audience: What is the role of overnight pulse oximetry versus a sleep study?

Dr. Shafazand: That is the Achilles’ heel of managing patients with OSA. Sleep labs are overbooked, so it is often not possible to order a sleep study for patients prior to surgery. Some studies have evaluated overnight pulse oximetry, noting the percentage of desaturation or the total time spent at less than 90% saturation during the night or per hour. This approach is probably adequate for screening for suspected severe OSA, but not all patients with OSA will have desaturations. Overnight pulse oximetry is at best a “poor man’s” screening tool—if it is negative, OSA cannot be ruled out.

Question from the audience: What is your opinion of surgical treatments for sleep apnea such as uvulopalatopharyngoplasty (UPPP)?

Dr. Shafazand: For patients with an AHI score below 15 and no comorbidities, some surgical correction may be advisable. For patients with an AHI score above 15, surgery can be recommended in some circumstances—for example, if there is a clear blockage of the nasal passage. But patients with moderate to severe OSA usually continue to require CPAP therapy after surgery. CPAP is still the recommended treatment for moderate to severe OSA, though surgery might help the patient tolerate CPAP better in certain instances by lowering the pressure requirements.

Question from the audience: A minimal number of hospitals actually screen patients for OSA and treat them differently. Do you know why the Joint Commission dropped a proposed safety goal to screen patients for OSA upon admission and treat based on the results?

Dr. Shafazand: I think the biggest problem is that results from the literature are so variable in terms of risks that it’s difficult to draw conclusions. Patients with desaturation are given oxygen to address the immediate problem, but there is no focus on complications. Depending on the study, there are true complications that affect patient safety but also add to the costs of care. Until there are more definitive results in the literature, there is not enough evidence to make and enforce recommendations.

Obstructive sleep apnea (OSA) is characterized by repeated complete or partial collapse of the pharyngeal airway during sleep, causing cessation of airflow (apnea) or shallow breathing (hypopnea). Persons with OSA may have repeated arousals from sleep (to reestablish breathing) with each episode of apnea or hypopnea. The resulting sleep disruption often leads to daytime somnolence and compromised neurocognitive function.

This pattern of sleep arousal, coupled with intermittent hypoxemia, is associated with serious adverse cardiovascular outcomes, including stroke. Among surgical patients, OSA is associated with postoperative complications and the need for increased medical intervention. This review discusses why OSA is important in the perioperative setting, preoperative screening for OSA risk, and perioperative management of patients with likely or confirmed OSA.

OSA AT A GLANCE

Prevalence in the general population

Four percent of middle-aged men and 2% of middle-aged women meet minimal diagnostic criteria for OSA, according to a landmark cohort study from the 1990s.¹ This makes OSA more common than asthma among adults. Risk increases with age, as 24% of persons older than 65 years have OSA and up to 50% of nursing home residents have clinically significant OSA.²

Prevalence in the surgical population

The prevalence of OSA in the surgical population is higher than that in the general population, and it can vary widely according to the underlying medical condition. A study of 433 patients undergoing general surgery reported a 3.2% prevalence of OSA,³ but this study excluded patients undergoing cardiac surgery, in whom the risk of OSA is higher. In contrast, the prevalence of OSA among obese bariatric surgery patients has been reported at greater than 70%.⁴ Notably, the patients in the general surgery study³ who appeared to be at risk for OSA based on screening questions were invited to participate in a sleep study, whereas all patients in the bariatric surgery study⁴ were evaluated through sleep studies. It is likely that the prevalence of OSA among the general surgery study patients would have been higher if all patients had been evaluated with polysomnography.

Pathophysiology

OSA can occur when any part of the upper airway does not function normally. Upper airway patency is determined by muscle activity, craniofacial and soft tissue structure, and sleep state. During sleep, upper airway muscles are relaxed, which reduces airway patency. Sleep is associated with pharyngeal narrowing and substantially increased inspiratory resistance even among persons without sleep apnea. A person who is awake can compensate for abnormal pharyngeal function through increased muscle activity. During sleep this muscle compensation fails, resulting in partial collapse and subsequent snoring, and sometimes prolonged obstructive hypoventilation. Complete closure results in apnea.

WHY OSA MATTERS

Health consequences of OSA

OSA is associated with serious health consequences, such as increased risk of motor vehicle accidents, stroke, and a number of cardiovascular conditions—hypertension, coronary artery disease, and atrial fibrillation.

Accidents. The daytime hypersomnolence resulting from OSA contributes to reduced vigilance and is likely responsible for an increased incidence of motor vehicle accidents. One study found that among a sample of men and women with unrecognized OSA undergoing polysomnography studies, the likelihood of motor vehicle accidents during the prior 5 years was significantly correlated with the subjects’ apnea-hypopnea index (AHI) score, which reflects the number of apnea or hypopnea episodes per hour of sleep.⁵ Other studies have demonstrated similar associations.

Stroke. Numerous observational studies have demonstrated an elevated prevalence of OSA among patients with stroke as compared with the general population, but these studies did not adjust for other cerebrovascular risk factors. A recent observational cohort study aimed to address this evidence gap by using proportional hazards analysis to determine the independent effect of OSA on the incidence of stroke or death from any cause among persons with no history of stroke or myocardial infarction.⁶ Study participants were 1,022 consecutive patients who underwent polysomnography for evaluation of sleep-disordered breathing. OSA was identified in 68% of patients. During the 3.4-year follow-up period, 22 strokes and 50 deaths occurred among the 697 patients with OSA compared with 2 strokes and 14 deaths among the 325 patients without OSA. The probability of survival was significantly lower for patients with OSA compared with their counterparts without OSA (P < .003). After adjustment for other risk factors, OSA was significantly associated with stroke or death (hazard ratio = 1.97; 95% CI, 1.12–3.48).⁶

Hypertension. Four large studies involving a total of 10,708 patients evaluated for sleep-disordered breathing have established an association between OSA and hypertension risk.^7–10 In each study, the risk of hypertension rose linearly with AHI scores. Clinically significant OSA, defined as an AHI score greater than 15, roughly doubled the risk of hypertension compared with the absence of apnea/hypopnea episodes, with odds ratios ranging from 1.37 to 2.89 across the four studies.^7–10 Each apnea event per hour of sleep was estimated to increase the odds of developing hypertension by approximately 1%.⁸ Notably, the effects of OSA on blood pressure are most pronounced in patients younger than age 50.⁷

Coronary artery disease. The Sleep Heart Health Study evaluated the association between sleep-disordered breathing and cardiovascular disease in 6,424 community-dwelling adults undergoing home polysomnography.¹¹ The population’s median AHI score was 4.4. At least one cardiovascular event was reported by 16% of partici­pants. Sleep-disordered breathing was associated with self-reported heart failure, stroke, and, more modestly, coronary artery disease. A linear relationship was noted between AHI and cardiovascular risk.

Snoring, which is often an indicator for OSA, has also been associated with cardiovascular risk. The Nurses’ Health Study evaluated 71,000 women who completed medical questionnaires that included questions about snoring. Over 8 years of follow-up, the relative risks for cardiovascular disease were 1.46 among occasional snorers (95% CI, 1.23–1.74) and 2.02 among regular snorers (95% CI, 1.62–2.53) in comparison with nonsnorers. Snoring, even without a diagnosis of OSA, emerged as an independent risk factor for cardiovascular disease.¹²

Atrial fibrillation. OSA has been identified as a predictor of new-onset atrial fibrillation in a retrospective cohort study (hazard ratio = 2.18; 95% CI, 1.34–3.54).¹³ In a prospective study, patients with atrial fibrillation but normal left ventricular function were found to have significantly higher AHI scores than matched normal controls.¹⁴ After adjustment for relevant covariates, the odds ratio for an association between atrial fibrillation and significant sleep-disordered breathing (AHI score > 15) was 3.04 (95% CI, 1.24–7.46).¹⁴ In another prospective trial, patients with atrial fibrillation and OSA who underwent cardioversion were at increased risk for a recurrence of atrial fibrillation if OSA was untreated (82% for untreated vs 42% for treated OSA; P = .013).¹⁵

 

 

An association with postoperative complications

OSA also has been shown to increase postoperative complication rates, increase the need for intensive care intervention, and prolong hospital stays. 

Representative evidence. One of the first studies to characterize the postoperative risks of OSA was conducted by Mayo Clinic researchers who retrospectively reviewed 4 years of data for 101 patients with OSA who had had hip or knee replacement surgery within 3 years before (n = 36) or any time after (n = 65) their OSA diagnosis.¹⁶ Outcomes were compared with those of 101 matched controls without OSA who underwent the same operations. Only half the patients with diagnosed OSA prior to their operation used continuous positive airway pressure (CPAP) therapy at home prior to hospitalization. Complications occurred among 39% of patients with OSA and among 18% of control patients (P = .001). Serious complications requiring intensive care unit transfer for cardiac ischemia or respiratory failure occurred in 24% of patients with OSA versus only 9% of controls (P = .004), and hospital stays were longer for patients with OSA compared with controls (P < .007). Most complications occurred during the first day after surgery, but a small number occurred as late as postoperative days 4 and 5.

In a separate study designed to evaluate OSA screening tools, postoperative complication rates were assessed in 211 patients who underwent polysomnography to determine the presence or absence of OSA prior to elective surgery.¹⁷ Patients undergoing various elective procedures were included, but none were undergoing cardiac or bariatric procedures. The overall rate of postoperative complications was more than twice as high among patients with OSA compared with those without OSA (27.4% vs 12.3%; P = .02). The most common complication was oxygen desaturation (ie, level ≤ 90%), which occurred among 20.6% of patients with OSA versus 9.2% of patients without OSA (P < .04). There were no deaths or serious complications.

Potential causes of complications. In the immediate postoperative period, OSA-associated complications may be attributable to lingering effects of sedatives, which can often lead to respiratory problems. Later in the postoperative course, so-called REM rebound is more likely to be implicated in complications. Patients often experience sleep deprivation in the hospital due to constant interruptions. Once a patient does sleep, the amount of REM sleep increases to compensate for this deprivation. The REM stage is when most apneas and hypopneas occur, so the risk of hypoxemia is greatest in the REM stage. As a result, respiratory and cardiovascular complications such as arrhythmias can increase.

OSA AND THE PREOPERATIVE EVALUATION

Risk factors for OSA

The top portion of Table 1 lists factors that reduce upper airway size or predispose to upper airway collapse and thereby increase risk for OSA. Fortunately, anesthesiologists are frequently aware of the craniofacial abnormalities listed in the table because they affect ease of intubation. The inclusion of menopausal status reflects the fact that women tend to catch up with men in their risk for OSA by the time they reach menopause.

Additionally, certain aspects of perioperative management can increase the risk of OSA in the perioperative setting. For example, general anesthesia can mimic the effects of sleep on the airway, reducing muscle tone and potentially leading to pharyngeal collapse. Normal response to hypercapnia is also diminished under general anesthesia and while patients remain sedated postoperatively, which subdues normal protective arousal mechanisms. This does not pose a problem while the patient remains intubated but highlights the need for respiratory monitoring in the extubated patient who is recovering from the residual effects of sedation.

History and physical examination

What to look for. A number of physical characteristics reveal potential risks for OSA. Obesity and hypertension are well established, as noted above. Large neck circumference (≥ 17 inches in men and ≥ 16 inches in women) is another characteristic associated with OSA. Examination of the upper airway can reveal obstruction due to tonsil enlargement, nasal obstruction, an elongated uvula, or macroglossia. Since retrognathia or micrognathia can produce a narrowed oropharynx, attention to mandible size and position is advised. 

Ask about sleep habits. Assessment of OSA risk in the preoperative evaluation need not be lengthy, but patients should be asked about snoring and waking habits, especially frequency of night wakening, to identify possible OSA. Patients generally do not volunteer information about sleep, so it is important to explicitly ask. Responses that suggest OSA include reports of tiredness or sleepiness during the day, or comments by a partner about the patient’s snoring. A patient who reports having a dry mouth in the morning may have nasal congestion or obstruction that leads to mouth breathing. Severe sleep disruption can lead to sleep deprivation, causing personality changes, confusion, intellectual impairment, impotence, or morning headaches (Table 1).

Preoperative screening tools. Screening tools can assist in identifying relevant questions about sleep. Three such tools for OSA have been validated for use in surgical patients: the Berlin questionnaire, the American Society of Anesthesiologists (ASA) checklist, and the STOP questionnaire.^17–20 The performance of these tools was evaluated in 177 surgical patients with OSA identified using polysomnography.¹⁷ Each tool’s sensitivity, specificity, and positive and negative predictive values were calculated according to polysomnography-based AHI severity. All three tools demonstrated moderately high sensitivity for detecting OSA.¹⁷

Use of any of these screening tools improves the likelihood of identifying OSA preoperatively. The quickest and simplest to use is the STOP questionnaire, which was recently modified to include questions about additional risk factors for OSA—body mass index, age, neck circumference, and gender; the modified tool is called the STOP-BANG questionnaire (Table 2).²⁰ In a validation study, the addition of the “BANG” questions about these risk factors increased the questionnaire’s specificity for moderate to severe OSA.²⁰ It is important to ask the questions as they are written (Table 2) to elicit the most complete response. For example, the question “Do you feel tired, fatigued, or sleepy?” may seem redundant, but all three terms should be included because men often complain of feeling sleepy while women are more likely to report feeling tired or fatigued.

Identifying levels of OSA severity. Physical examination and screening questions may be adequate to identify patients at risk for OSA prior to surgery. Mild OSA (AHI score of 5–15) can generally be managed after surgery, at the patient’s leisure. In contrast, moderate OSA (AHI score of 15–30) and severe OSA (AHI score > 30) can affect perioperative management (see next section). If moderate to severe OSA is suspected, and if there is enough time before surgery to consult a sleep lab, polysomnography can provide a more complete diagnosis.

 

 

PERIOPERATIVE MANAGEMENT OF OSA

When in doubt, proceed as if patient has OSA

Evidence of OSA’s association with postoperative complications is emerging, as noted above, but more specific information about risks is needed to develop effective management procedures. For surgical patients who are deemed to be at high risk for OSA, and for whom surgery cannot be delayed for diagnostic tests and OSA treatment, the most prudent course is to proceed with surgery but assume the patient has moderate to severe OSA. Anesthesiologists should be informed when patients are likely to have OSA, as they may choose a different strategy for managing anesthesia during surgery for patients at high risk. 

Management recommendations

The ASA published practice guidelines in 2006 for the perioperative management of patients with OSA.¹⁹ In view of the paucity of data on the best management strate­gies, the guidelines were based mostly on expert opinion. Their key recommendations include the following:

• Surgical patients should be screened clinically to determine their OSA risk. Any of the aforementioned screening tools is effective for this purpose. 
• For patients with a diagnosis of OSA or who are clinically determined to be at high risk, close attention to airway management is required, extubation should be done when the patient is fully awake (to reduce residual effects of anesthesia and sedatives), and regional anesthesia should be used whenever possible.
• Postoperative pain management in patients with confirmed or suspected OSA should minimize the use of opioids and other sedatives. Such patients also should undergo close pulse oximetry monitoring in a step-down setting after surgery and receive postoperative CPAP therapy as soon as possible.

These ASA recommendations are broadly echoed by a 2003 clinical practice review report of the American Academy of Sleep Medicine, which recommends careful attention during the first 24 hours after surgery in patients with presumed OSA and also cautions that patient-controlled analgesia may not be appropriate.²¹

Future research questions

Even with the insights reviewed above, many questions about perioperative management of OSA remain, including the following:

• Will the early diagnosis and treatment of OSA—usually with CPAP—improve perioperative and postoperative outcomes?
• What are the costs associated with observed complications of OSA, and will immediate and continued use of CPAP postoperatively prove cost-effective?
• Where should patients with OSA be monitored postoperatively, and for how long?
• Which pain-control strategies are best for patients with OSA?

DISCUSSION

Question from the audience: Have studies of OSA-associated postoperative complications stratified results on the basis of AHI score? 

Dr. Shafazand: Yes. In most studies, postoperative complications are more likely to occur among patients with AHI scores that indicate moderate to severe OSA. However, although the AHI is used extensively as a measure of OSA severity, it may not be the best measure. The degree and duration of oxygen desaturation are probably more relevant to the physiologic changes that occur than is the actual apnea or hypopnea event. The more severe the hypoxemia, the greater the risk of complications.

Comment from the audience: I want to reiterate the point from earlier in this summit that consultant physicians should avoid recommending a type of anesthetic in a preoperative consult. Despite the recommendations of the 2006 ASA guidelines,¹⁹ many anesthesiologists prefer to use a minimal opioid technique or a general anesthetic for patients with OSA rather than risk losing the airway during the operation and having to perform an emergent intubation.

Dr. Shafazand: I agree. In my own consultations I never presume to make recommendations about the type of anesthesia to be used. The important thing is to have a discussion with the anesthesiologist about the best way to manage patients with OSA, but not in the intraoperative context because the patient is going to be intubated and the airway will be protected. The discussion is really more about how to manage patients once they are extubated.

Question from the audience: Should patients with OSA undergo surgery in outpatient facilities?

Dr. Shafazand: It depends on the type and duration of the procedure. If it is a quick procedure, which is likely for an outpatient facility, with minimal sedation and a period of respiratory observation to ensure that the patient is fully awake, the outpatient setting is probably acceptable, especially if the patient is using CPAP at home. It also depends on the severity of OSA. For patients with more severe OSA, an outpatient facility is not recommended. Unfortunately, data about OSA complications in outpatient facilities are sparse.

Question from the audience: What is the role of overnight pulse oximetry versus a sleep study?

Dr. Shafazand: That is the Achilles’ heel of managing patients with OSA. Sleep labs are overbooked, so it is often not possible to order a sleep study for patients prior to surgery. Some studies have evaluated overnight pulse oximetry, noting the percentage of desaturation or the total time spent at less than 90% saturation during the night or per hour. This approach is probably adequate for screening for suspected severe OSA, but not all patients with OSA will have desaturations. Overnight pulse oximetry is at best a “poor man’s” screening tool—if it is negative, OSA cannot be ruled out.

Question from the audience: What is your opinion of surgical treatments for sleep apnea such as uvulopalatopharyngoplasty (UPPP)?

Dr. Shafazand: For patients with an AHI score below 15 and no comorbidities, some surgical correction may be advisable. For patients with an AHI score above 15, surgery can be recommended in some circumstances—for example, if there is a clear blockage of the nasal passage. But patients with moderate to severe OSA usually continue to require CPAP therapy after surgery. CPAP is still the recommended treatment for moderate to severe OSA, though surgery might help the patient tolerate CPAP better in certain instances by lowering the pressure requirements.

Question from the audience: A minimal number of hospitals actually screen patients for OSA and treat them differently. Do you know why the Joint Commission dropped a proposed safety goal to screen patients for OSA upon admission and treat based on the results?

Dr. Shafazand: I think the biggest problem is that results from the literature are so variable in terms of risks that it’s difficult to draw conclusions. Patients with desaturation are given oxygen to address the immediate problem, but there is no focus on complications. Depending on the study, there are true complications that affect patient safety but also add to the costs of care. Until there are more definitive results in the literature, there is not enough evidence to make and enforce recommendations.

Weiner Center for Preoperative Evaluation at Brigham and Women’s Hospital

By Angela M. Bader, MD, MPH

When organizing our preoperative clinic at Brigham and Women’s Hospital, we had several goals. Overall, we wanted a standardized process to help us achieve a high level of excellence. We hoped that creating a new system would eliminate ambiguity about who was responsible for following up on a patient’s abnormal laboratory test result—the surgeon, anesthesiologist, or primary care physician. We also wanted to better coordinate the various care teams involved throughout the perioperative period.

STANDARDIZATION HELPS MEET MANY GOALS

Standardization can occur at many levels:

• Performance of assessments and testing
• Organization of the patient chart and medical records
• Systems checks throughout the process to ensure that nothing is missed
• Team-to-team communication.

Documentation requirements apply regardless of institutional structure

When considering any system of preoperative assessment, keep in mind that the hospital must meet and appropriately document compliance with all regulatory, accreditation, and payer requirements and guidelines, such as those of the Joint Commission, the Centers for Medicare and Medicaid Services (CMS), and the National Surgical Quality Improvement Program. For example, the Joint Commission requires that a surgical history and physical examination be done within 30 days of a procedure. An anesthesiology assessment and a nursing assessment are also required. All of these assessments have mandatory elements, including documenting “never events” and ordering appropriate laboratory tests, electrocardiograms (ECGs), and radiographs.

Sometimes administrators of other hospitals say to me, “We can’t afford a preoperative clinic, and we don’t need one.” My response is that regardless of whether a hospital has a preoperative clinic, the regulatory requirements and guidelines must be met: it is not an issue of avoiding certain steps. Having a dedicated preoperative clinic simply shifts the work to a standardized, centralized system and avoids delaying these required steps until the day of surgery, when taking care of a problem involves the most inefficient use of resources.

Tailor system to institutional needs and characteristics

Within the regulatory framework, the organizational scheme of every institution must address issues of volume and acuity, the types of surgery performed, and the time frames required. A system must be able to deal with the preoperative needs of patients undergoing operations that are booked weeks in advance (often the case for ortho­pedic surgery) as well as those that may not be booked until a day before the procedure (eg, cancer surgery).

Our plan was developed for our very high-volume, tertiary care institution. In 2008, 24,000 patients used our clinic (roughly 100 patients per day).

DESIGN OF THE PREOPERATIVE CLINIC

A nurse practitioner–based model for ‘one-stop shopping’

We decided that the clinic should offer all elements of the preoperative assessment and thereby give patients “one-stop shopping.” Each patient sees a nurse practitioner, who performs the surgical history and physical examination as well as the anesthesiology and nursing assessments. The result is a multidisciplinary approach with a single assessment output. We shifted employees who had been responsible for preoperative assessment in the offices of various surgeons to a central clinic so that all assessments could be standardized, and we provided additional training to enable them to perform various assessments. The nurse practitioners are supervised by an on-site attending physician, as detailed below.

This model offers a number of advantages:

• Patients see a single provider.
• Assessment is facilitated for our surgeons, who may not be completely up-to-date on perioperative risk assessment and management.
• We have a central location for standardized education programs for our physicians, nurses, and residents.
• The clinic’s standardized records and processes facilitate data generation for research and clinical practice improvement.

Independent budgetary and staffing structure

The preoperative clinic is a separate cost center under the leadership of the department of anesthesiology. Resources were shifted to a central location so that as volume increases, we can add resources to meet the additional volume. We contracted with the hospital administration to provide payment for two full-time-equivalent anesthesiologists per day, who serve as on-site attending physicians. The hospital is willing to do this because not only do these attending physicians supervise the anesthesiology assessment, they are the collaborating physicians for the entire perioperative assessment. They review every patient, order tests and write prescriptions as needed, and discuss issues with the primary care physicians and referring specialists.

The preoperative clinic has an anesthesiologist director (me) who reports directly to the hospital’s vice president for surgical services on budget and staffing issues. I also report to the chairman of the department of anesthesiology, though he is not involved in budgetary functions (the hospital contracts with him to provide the anesthesiology staffing). The clerical and nursing staff work directly for the clinic.

The clinic is run in a self-contained area with a central waiting room and space for doing all the assessments and laboratory work internally, including 16 examination rooms and a room for chart organization.

 

 

MORE BENEFITS OF STANDARDIZATION

Standardized scheduling ensures reliability

The secretaries in each surgeon’s office schedule appointments through a central computer system after registration and insurance precertification. Our computer system does not allow an operation to be scheduled without an evaluation also being scheduled. The evaluation can involve either a visit or a telephone screen; we provide algorithms so that the surgeons’ secretaries know which is required. This system has substantially reduced the number of walk-ins, allowing for a more even distribution of patients and ensuring that medical records will be available when a patient is seen.

We watch our schedule carefully. Our computer system monitors the time that each patient is in our clinic to determine his or her waiting time and assessment time. It takes about 75 minutes to go through the whole process, including the time for a nurse practitioner to do the surgical history and physical examination and the anesthesiology and nursing assessments, a laboratory technician to do an ECG and laboratory tests if indicated, and completion of all required documentation. Accordingly, patients are scheduled in 75-minute blocks between 7:00 am and 6:30 pm. We do not have evening or weekend hours because of the difficulty of contacting surgeons and primary care physicians when questions arise. It is simply not cost-effective to have to do that type of follow-up on a case after the patient leaves.

Only about 10% of our patients are screened by telephone, since most of our operations are complicated and require in-person assessment (most low-acuity procedures are done at other hospitals). Of the patients who visit the preoperative clinic, about 75% undergo the single assessment model for surgery, anesthesiology, and nursing as described above. The remaining 25% of patients have their history and physical exam completed outside Brigham and Women’s Hospital for insurance reasons; the remainder of their assessment is conducted in our preoperative clinic by a registered nurse and an anesthesiology resident.

Multiple systems checks

Our model also incorporates standardization in the form of multiple systems checks:

• Case presentation. Every case is presented to an attending anesthesiologist, who reviews the ECG (if ordered) before the patient leaves the clinic.
• Post-visit chart check. A registered nurse or nurse practitioner signs off on each chart after the visit, confirming test results and resolution of all paperwork issues.
• Surgical checklist. The end result is a checklist that serves as the front sheet of the operating room chart.

Our ability to use this system of checks to get the chart completed comprehensively and reliably and deliver it to the operating room when needed was key to securing institutional support and funding for the preoperative clinic.

ROLE OF THE ATTENDING ANESTHESIOLOGISTS

Two full-time attending anesthesiologists are present in the preoperative clinic each day. One is responsible largely for supervising the nurse practitioner assessments and reviewing case presentations, while the other also oversees the education and supervision of residents. Residents rotate through the clinic for 2 weeks (one or two at a time) and have a designated curriculum consisting of daily lectures and competencies in preoperative evaluation.

Because our anesthesiologists are expert in pre­operative assessment, we require very few outside consults. We can communicate directly with the cardiologists and other physicians and order tests when indicated. We have a clerical assistant who obtains all necessary paperwork and prior testing from outside providers so that the clinicians need not waste time on this.

A GROWING CHALLENGE: ASSESSMENT FOR PROCEDURES IN AMBULATORY SETTINGS

Looking forward, a rapidly growing challenge facing our clinic stems from the tremendous growth in patients who require anesthesia for procedures performed outside the operating room. In these situations, the proceduralists need a system for deciding whether an anesthesiologist must be present for any given case.

We have started to develop appropriate screening processes to ensure that the proceduralists in multiple departments know which patients to refer for pre­procedure assessment. We hope to soon develop protocols for high-risk patients and for various procedures such as implanting a pacemaker or defibrillator, catheter procedures, interventional radiology, and endoscopy.

 

 

Anesthesia Perioperative Medicine Clinic at University of Chicago

By BobbieJean Sweitzer, MD

Detsky and Naglie have argued that the costs and clinical outcomes associated with any intervention must be compared with those of alternate strategies for treating the same patients,¹ and I believe their point applies well to preoperative clinics. Although certain requirements of the Joint Commission and CMS must be met, as noted by Dr. Bader, they can be met in various ways. I will preface my comments by emphasizing that one size does not fit all: every institution must decide the best approach to preoperative assessment based on its patient population, the types of procedures it performs, and the volume it handles. 

TRIAGE STREAMLINES THE PROCESS

Our preoperative clinic at the University of Chicago emphasizes triage. Not every patient should have to go to the trouble of coming in to see a provider. In the future, we will likely see more “virtual” preoperative assessments using devices in development, such as handheld ultrasonography machines. Just as patients can have their pacemakers and implantable cardiac defibrillators remotely checked via phone contact, more tools will one day be available for remote assessment.

Although not every surgical patient needs to come in to the preoperative clinic, every patient must have a physical examination. All patients will be seen on the day of surgery, so in some cases the physical exam may be able to wait until then. For example, an airway assessment need not be done ahead of time. Most anesthesiologists are prepared to manage airways on very short notice, so extensive advance planning is not always necessary.

Obtain basic info by questionnaire to save staff time

Information about the patient is key to triage, and it may be either paper- or computer-based. An initial priority should be to develop some mechanism for getting information from patients before the day of their procedure without a visit to the hospital or ambulatory surgery center.

We use a two-page paper questionnaire to obtain basic information from patients, including (among other pertinent questions) age, planned operation, names of the surgeon and primary doctor, past operations and medical history, allergies, a list of medications, social history (drug, alcohol, tobacco use), whether they have ever taken steroids, whether they have high blood pressure, and whether they can comfortably walk up a flight of stairs. We provide the primary care physicians and surgeons with blank questionnaires, which their patients can fill out in their waiting rooms or take home and fax to us (or drop off) later. The questionnaire gives us a good deal of essential information without using staff time.

Various computer-based and Web-based systems are also available for collecting basic patient information. Smaller institutions need not purchase an entire electronic medical record system, which can be very expensive. Some Web-based tools operate on a pay-per-use basis and can be very helpful.

Review the information to guide triage

We then review the patient information to determine the extent of preoperative evaluation required. Some patients, especially those scheduled at an ambulatory surgery center, are healthy enough that they can just come in on the day of surgery for an examination and an update of their information. Others will need an appointment at the clinic before the day of surgery for more extensive preoperative evaluation. For other patients, review of their questionnaire responses may prompt a phone call or e-mail from the clinic for more information to determine whether a day-of-surgery exam will suffice or whether evaluation in advance is needed. When in doubt, concerns raised by the questionnaire should be explored before the day of surgery to avoid surprises and allow sufficient time for a consultation, if needed.

STANDARDIZED GUIDELINES KEEP CARE CONSISTENT

We encourage our staff to minimize preoperative testing and ECGs. A majority of diagnoses are made based on the history and physical exam.² Generally, a test should confirm what is already suspected and merely provide objective evidence when needed. Testing in this setting should not be done to “find out what is wrong” with a patient.

It is helpful to develop standardized guidelines for preoperative assessment and make them available to everyone in the institution via the Web. The guidelines should address recommended preoperative tests and management practices according to specific patient conditions or surgical procedures. The clear objective is to avoid disagreement about what a patient needs between the provider who evaluated the patient in advance and the surgeon or anesthesiologist who evaluates the patient on the day of surgery.

Our guidelines at the University of Chicago include recommendations for patients on long-term anticoagulant therapy, for patients with coronary stents, for medications that should be discontinued (and those that may be continued) on the day of surgery, and for numerous other conditions and issues. Our testing guidelines list indicated tests for various medical problems, which in turn link to other guidelines. Other links are based on the medications a patient is using or the type of operation that is planned.

We collaborated with our electrophysiology department to create guidelines for managing patients with pacemakers and defibrillators. Almost every patient with one of these devices has a little card associated with the device, and we ask the surgeons to copy the card and send it to the clinic if we will not be directly seeing the patient. Using a national database, the electro­physiology department can determine from the card the type of pacemaker or defibrillator a patient has, and they fax or e-mail us back a page of instructions to let us know whether the device requires special consideration during surgery, whether it should be checked preoperatively, and whether its battery needs replacing. With this system, we have markedly reduced problems on the day of surgery.

 

 

CONSULTS HAVE AN IMPORTANT ROLE

Consults should never be requested in order to “clear a patient for surgery.” Consult requests should rather address specific issues, such as, “Is this patient medically optimized?” or “Please address this patient’s hypertension.” In turn, consult notes should provide meaningful information that can be used in a specific way. A clearance letter or simple risk assessment is not helpful.

If a patient has not seen a primary care doctor in a long time, a consult request should (in addition to requesting a global risk assessment) specify any particular concerns, such as, “The patient reports snoring; please address sleep apnea and cardiac risk.”

Case study: Beware consult notes with no specifics

Consider a case we encountered of a 54-year-old man who had a preoperative cardiac risk assessment. The cardiology consultant completed a short form consisting of a multiple-choice check-off list indicating low, moderate, or high cardiac risk. The consultant checked that the patient had low cardiac risk but provided no other instructions or information other than his own contact information.

When we reviewed the patient’s questionnaire, we saw that his medications included metoprolol, clopidogrel, and aspirin even though the patient did not mention that he had coronary artery disease. On this basis, we requested details about his cardiac evaluation from his cardiologist. It turned out that the patient had a history of four catheterizations with several cardiac stents placed. The most recent stent was implanted to overlap a previous stent that had been found “floating” in the blood vessel; this last stent was placed just 6 months before the cardiologist issued the consult note indicating “low cardiac risk.”

The moral is to approach consult notes with caution, especially if they offer no specifics. It actually makes me nervous when a note states “low risk” because if something unexpectedly goes wrong in surgery, it appears that the perioperative team took poor care of the patient even if the complication actually may have stemmed from higher-than-recognized underlying patient risk.

PROVIDE, AND REINFORCE, CLEAR INSTRUCTIONS

We give patients written preoperative instructions that become part of our computerized records. We first verbally give explicit instructions for each medication—ie, whether it can be taken as usual or when it needs to be stopped before surgery (and why). Then we provide the same information in writing, after which we try to have the patient repeat the instructions back to the clinician. We include a phone number that patients can call if they need help understanding their preoperative instructions.

Web-based programs also can provide patients online instructions about their medications. Some services even customize information by providing, for example, lists of local surgeons who are willing to allow a patient to continue on aspirin therapy until the day of surgery.

USE THE RIGHT RESOURCES

Staffing

Our model at the University of Chicago relies mainly on residents in training and physician assistants, but advanced nurse practitioners are well suited to a pre­operative clinic as well. These types of providers have background training in history-taking, physical examination, diagnostic testing, and disease management. Registered nurses have more limited abilities, although they may be appropriate for a clinic that deals primarily with healthy patients for whom only history taking and a list of medications is needed. Additionally, our clinic is staffed by one attending anesthesiologist at all times (from among a group of rotating anesthesiologists) as well as medical assistants and clerical staff.

Some clinics perform the surgical history and physical exam at the same time as the anesthesia assessment. I would urge caution with this practice. Just as primary care doctors should not be conducting the anesthesia assessment, nonsurgeons should not be conducting the surgical assessment; doing so puts them out on a limb from a medicolegal standpoint. Advanced nurse practitioners and physician assistants may do surgical assessments under the supervision of a surgeon, but only surgeons should ultimately decide—and document—whether an operation is necessary and what degree of examination is required in advance.

Computer technology for records, messaging, billing

Using electronic medical records and corresponding with colleagues by e-mail make preoperative care much more efficient. We have standardized computer forms for ordering tests and documenting the physical exam. Patients usually understand that electronic medical records are safe and more efficient, and they are often more accepting of their use than practitioners are. Many patients want e-mail access to doctors, to schedule appointments online, and to receive appointment reminders by e-mail.³

Electronic medical records also avoid redundancy. If a patient has been seen in our preoperative clinic and is later scheduled for another surgery (even if a different surgeon is involved), a return visit to our clinic may not be necessary. In some cases, we can send the old work-up stamped “For information only,” which can then be updated by the anesthesiologist on the day of surgery.

A central, standardized process also makes billing more efficient and helps to ensure that payment is received for all services provided. Standardized documentation makes it easier for coders to enter the correct evaluation and management codes and ensures that all required criteria are met.

THE PAYOFF: LIVES AND DOLLARS SAVED

A thorough and efficient preoperative assessment system is cost-effective. Every minute of operating room time is worth $10 to $15,^4,5 so delays should be avoided. Everything that is done ahead of time saves money for the whole enterprise by reducing unnecessary case setups and reducing “down time” due to lack of patient, equipment, or staff readiness. We routinely bill for preoperative evaluations when this service goes beyond a routine preoperative assessment based on CMS (and other insurance) requirements. However, a preoperative evaluation is required by CMS and most payers if one wants to be paid for any anesthesia-provided service. As a result, a cost is incurred without offsetting revenue if a case is cancelled on the day of surgery after one performs the anesthesia evaluation.

A study we published a few years ago showed that patients who were seen in our preoperative clinic were significantly less likely to have day-of-surgery cancellations than were patients not seen in our clinic, a finding that applied to both our ambulatory surgery center and our main operating rooms (Table 1).⁵ These findings held even after adjustment for American Society of Anesthesiologists severity class. In addition, the median delay in surgery start time was significantly less among patients who were seen in the preoperative clinic.

Yesterday I heard someone ask, “Do we really need all this preoperative evaluation? Does it really improve outcomes?” There is some evidence that it does. A study from 2000 based on data from the Australian Incident Monitoring Study found that 11% of the 6,271 critical incidents that occurred following operations were attributable to inadequate preoperative evaluation and that 3% were unequivocally related to problems with preoperative assessment or preparation. More than half of the incidents were deemed preventable.⁶

Preoperative clinics are good for patients and make good sense economically. We just need to demonstrate to our administrators and to payers that we are offering an excellent service.

 

 

Cleveland Clinic IMPACT Center

By Ajay Kumar, MD

Cleveland Clinic is structured differently from most other institutions in that its surgeons, anesthesiologists, and hospitalists are all direct employees of the institution. Despite this unique structure, many aspects of our preoperative clinic—known as the Internal Medicine Preoperative Assessment, Consultation and Treatment (IMPACT) Center—are applicable to other institutions.

Cleveland Clinic is a busy surgical hospital whose preoperative optimization system is designed to provide high-quality care. The IMPACT Center is consulted for most complicated noncardiac surgery patients, and its referral sources include most of the institution’s surgical specialties.

QUEST FOR A BETTER PATIENT EXPERIENCE

When the IMPACT Center was created in 1997, the aim was to focus on the same objectives highlighted by Drs. Bader and Sweitzer: safety, a positive patient experience, enhanced communication, better continuity of care, effective use of resources, and improving throughput by standardizing care.

A prime motivator was the desire to move away from the tendency for presurgical consults to simply “clear the patient for surgery,” and we have indeed evolved considerably from that point. The focus of our peri­operative care program today is to comprehensively evaluate risk by taking into account patient-, procedure-, and anesthesia-related factors.

We offer “one-stop shopping,” and our priority is for efficient throughput. We are located in a 12-story building that includes outpatient, preoperative, and surgical clinics and offices. The IMPACT Center is on the first floor along with the preoperative anesthesia consultation and evaluation (PACE) clinic, the laboratory, and ECG and stress-test labs. Patients can undergo radiographic studies on the second floor.

The patient experience counts for a lot. Many of our patients are from another state or country, so efficiency and convenience are especially important. Patients can usually get all assessment and testing done in a single day.

A TIGHTLY MANAGED PROCESS

A ‘smart’ questionnaire starts the process

Our process (Figure 1) begins in the surgeons’ offices, where a patient is seen by a surgeon and an operation is deemed necessary. There the patient is asked to fill out a computer-assisted health screening questionnaire available online. The questionnaire is very sophisticated: based on the patient’s answers, it asks further pertinent questions and requests details if the history is complicated. A patient with multiple health problems may take 20 minutes to complete it, while a healthy patient may take only 3 minutes.

A computerized report based on the questionnaire guides the surgical office in scheduling the patient to specific areas according to algorithms. Based on case complexity and clinical needs, patients are scheduled for the IMPACT Center along with the PACE clinic; if needed (based on the algorithms), patients also are scheduled for laboratory tests or imaging. This standardized approach helps create a safe passage for patients through the preoperative process with less confusion.

Patient is given a personalized binder

Once all appointments and tests are scheduled, the patient is given a binder containing specific information about the procedure and preoperative instructions. The medical appointment at the IMPACT Center is usually scheduled before the PACE clinic appointment. Patients receive an itinerary for all preoperative appointments and surgical office appointments before the planned surgery. The itinerary is planned so that if additional testing is requested, it can be accommodated on the same day.

At the end of the preoperative assessment, the patient receives printed information with specific preoperative instructions, including which medications to continue or stop.

Standardized, computer-based medical records

Our systems and processes have undergone a good deal of evolution. We have integrated our medical records and use a standard outside medical record retrieval process. The template for the history and physical exam is standard for all Cleveland Clinic patients and is used for all presurgical assessments before all noncardiac surgeries. The template is comprehensive, including the history of the present illness, the review of systems, the physical exam, and anesthesia-related issues. All outside documents are scanned into our electronic medical record system and are available for viewing prior to surgery from any computer connected to the system.

Our preoperative assessment guidelines are also kept updated at a central online location so that all providers have access to them.

Staff keeps process running efficiently

The IMPACT Center is managed by the department of hospital medicine and supported by at least 5.5 full-time physicians every day. We also have two registered nurses, two assistants who help with scheduling and testing, and three secretaries who support the doctors, obtain records, and make arrangements with outside doctors for testing if a patient wants to return home before our testing can be completed.

A secretary also keeps a log for each patient seen in the clinic, tracking all pending issues. The day before surgery, the secretary contacts the appropriate office for anything that is still pending. If she gets no response, the matter is transferred to one of our doctors so that the problem can be resolved at once. This strategy allows us to achieve a nearly 0% rate of surgery delay or cancellation attributable to unavailable test results.

Our patient volumes have increased significantly since we started in 1997. Last year more than 15,000 patients visited the IMPACT Center and now we have expanded our services to regional hospitals within the Cleveland Clinic Health System.

INTERDEPARTMENTAL COMMUNICATION IS CRITICAL

Interdepartmental communication is a must for patient safety, so we encourage a culture of communication between the hospitalist and the surgical team. The location of most of our surgical clinics within the same building as the IMPACT Center further facilitates communication, as does the proximity of the PACE clinic. Additionally, one of our IMPACT Center physicians is accessible around the clock to answer to our surgeon or anesthesiologist colleagues as needed.

We regularly assess our process and seek feedback from surgeons and anesthesiologists. We also conduct yearly patient experience surveys to make sure we are providing patients with the highest quality of care.

 

 

Discussion

Question from the audience: Our anesthesia assessment department was approached by our surgeons to do both the anesthesia and surgical assessments, but we felt that would put us in a potential legal conflict if a patient who was assessed that way developed problems. Can you comment?

Dr. Bader: Although we do surgical assessments at our preoperative clinic, we don’t make any decisions about whether or not to proceed with an operation. We get an office note from the surgeon that is directed specifically toward the need for surgery, indications for surgery, and surgical consent. We perform the surgical history and physical examination. Our process is essentially the same as when surgeons have a physician assistant do the history and physical examination in their office. Our practitioners are employed by the hospital, so there is no conflict of interest there.

Comment from the audience: I’m a strong believer in hands-on patient contact. Over my 15 years of practice, we have encountered a lot of unexpected problems during the preoperative exam—aortic stenoses, infections, ventricular septal defects—all of which would never have been detected from a screening form.

Dr. Sweitzer: I agree that we pick up many things by seeing the patient in person. I’ve picked up more cases of aortic stenosis as an anesthesiologist in the preoperative clinic than I ever did as an internist, because the population is high-risk. But patients who have such problems tend to have risk factors and be in certain age groups. Studies indicate that the history is more important than the physical exam: the history suggests about 75% of conditions that are present. The physical exam adds only a little more—perhaps another 15%. Our recommendations are very much consistent with the American College of Cardiology and American Heart Association guidelines on preoperative cardiac evaluation.⁷ It is more important to identify whether a patient has risk factors for coronary artery disease than to find out whether a stress test or ECG is normal. One needs to do a really good history, but it can be done remotely. Based on certain risk factors identified, high-risk patients can be selected who need to come in and have a physical exam.

Question from the audience: Could you elaborate on the electronic medical record system used at the University of Chicago? I’ve heard there’s a steep learning curve when implementing these kinds of systems. They also are very expensive—I’ve heard that some cost $40 to $80 million. Has enhanced revenue flow offset the costs?

Dr. Sweitzer: We have a home-grown system developed with FileMaker Pro by a computer programmer at our institution. It was a lot easier to develop than people tend to think. There are many savvy computer programmers out there; I’ve had medical students assist me with updating it. We’re now considering developing it as a commercial system. Many systems are available for purchase, including Epic, Pyxis, one from General Electric, and many others. They are very expensive, so smaller institutions might want to use a pay-for-service system.

There definitely is a learning curve to switching to electronic medical records, but it is not nearly as steep as many believe. The extra time it takes a clinician to initially make a computer entry rather than write on paper is vastly recouped downstream: the electronic medical record is legible and organized, and it doesn’t get lost or need to be redone. You can bring up a patient record from 6 months before and reuse it as a template.

Dr. Bader: The discussion of cost savings from preoperative clinics usually focuses on savings from avoiding surgery cancellations and delays and from more efficient laboratory testing, but the biggest savings for an institution is better reimbursement through better diagnosis-related groups (DRG) coding. That’s an important reason our institution is funding our clinic. Electronic medical records allow standardization of information so that coders know exactly where to look for the comorbidities and other pertinent information. This increases payments for DRGs, which can be documented for the hospital. This literally runs into millions of dollars a year and more than offsets the costs of the system.

Question from the audience: Dr. Bader, I’m impressed with the number of patients going through your pre­operative clinic. How many patients are seen per nurse practitioner in your clinic?

Dr. Bader: The nurse practitioners have 10-hour shifts and see one patient every 75 minutes. The process of seeing a patient takes a lot less time now than with the old system, in which patients saw an anesthesiologist plus a nurse. Our current system eliminates redundancy: questions need to be asked only once.

Question from the audience: My compliance office says that preoperative assessments for early-morning admission patients are good for only 7 days. Is that true?

Dr. Bader: There are sometimes differences between Joint Commission requirements and those of certain insurance companies. That kind of issue needs to be discussed with your hospital compliance office. We program rules into our scheduling system to accommodate different insurance policies and other requirements so that a patient is not scheduled beyond the allowable period.

Weiner Center for Preoperative Evaluation at Brigham and Women’s Hospital

By Angela M. Bader, MD, MPH

When organizing our preoperative clinic at Brigham and Women’s Hospital, we had several goals. Overall, we wanted a standardized process to help us achieve a high level of excellence. We hoped that creating a new system would eliminate ambiguity about who was responsible for following up on a patient’s abnormal laboratory test result—the surgeon, anesthesiologist, or primary care physician. We also wanted to better coordinate the various care teams involved throughout the perioperative period.

STANDARDIZATION HELPS MEET MANY GOALS

Standardization can occur at many levels:

• Performance of assessments and testing
• Organization of the patient chart and medical records
• Systems checks throughout the process to ensure that nothing is missed
• Team-to-team communication.

Documentation requirements apply regardless of institutional structure

When considering any system of preoperative assessment, keep in mind that the hospital must meet and appropriately document compliance with all regulatory, accreditation, and payer requirements and guidelines, such as those of the Joint Commission, the Centers for Medicare and Medicaid Services (CMS), and the National Surgical Quality Improvement Program. For example, the Joint Commission requires that a surgical history and physical examination be done within 30 days of a procedure. An anesthesiology assessment and a nursing assessment are also required. All of these assessments have mandatory elements, including documenting “never events” and ordering appropriate laboratory tests, electrocardiograms (ECGs), and radiographs.

Sometimes administrators of other hospitals say to me, “We can’t afford a preoperative clinic, and we don’t need one.” My response is that regardless of whether a hospital has a preoperative clinic, the regulatory requirements and guidelines must be met: it is not an issue of avoiding certain steps. Having a dedicated preoperative clinic simply shifts the work to a standardized, centralized system and avoids delaying these required steps until the day of surgery, when taking care of a problem involves the most inefficient use of resources.

Tailor system to institutional needs and characteristics

Within the regulatory framework, the organizational scheme of every institution must address issues of volume and acuity, the types of surgery performed, and the time frames required. A system must be able to deal with the preoperative needs of patients undergoing operations that are booked weeks in advance (often the case for ortho­pedic surgery) as well as those that may not be booked until a day before the procedure (eg, cancer surgery).

Our plan was developed for our very high-volume, tertiary care institution. In 2008, 24,000 patients used our clinic (roughly 100 patients per day).

DESIGN OF THE PREOPERATIVE CLINIC

A nurse practitioner–based model for ‘one-stop shopping’

We decided that the clinic should offer all elements of the preoperative assessment and thereby give patients “one-stop shopping.” Each patient sees a nurse practitioner, who performs the surgical history and physical examination as well as the anesthesiology and nursing assessments. The result is a multidisciplinary approach with a single assessment output. We shifted employees who had been responsible for preoperative assessment in the offices of various surgeons to a central clinic so that all assessments could be standardized, and we provided additional training to enable them to perform various assessments. The nurse practitioners are supervised by an on-site attending physician, as detailed below.

This model offers a number of advantages:

• Patients see a single provider.
• Assessment is facilitated for our surgeons, who may not be completely up-to-date on perioperative risk assessment and management.
• We have a central location for standardized education programs for our physicians, nurses, and residents.
• The clinic’s standardized records and processes facilitate data generation for research and clinical practice improvement.

Independent budgetary and staffing structure

The preoperative clinic is a separate cost center under the leadership of the department of anesthesiology. Resources were shifted to a central location so that as volume increases, we can add resources to meet the additional volume. We contracted with the hospital administration to provide payment for two full-time-equivalent anesthesiologists per day, who serve as on-site attending physicians. The hospital is willing to do this because not only do these attending physicians supervise the anesthesiology assessment, they are the collaborating physicians for the entire perioperative assessment. They review every patient, order tests and write prescriptions as needed, and discuss issues with the primary care physicians and referring specialists.

The preoperative clinic has an anesthesiologist director (me) who reports directly to the hospital’s vice president for surgical services on budget and staffing issues. I also report to the chairman of the department of anesthesiology, though he is not involved in budgetary functions (the hospital contracts with him to provide the anesthesiology staffing). The clerical and nursing staff work directly for the clinic.

The clinic is run in a self-contained area with a central waiting room and space for doing all the assessments and laboratory work internally, including 16 examination rooms and a room for chart organization.

 

 

MORE BENEFITS OF STANDARDIZATION

Standardized scheduling ensures reliability

The secretaries in each surgeon’s office schedule appointments through a central computer system after registration and insurance precertification. Our computer system does not allow an operation to be scheduled without an evaluation also being scheduled. The evaluation can involve either a visit or a telephone screen; we provide algorithms so that the surgeons’ secretaries know which is required. This system has substantially reduced the number of walk-ins, allowing for a more even distribution of patients and ensuring that medical records will be available when a patient is seen.

We watch our schedule carefully. Our computer system monitors the time that each patient is in our clinic to determine his or her waiting time and assessment time. It takes about 75 minutes to go through the whole process, including the time for a nurse practitioner to do the surgical history and physical examination and the anesthesiology and nursing assessments, a laboratory technician to do an ECG and laboratory tests if indicated, and completion of all required documentation. Accordingly, patients are scheduled in 75-minute blocks between 7:00 am and 6:30 pm. We do not have evening or weekend hours because of the difficulty of contacting surgeons and primary care physicians when questions arise. It is simply not cost-effective to have to do that type of follow-up on a case after the patient leaves.

Only about 10% of our patients are screened by telephone, since most of our operations are complicated and require in-person assessment (most low-acuity procedures are done at other hospitals). Of the patients who visit the preoperative clinic, about 75% undergo the single assessment model for surgery, anesthesiology, and nursing as described above. The remaining 25% of patients have their history and physical exam completed outside Brigham and Women’s Hospital for insurance reasons; the remainder of their assessment is conducted in our preoperative clinic by a registered nurse and an anesthesiology resident.

Multiple systems checks

Our model also incorporates standardization in the form of multiple systems checks:

• Case presentation. Every case is presented to an attending anesthesiologist, who reviews the ECG (if ordered) before the patient leaves the clinic.
• Post-visit chart check. A registered nurse or nurse practitioner signs off on each chart after the visit, confirming test results and resolution of all paperwork issues.
• Surgical checklist. The end result is a checklist that serves as the front sheet of the operating room chart.

Our ability to use this system of checks to get the chart completed comprehensively and reliably and deliver it to the operating room when needed was key to securing institutional support and funding for the preoperative clinic.

ROLE OF THE ATTENDING ANESTHESIOLOGISTS

Two full-time attending anesthesiologists are present in the preoperative clinic each day. One is responsible largely for supervising the nurse practitioner assessments and reviewing case presentations, while the other also oversees the education and supervision of residents. Residents rotate through the clinic for 2 weeks (one or two at a time) and have a designated curriculum consisting of daily lectures and competencies in preoperative evaluation.

Because our anesthesiologists are expert in pre­operative assessment, we require very few outside consults. We can communicate directly with the cardiologists and other physicians and order tests when indicated. We have a clerical assistant who obtains all necessary paperwork and prior testing from outside providers so that the clinicians need not waste time on this.

A GROWING CHALLENGE: ASSESSMENT FOR PROCEDURES IN AMBULATORY SETTINGS

Looking forward, a rapidly growing challenge facing our clinic stems from the tremendous growth in patients who require anesthesia for procedures performed outside the operating room. In these situations, the proceduralists need a system for deciding whether an anesthesiologist must be present for any given case.

We have started to develop appropriate screening processes to ensure that the proceduralists in multiple departments know which patients to refer for pre­procedure assessment. We hope to soon develop protocols for high-risk patients and for various procedures such as implanting a pacemaker or defibrillator, catheter procedures, interventional radiology, and endoscopy.

 

 

Anesthesia Perioperative Medicine Clinic at University of Chicago

By BobbieJean Sweitzer, MD

Detsky and Naglie have argued that the costs and clinical outcomes associated with any intervention must be compared with those of alternate strategies for treating the same patients,¹ and I believe their point applies well to preoperative clinics. Although certain requirements of the Joint Commission and CMS must be met, as noted by Dr. Bader, they can be met in various ways. I will preface my comments by emphasizing that one size does not fit all: every institution must decide the best approach to preoperative assessment based on its patient population, the types of procedures it performs, and the volume it handles. 

TRIAGE STREAMLINES THE PROCESS

Our preoperative clinic at the University of Chicago emphasizes triage. Not every patient should have to go to the trouble of coming in to see a provider. In the future, we will likely see more “virtual” preoperative assessments using devices in development, such as handheld ultrasonography machines. Just as patients can have their pacemakers and implantable cardiac defibrillators remotely checked via phone contact, more tools will one day be available for remote assessment.

Although not every surgical patient needs to come in to the preoperative clinic, every patient must have a physical examination. All patients will be seen on the day of surgery, so in some cases the physical exam may be able to wait until then. For example, an airway assessment need not be done ahead of time. Most anesthesiologists are prepared to manage airways on very short notice, so extensive advance planning is not always necessary.

Obtain basic info by questionnaire to save staff time

Information about the patient is key to triage, and it may be either paper- or computer-based. An initial priority should be to develop some mechanism for getting information from patients before the day of their procedure without a visit to the hospital or ambulatory surgery center.

We use a two-page paper questionnaire to obtain basic information from patients, including (among other pertinent questions) age, planned operation, names of the surgeon and primary doctor, past operations and medical history, allergies, a list of medications, social history (drug, alcohol, tobacco use), whether they have ever taken steroids, whether they have high blood pressure, and whether they can comfortably walk up a flight of stairs. We provide the primary care physicians and surgeons with blank questionnaires, which their patients can fill out in their waiting rooms or take home and fax to us (or drop off) later. The questionnaire gives us a good deal of essential information without using staff time.

Various computer-based and Web-based systems are also available for collecting basic patient information. Smaller institutions need not purchase an entire electronic medical record system, which can be very expensive. Some Web-based tools operate on a pay-per-use basis and can be very helpful.

Review the information to guide triage

We then review the patient information to determine the extent of preoperative evaluation required. Some patients, especially those scheduled at an ambulatory surgery center, are healthy enough that they can just come in on the day of surgery for an examination and an update of their information. Others will need an appointment at the clinic before the day of surgery for more extensive preoperative evaluation. For other patients, review of their questionnaire responses may prompt a phone call or e-mail from the clinic for more information to determine whether a day-of-surgery exam will suffice or whether evaluation in advance is needed. When in doubt, concerns raised by the questionnaire should be explored before the day of surgery to avoid surprises and allow sufficient time for a consultation, if needed.

STANDARDIZED GUIDELINES KEEP CARE CONSISTENT

We encourage our staff to minimize preoperative testing and ECGs. A majority of diagnoses are made based on the history and physical exam.² Generally, a test should confirm what is already suspected and merely provide objective evidence when needed. Testing in this setting should not be done to “find out what is wrong” with a patient.

It is helpful to develop standardized guidelines for preoperative assessment and make them available to everyone in the institution via the Web. The guidelines should address recommended preoperative tests and management practices according to specific patient conditions or surgical procedures. The clear objective is to avoid disagreement about what a patient needs between the provider who evaluated the patient in advance and the surgeon or anesthesiologist who evaluates the patient on the day of surgery.

Our guidelines at the University of Chicago include recommendations for patients on long-term anticoagulant therapy, for patients with coronary stents, for medications that should be discontinued (and those that may be continued) on the day of surgery, and for numerous other conditions and issues. Our testing guidelines list indicated tests for various medical problems, which in turn link to other guidelines. Other links are based on the medications a patient is using or the type of operation that is planned.

We collaborated with our electrophysiology department to create guidelines for managing patients with pacemakers and defibrillators. Almost every patient with one of these devices has a little card associated with the device, and we ask the surgeons to copy the card and send it to the clinic if we will not be directly seeing the patient. Using a national database, the electro­physiology department can determine from the card the type of pacemaker or defibrillator a patient has, and they fax or e-mail us back a page of instructions to let us know whether the device requires special consideration during surgery, whether it should be checked preoperatively, and whether its battery needs replacing. With this system, we have markedly reduced problems on the day of surgery.

 

 

CONSULTS HAVE AN IMPORTANT ROLE

Consults should never be requested in order to “clear a patient for surgery.” Consult requests should rather address specific issues, such as, “Is this patient medically optimized?” or “Please address this patient’s hypertension.” In turn, consult notes should provide meaningful information that can be used in a specific way. A clearance letter or simple risk assessment is not helpful.

If a patient has not seen a primary care doctor in a long time, a consult request should (in addition to requesting a global risk assessment) specify any particular concerns, such as, “The patient reports snoring; please address sleep apnea and cardiac risk.”

Case study: Beware consult notes with no specifics

Consider a case we encountered of a 54-year-old man who had a preoperative cardiac risk assessment. The cardiology consultant completed a short form consisting of a multiple-choice check-off list indicating low, moderate, or high cardiac risk. The consultant checked that the patient had low cardiac risk but provided no other instructions or information other than his own contact information.

When we reviewed the patient’s questionnaire, we saw that his medications included metoprolol, clopidogrel, and aspirin even though the patient did not mention that he had coronary artery disease. On this basis, we requested details about his cardiac evaluation from his cardiologist. It turned out that the patient had a history of four catheterizations with several cardiac stents placed. The most recent stent was implanted to overlap a previous stent that had been found “floating” in the blood vessel; this last stent was placed just 6 months before the cardiologist issued the consult note indicating “low cardiac risk.”

The moral is to approach consult notes with caution, especially if they offer no specifics. It actually makes me nervous when a note states “low risk” because if something unexpectedly goes wrong in surgery, it appears that the perioperative team took poor care of the patient even if the complication actually may have stemmed from higher-than-recognized underlying patient risk.

PROVIDE, AND REINFORCE, CLEAR INSTRUCTIONS

We give patients written preoperative instructions that become part of our computerized records. We first verbally give explicit instructions for each medication—ie, whether it can be taken as usual or when it needs to be stopped before surgery (and why). Then we provide the same information in writing, after which we try to have the patient repeat the instructions back to the clinician. We include a phone number that patients can call if they need help understanding their preoperative instructions.

Web-based programs also can provide patients online instructions about their medications. Some services even customize information by providing, for example, lists of local surgeons who are willing to allow a patient to continue on aspirin therapy until the day of surgery.

USE THE RIGHT RESOURCES

Staffing

Our model at the University of Chicago relies mainly on residents in training and physician assistants, but advanced nurse practitioners are well suited to a pre­operative clinic as well. These types of providers have background training in history-taking, physical examination, diagnostic testing, and disease management. Registered nurses have more limited abilities, although they may be appropriate for a clinic that deals primarily with healthy patients for whom only history taking and a list of medications is needed. Additionally, our clinic is staffed by one attending anesthesiologist at all times (from among a group of rotating anesthesiologists) as well as medical assistants and clerical staff.

Some clinics perform the surgical history and physical exam at the same time as the anesthesia assessment. I would urge caution with this practice. Just as primary care doctors should not be conducting the anesthesia assessment, nonsurgeons should not be conducting the surgical assessment; doing so puts them out on a limb from a medicolegal standpoint. Advanced nurse practitioners and physician assistants may do surgical assessments under the supervision of a surgeon, but only surgeons should ultimately decide—and document—whether an operation is necessary and what degree of examination is required in advance.

Computer technology for records, messaging, billing

Using electronic medical records and corresponding with colleagues by e-mail make preoperative care much more efficient. We have standardized computer forms for ordering tests and documenting the physical exam. Patients usually understand that electronic medical records are safe and more efficient, and they are often more accepting of their use than practitioners are. Many patients want e-mail access to doctors, to schedule appointments online, and to receive appointment reminders by e-mail.³

Electronic medical records also avoid redundancy. If a patient has been seen in our preoperative clinic and is later scheduled for another surgery (even if a different surgeon is involved), a return visit to our clinic may not be necessary. In some cases, we can send the old work-up stamped “For information only,” which can then be updated by the anesthesiologist on the day of surgery.

A central, standardized process also makes billing more efficient and helps to ensure that payment is received for all services provided. Standardized documentation makes it easier for coders to enter the correct evaluation and management codes and ensures that all required criteria are met.

THE PAYOFF: LIVES AND DOLLARS SAVED

A thorough and efficient preoperative assessment system is cost-effective. Every minute of operating room time is worth $10 to $15,^4,5 so delays should be avoided. Everything that is done ahead of time saves money for the whole enterprise by reducing unnecessary case setups and reducing “down time” due to lack of patient, equipment, or staff readiness. We routinely bill for preoperative evaluations when this service goes beyond a routine preoperative assessment based on CMS (and other insurance) requirements. However, a preoperative evaluation is required by CMS and most payers if one wants to be paid for any anesthesia-provided service. As a result, a cost is incurred without offsetting revenue if a case is cancelled on the day of surgery after one performs the anesthesia evaluation.

A study we published a few years ago showed that patients who were seen in our preoperative clinic were significantly less likely to have day-of-surgery cancellations than were patients not seen in our clinic, a finding that applied to both our ambulatory surgery center and our main operating rooms (Table 1).⁵ These findings held even after adjustment for American Society of Anesthesiologists severity class. In addition, the median delay in surgery start time was significantly less among patients who were seen in the preoperative clinic.

Yesterday I heard someone ask, “Do we really need all this preoperative evaluation? Does it really improve outcomes?” There is some evidence that it does. A study from 2000 based on data from the Australian Incident Monitoring Study found that 11% of the 6,271 critical incidents that occurred following operations were attributable to inadequate preoperative evaluation and that 3% were unequivocally related to problems with preoperative assessment or preparation. More than half of the incidents were deemed preventable.⁶

Preoperative clinics are good for patients and make good sense economically. We just need to demonstrate to our administrators and to payers that we are offering an excellent service.

 

 

Cleveland Clinic IMPACT Center

By Ajay Kumar, MD

Cleveland Clinic is structured differently from most other institutions in that its surgeons, anesthesiologists, and hospitalists are all direct employees of the institution. Despite this unique structure, many aspects of our preoperative clinic—known as the Internal Medicine Preoperative Assessment, Consultation and Treatment (IMPACT) Center—are applicable to other institutions.

Cleveland Clinic is a busy surgical hospital whose preoperative optimization system is designed to provide high-quality care. The IMPACT Center is consulted for most complicated noncardiac surgery patients, and its referral sources include most of the institution’s surgical specialties.

QUEST FOR A BETTER PATIENT EXPERIENCE

When the IMPACT Center was created in 1997, the aim was to focus on the same objectives highlighted by Drs. Bader and Sweitzer: safety, a positive patient experience, enhanced communication, better continuity of care, effective use of resources, and improving throughput by standardizing care.

A prime motivator was the desire to move away from the tendency for presurgical consults to simply “clear the patient for surgery,” and we have indeed evolved considerably from that point. The focus of our peri­operative care program today is to comprehensively evaluate risk by taking into account patient-, procedure-, and anesthesia-related factors.

We offer “one-stop shopping,” and our priority is for efficient throughput. We are located in a 12-story building that includes outpatient, preoperative, and surgical clinics and offices. The IMPACT Center is on the first floor along with the preoperative anesthesia consultation and evaluation (PACE) clinic, the laboratory, and ECG and stress-test labs. Patients can undergo radiographic studies on the second floor.

The patient experience counts for a lot. Many of our patients are from another state or country, so efficiency and convenience are especially important. Patients can usually get all assessment and testing done in a single day.

A TIGHTLY MANAGED PROCESS

A ‘smart’ questionnaire starts the process

Our process (Figure 1) begins in the surgeons’ offices, where a patient is seen by a surgeon and an operation is deemed necessary. There the patient is asked to fill out a computer-assisted health screening questionnaire available online. The questionnaire is very sophisticated: based on the patient’s answers, it asks further pertinent questions and requests details if the history is complicated. A patient with multiple health problems may take 20 minutes to complete it, while a healthy patient may take only 3 minutes.

A computerized report based on the questionnaire guides the surgical office in scheduling the patient to specific areas according to algorithms. Based on case complexity and clinical needs, patients are scheduled for the IMPACT Center along with the PACE clinic; if needed (based on the algorithms), patients also are scheduled for laboratory tests or imaging. This standardized approach helps create a safe passage for patients through the preoperative process with less confusion.

Patient is given a personalized binder

Once all appointments and tests are scheduled, the patient is given a binder containing specific information about the procedure and preoperative instructions. The medical appointment at the IMPACT Center is usually scheduled before the PACE clinic appointment. Patients receive an itinerary for all preoperative appointments and surgical office appointments before the planned surgery. The itinerary is planned so that if additional testing is requested, it can be accommodated on the same day.

At the end of the preoperative assessment, the patient receives printed information with specific preoperative instructions, including which medications to continue or stop.

Standardized, computer-based medical records

Our systems and processes have undergone a good deal of evolution. We have integrated our medical records and use a standard outside medical record retrieval process. The template for the history and physical exam is standard for all Cleveland Clinic patients and is used for all presurgical assessments before all noncardiac surgeries. The template is comprehensive, including the history of the present illness, the review of systems, the physical exam, and anesthesia-related issues. All outside documents are scanned into our electronic medical record system and are available for viewing prior to surgery from any computer connected to the system.

Our preoperative assessment guidelines are also kept updated at a central online location so that all providers have access to them.

Staff keeps process running efficiently

The IMPACT Center is managed by the department of hospital medicine and supported by at least 5.5 full-time physicians every day. We also have two registered nurses, two assistants who help with scheduling and testing, and three secretaries who support the doctors, obtain records, and make arrangements with outside doctors for testing if a patient wants to return home before our testing can be completed.

A secretary also keeps a log for each patient seen in the clinic, tracking all pending issues. The day before surgery, the secretary contacts the appropriate office for anything that is still pending. If she gets no response, the matter is transferred to one of our doctors so that the problem can be resolved at once. This strategy allows us to achieve a nearly 0% rate of surgery delay or cancellation attributable to unavailable test results.

Our patient volumes have increased significantly since we started in 1997. Last year more than 15,000 patients visited the IMPACT Center and now we have expanded our services to regional hospitals within the Cleveland Clinic Health System.

INTERDEPARTMENTAL COMMUNICATION IS CRITICAL

Interdepartmental communication is a must for patient safety, so we encourage a culture of communication between the hospitalist and the surgical team. The location of most of our surgical clinics within the same building as the IMPACT Center further facilitates communication, as does the proximity of the PACE clinic. Additionally, one of our IMPACT Center physicians is accessible around the clock to answer to our surgeon or anesthesiologist colleagues as needed.

We regularly assess our process and seek feedback from surgeons and anesthesiologists. We also conduct yearly patient experience surveys to make sure we are providing patients with the highest quality of care.

 

 

Discussion

Question from the audience: Our anesthesia assessment department was approached by our surgeons to do both the anesthesia and surgical assessments, but we felt that would put us in a potential legal conflict if a patient who was assessed that way developed problems. Can you comment?

Dr. Bader: Although we do surgical assessments at our preoperative clinic, we don’t make any decisions about whether or not to proceed with an operation. We get an office note from the surgeon that is directed specifically toward the need for surgery, indications for surgery, and surgical consent. We perform the surgical history and physical examination. Our process is essentially the same as when surgeons have a physician assistant do the history and physical examination in their office. Our practitioners are employed by the hospital, so there is no conflict of interest there.

Comment from the audience: I’m a strong believer in hands-on patient contact. Over my 15 years of practice, we have encountered a lot of unexpected problems during the preoperative exam—aortic stenoses, infections, ventricular septal defects—all of which would never have been detected from a screening form.

Dr. Sweitzer: I agree that we pick up many things by seeing the patient in person. I’ve picked up more cases of aortic stenosis as an anesthesiologist in the preoperative clinic than I ever did as an internist, because the population is high-risk. But patients who have such problems tend to have risk factors and be in certain age groups. Studies indicate that the history is more important than the physical exam: the history suggests about 75% of conditions that are present. The physical exam adds only a little more—perhaps another 15%. Our recommendations are very much consistent with the American College of Cardiology and American Heart Association guidelines on preoperative cardiac evaluation.⁷ It is more important to identify whether a patient has risk factors for coronary artery disease than to find out whether a stress test or ECG is normal. One needs to do a really good history, but it can be done remotely. Based on certain risk factors identified, high-risk patients can be selected who need to come in and have a physical exam.

Question from the audience: Could you elaborate on the electronic medical record system used at the University of Chicago? I’ve heard there’s a steep learning curve when implementing these kinds of systems. They also are very expensive—I’ve heard that some cost $40 to $80 million. Has enhanced revenue flow offset the costs?

Dr. Sweitzer: We have a home-grown system developed with FileMaker Pro by a computer programmer at our institution. It was a lot easier to develop than people tend to think. There are many savvy computer programmers out there; I’ve had medical students assist me with updating it. We’re now considering developing it as a commercial system. Many systems are available for purchase, including Epic, Pyxis, one from General Electric, and many others. They are very expensive, so smaller institutions might want to use a pay-for-service system.

There definitely is a learning curve to switching to electronic medical records, but it is not nearly as steep as many believe. The extra time it takes a clinician to initially make a computer entry rather than write on paper is vastly recouped downstream: the electronic medical record is legible and organized, and it doesn’t get lost or need to be redone. You can bring up a patient record from 6 months before and reuse it as a template.

Dr. Bader: The discussion of cost savings from preoperative clinics usually focuses on savings from avoiding surgery cancellations and delays and from more efficient laboratory testing, but the biggest savings for an institution is better reimbursement through better diagnosis-related groups (DRG) coding. That’s an important reason our institution is funding our clinic. Electronic medical records allow standardization of information so that coders know exactly where to look for the comorbidities and other pertinent information. This increases payments for DRGs, which can be documented for the hospital. This literally runs into millions of dollars a year and more than offsets the costs of the system.

Question from the audience: Dr. Bader, I’m impressed with the number of patients going through your pre­operative clinic. How many patients are seen per nurse practitioner in your clinic?

Dr. Bader: The nurse practitioners have 10-hour shifts and see one patient every 75 minutes. The process of seeing a patient takes a lot less time now than with the old system, in which patients saw an anesthesiologist plus a nurse. Our current system eliminates redundancy: questions need to be asked only once.

Question from the audience: My compliance office says that preoperative assessments for early-morning admission patients are good for only 7 days. Is that true?

Dr. Bader: There are sometimes differences between Joint Commission requirements and those of certain insurance companies. That kind of issue needs to be discussed with your hospital compliance office. We program rules into our scheduling system to accommodate different insurance policies and other requirements so that a patient is not scheduled beyond the allowable period.

Weiner Center for Preoperative Evaluation at Brigham and Women’s Hospital

By Angela M. Bader, MD, MPH

When organizing our preoperative clinic at Brigham and Women’s Hospital, we had several goals. Overall, we wanted a standardized process to help us achieve a high level of excellence. We hoped that creating a new system would eliminate ambiguity about who was responsible for following up on a patient’s abnormal laboratory test result—the surgeon, anesthesiologist, or primary care physician. We also wanted to better coordinate the various care teams involved throughout the perioperative period.

STANDARDIZATION HELPS MEET MANY GOALS

Standardization can occur at many levels:

• Performance of assessments and testing
• Organization of the patient chart and medical records
• Systems checks throughout the process to ensure that nothing is missed
• Team-to-team communication.

Documentation requirements apply regardless of institutional structure

When considering any system of preoperative assessment, keep in mind that the hospital must meet and appropriately document compliance with all regulatory, accreditation, and payer requirements and guidelines, such as those of the Joint Commission, the Centers for Medicare and Medicaid Services (CMS), and the National Surgical Quality Improvement Program. For example, the Joint Commission requires that a surgical history and physical examination be done within 30 days of a procedure. An anesthesiology assessment and a nursing assessment are also required. All of these assessments have mandatory elements, including documenting “never events” and ordering appropriate laboratory tests, electrocardiograms (ECGs), and radiographs.

Sometimes administrators of other hospitals say to me, “We can’t afford a preoperative clinic, and we don’t need one.” My response is that regardless of whether a hospital has a preoperative clinic, the regulatory requirements and guidelines must be met: it is not an issue of avoiding certain steps. Having a dedicated preoperative clinic simply shifts the work to a standardized, centralized system and avoids delaying these required steps until the day of surgery, when taking care of a problem involves the most inefficient use of resources.

Tailor system to institutional needs and characteristics

Within the regulatory framework, the organizational scheme of every institution must address issues of volume and acuity, the types of surgery performed, and the time frames required. A system must be able to deal with the preoperative needs of patients undergoing operations that are booked weeks in advance (often the case for ortho­pedic surgery) as well as those that may not be booked until a day before the procedure (eg, cancer surgery).

Our plan was developed for our very high-volume, tertiary care institution. In 2008, 24,000 patients used our clinic (roughly 100 patients per day).

DESIGN OF THE PREOPERATIVE CLINIC

A nurse practitioner–based model for ‘one-stop shopping’

We decided that the clinic should offer all elements of the preoperative assessment and thereby give patients “one-stop shopping.” Each patient sees a nurse practitioner, who performs the surgical history and physical examination as well as the anesthesiology and nursing assessments. The result is a multidisciplinary approach with a single assessment output. We shifted employees who had been responsible for preoperative assessment in the offices of various surgeons to a central clinic so that all assessments could be standardized, and we provided additional training to enable them to perform various assessments. The nurse practitioners are supervised by an on-site attending physician, as detailed below.

This model offers a number of advantages:

• Patients see a single provider.
• Assessment is facilitated for our surgeons, who may not be completely up-to-date on perioperative risk assessment and management.
• We have a central location for standardized education programs for our physicians, nurses, and residents.
• The clinic’s standardized records and processes facilitate data generation for research and clinical practice improvement.

Independent budgetary and staffing structure

The preoperative clinic is a separate cost center under the leadership of the department of anesthesiology. Resources were shifted to a central location so that as volume increases, we can add resources to meet the additional volume. We contracted with the hospital administration to provide payment for two full-time-equivalent anesthesiologists per day, who serve as on-site attending physicians. The hospital is willing to do this because not only do these attending physicians supervise the anesthesiology assessment, they are the collaborating physicians for the entire perioperative assessment. They review every patient, order tests and write prescriptions as needed, and discuss issues with the primary care physicians and referring specialists.

The preoperative clinic has an anesthesiologist director (me) who reports directly to the hospital’s vice president for surgical services on budget and staffing issues. I also report to the chairman of the department of anesthesiology, though he is not involved in budgetary functions (the hospital contracts with him to provide the anesthesiology staffing). The clerical and nursing staff work directly for the clinic.

The clinic is run in a self-contained area with a central waiting room and space for doing all the assessments and laboratory work internally, including 16 examination rooms and a room for chart organization.

 

 

MORE BENEFITS OF STANDARDIZATION

Standardized scheduling ensures reliability

The secretaries in each surgeon’s office schedule appointments through a central computer system after registration and insurance precertification. Our computer system does not allow an operation to be scheduled without an evaluation also being scheduled. The evaluation can involve either a visit or a telephone screen; we provide algorithms so that the surgeons’ secretaries know which is required. This system has substantially reduced the number of walk-ins, allowing for a more even distribution of patients and ensuring that medical records will be available when a patient is seen.

We watch our schedule carefully. Our computer system monitors the time that each patient is in our clinic to determine his or her waiting time and assessment time. It takes about 75 minutes to go through the whole process, including the time for a nurse practitioner to do the surgical history and physical examination and the anesthesiology and nursing assessments, a laboratory technician to do an ECG and laboratory tests if indicated, and completion of all required documentation. Accordingly, patients are scheduled in 75-minute blocks between 7:00 am and 6:30 pm. We do not have evening or weekend hours because of the difficulty of contacting surgeons and primary care physicians when questions arise. It is simply not cost-effective to have to do that type of follow-up on a case after the patient leaves.

Only about 10% of our patients are screened by telephone, since most of our operations are complicated and require in-person assessment (most low-acuity procedures are done at other hospitals). Of the patients who visit the preoperative clinic, about 75% undergo the single assessment model for surgery, anesthesiology, and nursing as described above. The remaining 25% of patients have their history and physical exam completed outside Brigham and Women’s Hospital for insurance reasons; the remainder of their assessment is conducted in our preoperative clinic by a registered nurse and an anesthesiology resident.

Multiple systems checks

Our model also incorporates standardization in the form of multiple systems checks:

• Case presentation. Every case is presented to an attending anesthesiologist, who reviews the ECG (if ordered) before the patient leaves the clinic.
• Post-visit chart check. A registered nurse or nurse practitioner signs off on each chart after the visit, confirming test results and resolution of all paperwork issues.
• Surgical checklist. The end result is a checklist that serves as the front sheet of the operating room chart.

Our ability to use this system of checks to get the chart completed comprehensively and reliably and deliver it to the operating room when needed was key to securing institutional support and funding for the preoperative clinic.

ROLE OF THE ATTENDING ANESTHESIOLOGISTS

Two full-time attending anesthesiologists are present in the preoperative clinic each day. One is responsible largely for supervising the nurse practitioner assessments and reviewing case presentations, while the other also oversees the education and supervision of residents. Residents rotate through the clinic for 2 weeks (one or two at a time) and have a designated curriculum consisting of daily lectures and competencies in preoperative evaluation.

Because our anesthesiologists are expert in pre­operative assessment, we require very few outside consults. We can communicate directly with the cardiologists and other physicians and order tests when indicated. We have a clerical assistant who obtains all necessary paperwork and prior testing from outside providers so that the clinicians need not waste time on this.

A GROWING CHALLENGE: ASSESSMENT FOR PROCEDURES IN AMBULATORY SETTINGS

Looking forward, a rapidly growing challenge facing our clinic stems from the tremendous growth in patients who require anesthesia for procedures performed outside the operating room. In these situations, the proceduralists need a system for deciding whether an anesthesiologist must be present for any given case.

We have started to develop appropriate screening processes to ensure that the proceduralists in multiple departments know which patients to refer for pre­procedure assessment. We hope to soon develop protocols for high-risk patients and for various procedures such as implanting a pacemaker or defibrillator, catheter procedures, interventional radiology, and endoscopy.

 

 

Anesthesia Perioperative Medicine Clinic at University of Chicago

By BobbieJean Sweitzer, MD

Detsky and Naglie have argued that the costs and clinical outcomes associated with any intervention must be compared with those of alternate strategies for treating the same patients,¹ and I believe their point applies well to preoperative clinics. Although certain requirements of the Joint Commission and CMS must be met, as noted by Dr. Bader, they can be met in various ways. I will preface my comments by emphasizing that one size does not fit all: every institution must decide the best approach to preoperative assessment based on its patient population, the types of procedures it performs, and the volume it handles. 

TRIAGE STREAMLINES THE PROCESS

Our preoperative clinic at the University of Chicago emphasizes triage. Not every patient should have to go to the trouble of coming in to see a provider. In the future, we will likely see more “virtual” preoperative assessments using devices in development, such as handheld ultrasonography machines. Just as patients can have their pacemakers and implantable cardiac defibrillators remotely checked via phone contact, more tools will one day be available for remote assessment.

Although not every surgical patient needs to come in to the preoperative clinic, every patient must have a physical examination. All patients will be seen on the day of surgery, so in some cases the physical exam may be able to wait until then. For example, an airway assessment need not be done ahead of time. Most anesthesiologists are prepared to manage airways on very short notice, so extensive advance planning is not always necessary.

Obtain basic info by questionnaire to save staff time

Information about the patient is key to triage, and it may be either paper- or computer-based. An initial priority should be to develop some mechanism for getting information from patients before the day of their procedure without a visit to the hospital or ambulatory surgery center.

We use a two-page paper questionnaire to obtain basic information from patients, including (among other pertinent questions) age, planned operation, names of the surgeon and primary doctor, past operations and medical history, allergies, a list of medications, social history (drug, alcohol, tobacco use), whether they have ever taken steroids, whether they have high blood pressure, and whether they can comfortably walk up a flight of stairs. We provide the primary care physicians and surgeons with blank questionnaires, which their patients can fill out in their waiting rooms or take home and fax to us (or drop off) later. The questionnaire gives us a good deal of essential information without using staff time.

Various computer-based and Web-based systems are also available for collecting basic patient information. Smaller institutions need not purchase an entire electronic medical record system, which can be very expensive. Some Web-based tools operate on a pay-per-use basis and can be very helpful.

Review the information to guide triage

We then review the patient information to determine the extent of preoperative evaluation required. Some patients, especially those scheduled at an ambulatory surgery center, are healthy enough that they can just come in on the day of surgery for an examination and an update of their information. Others will need an appointment at the clinic before the day of surgery for more extensive preoperative evaluation. For other patients, review of their questionnaire responses may prompt a phone call or e-mail from the clinic for more information to determine whether a day-of-surgery exam will suffice or whether evaluation in advance is needed. When in doubt, concerns raised by the questionnaire should be explored before the day of surgery to avoid surprises and allow sufficient time for a consultation, if needed.

STANDARDIZED GUIDELINES KEEP CARE CONSISTENT

We encourage our staff to minimize preoperative testing and ECGs. A majority of diagnoses are made based on the history and physical exam.² Generally, a test should confirm what is already suspected and merely provide objective evidence when needed. Testing in this setting should not be done to “find out what is wrong” with a patient.

It is helpful to develop standardized guidelines for preoperative assessment and make them available to everyone in the institution via the Web. The guidelines should address recommended preoperative tests and management practices according to specific patient conditions or surgical procedures. The clear objective is to avoid disagreement about what a patient needs between the provider who evaluated the patient in advance and the surgeon or anesthesiologist who evaluates the patient on the day of surgery.

Our guidelines at the University of Chicago include recommendations for patients on long-term anticoagulant therapy, for patients with coronary stents, for medications that should be discontinued (and those that may be continued) on the day of surgery, and for numerous other conditions and issues. Our testing guidelines list indicated tests for various medical problems, which in turn link to other guidelines. Other links are based on the medications a patient is using or the type of operation that is planned.

We collaborated with our electrophysiology department to create guidelines for managing patients with pacemakers and defibrillators. Almost every patient with one of these devices has a little card associated with the device, and we ask the surgeons to copy the card and send it to the clinic if we will not be directly seeing the patient. Using a national database, the electro­physiology department can determine from the card the type of pacemaker or defibrillator a patient has, and they fax or e-mail us back a page of instructions to let us know whether the device requires special consideration during surgery, whether it should be checked preoperatively, and whether its battery needs replacing. With this system, we have markedly reduced problems on the day of surgery.

 

 

CONSULTS HAVE AN IMPORTANT ROLE

Consults should never be requested in order to “clear a patient for surgery.” Consult requests should rather address specific issues, such as, “Is this patient medically optimized?” or “Please address this patient’s hypertension.” In turn, consult notes should provide meaningful information that can be used in a specific way. A clearance letter or simple risk assessment is not helpful.

If a patient has not seen a primary care doctor in a long time, a consult request should (in addition to requesting a global risk assessment) specify any particular concerns, such as, “The patient reports snoring; please address sleep apnea and cardiac risk.”

Case study: Beware consult notes with no specifics

Consider a case we encountered of a 54-year-old man who had a preoperative cardiac risk assessment. The cardiology consultant completed a short form consisting of a multiple-choice check-off list indicating low, moderate, or high cardiac risk. The consultant checked that the patient had low cardiac risk but provided no other instructions or information other than his own contact information.

When we reviewed the patient’s questionnaire, we saw that his medications included metoprolol, clopidogrel, and aspirin even though the patient did not mention that he had coronary artery disease. On this basis, we requested details about his cardiac evaluation from his cardiologist. It turned out that the patient had a history of four catheterizations with several cardiac stents placed. The most recent stent was implanted to overlap a previous stent that had been found “floating” in the blood vessel; this last stent was placed just 6 months before the cardiologist issued the consult note indicating “low cardiac risk.”

The moral is to approach consult notes with caution, especially if they offer no specifics. It actually makes me nervous when a note states “low risk” because if something unexpectedly goes wrong in surgery, it appears that the perioperative team took poor care of the patient even if the complication actually may have stemmed from higher-than-recognized underlying patient risk.

PROVIDE, AND REINFORCE, CLEAR INSTRUCTIONS

We give patients written preoperative instructions that become part of our computerized records. We first verbally give explicit instructions for each medication—ie, whether it can be taken as usual or when it needs to be stopped before surgery (and why). Then we provide the same information in writing, after which we try to have the patient repeat the instructions back to the clinician. We include a phone number that patients can call if they need help understanding their preoperative instructions.

Web-based programs also can provide patients online instructions about their medications. Some services even customize information by providing, for example, lists of local surgeons who are willing to allow a patient to continue on aspirin therapy until the day of surgery.

USE THE RIGHT RESOURCES

Staffing

Our model at the University of Chicago relies mainly on residents in training and physician assistants, but advanced nurse practitioners are well suited to a pre­operative clinic as well. These types of providers have background training in history-taking, physical examination, diagnostic testing, and disease management. Registered nurses have more limited abilities, although they may be appropriate for a clinic that deals primarily with healthy patients for whom only history taking and a list of medications is needed. Additionally, our clinic is staffed by one attending anesthesiologist at all times (from among a group of rotating anesthesiologists) as well as medical assistants and clerical staff.

Some clinics perform the surgical history and physical exam at the same time as the anesthesia assessment. I would urge caution with this practice. Just as primary care doctors should not be conducting the anesthesia assessment, nonsurgeons should not be conducting the surgical assessment; doing so puts them out on a limb from a medicolegal standpoint. Advanced nurse practitioners and physician assistants may do surgical assessments under the supervision of a surgeon, but only surgeons should ultimately decide—and document—whether an operation is necessary and what degree of examination is required in advance.

Computer technology for records, messaging, billing

Using electronic medical records and corresponding with colleagues by e-mail make preoperative care much more efficient. We have standardized computer forms for ordering tests and documenting the physical exam. Patients usually understand that electronic medical records are safe and more efficient, and they are often more accepting of their use than practitioners are. Many patients want e-mail access to doctors, to schedule appointments online, and to receive appointment reminders by e-mail.³

Electronic medical records also avoid redundancy. If a patient has been seen in our preoperative clinic and is later scheduled for another surgery (even if a different surgeon is involved), a return visit to our clinic may not be necessary. In some cases, we can send the old work-up stamped “For information only,” which can then be updated by the anesthesiologist on the day of surgery.

A central, standardized process also makes billing more efficient and helps to ensure that payment is received for all services provided. Standardized documentation makes it easier for coders to enter the correct evaluation and management codes and ensures that all required criteria are met.

THE PAYOFF: LIVES AND DOLLARS SAVED

A thorough and efficient preoperative assessment system is cost-effective. Every minute of operating room time is worth $10 to $15,^4,5 so delays should be avoided. Everything that is done ahead of time saves money for the whole enterprise by reducing unnecessary case setups and reducing “down time” due to lack of patient, equipment, or staff readiness. We routinely bill for preoperative evaluations when this service goes beyond a routine preoperative assessment based on CMS (and other insurance) requirements. However, a preoperative evaluation is required by CMS and most payers if one wants to be paid for any anesthesia-provided service. As a result, a cost is incurred without offsetting revenue if a case is cancelled on the day of surgery after one performs the anesthesia evaluation.

A study we published a few years ago showed that patients who were seen in our preoperative clinic were significantly less likely to have day-of-surgery cancellations than were patients not seen in our clinic, a finding that applied to both our ambulatory surgery center and our main operating rooms (Table 1).⁵ These findings held even after adjustment for American Society of Anesthesiologists severity class. In addition, the median delay in surgery start time was significantly less among patients who were seen in the preoperative clinic.

Yesterday I heard someone ask, “Do we really need all this preoperative evaluation? Does it really improve outcomes?” There is some evidence that it does. A study from 2000 based on data from the Australian Incident Monitoring Study found that 11% of the 6,271 critical incidents that occurred following operations were attributable to inadequate preoperative evaluation and that 3% were unequivocally related to problems with preoperative assessment or preparation. More than half of the incidents were deemed preventable.⁶

Preoperative clinics are good for patients and make good sense economically. We just need to demonstrate to our administrators and to payers that we are offering an excellent service.

 

 

Cleveland Clinic IMPACT Center

By Ajay Kumar, MD

Cleveland Clinic is structured differently from most other institutions in that its surgeons, anesthesiologists, and hospitalists are all direct employees of the institution. Despite this unique structure, many aspects of our preoperative clinic—known as the Internal Medicine Preoperative Assessment, Consultation and Treatment (IMPACT) Center—are applicable to other institutions.

Cleveland Clinic is a busy surgical hospital whose preoperative optimization system is designed to provide high-quality care. The IMPACT Center is consulted for most complicated noncardiac surgery patients, and its referral sources include most of the institution’s surgical specialties.

QUEST FOR A BETTER PATIENT EXPERIENCE

When the IMPACT Center was created in 1997, the aim was to focus on the same objectives highlighted by Drs. Bader and Sweitzer: safety, a positive patient experience, enhanced communication, better continuity of care, effective use of resources, and improving throughput by standardizing care.

A prime motivator was the desire to move away from the tendency for presurgical consults to simply “clear the patient for surgery,” and we have indeed evolved considerably from that point. The focus of our peri­operative care program today is to comprehensively evaluate risk by taking into account patient-, procedure-, and anesthesia-related factors.

We offer “one-stop shopping,” and our priority is for efficient throughput. We are located in a 12-story building that includes outpatient, preoperative, and surgical clinics and offices. The IMPACT Center is on the first floor along with the preoperative anesthesia consultation and evaluation (PACE) clinic, the laboratory, and ECG and stress-test labs. Patients can undergo radiographic studies on the second floor.

The patient experience counts for a lot. Many of our patients are from another state or country, so efficiency and convenience are especially important. Patients can usually get all assessment and testing done in a single day.

A TIGHTLY MANAGED PROCESS

A ‘smart’ questionnaire starts the process

Our process (Figure 1) begins in the surgeons’ offices, where a patient is seen by a surgeon and an operation is deemed necessary. There the patient is asked to fill out a computer-assisted health screening questionnaire available online. The questionnaire is very sophisticated: based on the patient’s answers, it asks further pertinent questions and requests details if the history is complicated. A patient with multiple health problems may take 20 minutes to complete it, while a healthy patient may take only 3 minutes.

A computerized report based on the questionnaire guides the surgical office in scheduling the patient to specific areas according to algorithms. Based on case complexity and clinical needs, patients are scheduled for the IMPACT Center along with the PACE clinic; if needed (based on the algorithms), patients also are scheduled for laboratory tests or imaging. This standardized approach helps create a safe passage for patients through the preoperative process with less confusion.

Patient is given a personalized binder

Once all appointments and tests are scheduled, the patient is given a binder containing specific information about the procedure and preoperative instructions. The medical appointment at the IMPACT Center is usually scheduled before the PACE clinic appointment. Patients receive an itinerary for all preoperative appointments and surgical office appointments before the planned surgery. The itinerary is planned so that if additional testing is requested, it can be accommodated on the same day.

At the end of the preoperative assessment, the patient receives printed information with specific preoperative instructions, including which medications to continue or stop.

Standardized, computer-based medical records

Our systems and processes have undergone a good deal of evolution. We have integrated our medical records and use a standard outside medical record retrieval process. The template for the history and physical exam is standard for all Cleveland Clinic patients and is used for all presurgical assessments before all noncardiac surgeries. The template is comprehensive, including the history of the present illness, the review of systems, the physical exam, and anesthesia-related issues. All outside documents are scanned into our electronic medical record system and are available for viewing prior to surgery from any computer connected to the system.

Our preoperative assessment guidelines are also kept updated at a central online location so that all providers have access to them.

Staff keeps process running efficiently

The IMPACT Center is managed by the department of hospital medicine and supported by at least 5.5 full-time physicians every day. We also have two registered nurses, two assistants who help with scheduling and testing, and three secretaries who support the doctors, obtain records, and make arrangements with outside doctors for testing if a patient wants to return home before our testing can be completed.

A secretary also keeps a log for each patient seen in the clinic, tracking all pending issues. The day before surgery, the secretary contacts the appropriate office for anything that is still pending. If she gets no response, the matter is transferred to one of our doctors so that the problem can be resolved at once. This strategy allows us to achieve a nearly 0% rate of surgery delay or cancellation attributable to unavailable test results.

Our patient volumes have increased significantly since we started in 1997. Last year more than 15,000 patients visited the IMPACT Center and now we have expanded our services to regional hospitals within the Cleveland Clinic Health System.

INTERDEPARTMENTAL COMMUNICATION IS CRITICAL

Interdepartmental communication is a must for patient safety, so we encourage a culture of communication between the hospitalist and the surgical team. The location of most of our surgical clinics within the same building as the IMPACT Center further facilitates communication, as does the proximity of the PACE clinic. Additionally, one of our IMPACT Center physicians is accessible around the clock to answer to our surgeon or anesthesiologist colleagues as needed.

We regularly assess our process and seek feedback from surgeons and anesthesiologists. We also conduct yearly patient experience surveys to make sure we are providing patients with the highest quality of care.

 

 

Discussion

Question from the audience: Our anesthesia assessment department was approached by our surgeons to do both the anesthesia and surgical assessments, but we felt that would put us in a potential legal conflict if a patient who was assessed that way developed problems. Can you comment?

Dr. Bader: Although we do surgical assessments at our preoperative clinic, we don’t make any decisions about whether or not to proceed with an operation. We get an office note from the surgeon that is directed specifically toward the need for surgery, indications for surgery, and surgical consent. We perform the surgical history and physical examination. Our process is essentially the same as when surgeons have a physician assistant do the history and physical examination in their office. Our practitioners are employed by the hospital, so there is no conflict of interest there.

Comment from the audience: I’m a strong believer in hands-on patient contact. Over my 15 years of practice, we have encountered a lot of unexpected problems during the preoperative exam—aortic stenoses, infections, ventricular septal defects—all of which would never have been detected from a screening form.

Dr. Sweitzer: I agree that we pick up many things by seeing the patient in person. I’ve picked up more cases of aortic stenosis as an anesthesiologist in the preoperative clinic than I ever did as an internist, because the population is high-risk. But patients who have such problems tend to have risk factors and be in certain age groups. Studies indicate that the history is more important than the physical exam: the history suggests about 75% of conditions that are present. The physical exam adds only a little more—perhaps another 15%. Our recommendations are very much consistent with the American College of Cardiology and American Heart Association guidelines on preoperative cardiac evaluation.⁷ It is more important to identify whether a patient has risk factors for coronary artery disease than to find out whether a stress test or ECG is normal. One needs to do a really good history, but it can be done remotely. Based on certain risk factors identified, high-risk patients can be selected who need to come in and have a physical exam.

Question from the audience: Could you elaborate on the electronic medical record system used at the University of Chicago? I’ve heard there’s a steep learning curve when implementing these kinds of systems. They also are very expensive—I’ve heard that some cost $40 to $80 million. Has enhanced revenue flow offset the costs?

Dr. Sweitzer: We have a home-grown system developed with FileMaker Pro by a computer programmer at our institution. It was a lot easier to develop than people tend to think. There are many savvy computer programmers out there; I’ve had medical students assist me with updating it. We’re now considering developing it as a commercial system. Many systems are available for purchase, including Epic, Pyxis, one from General Electric, and many others. They are very expensive, so smaller institutions might want to use a pay-for-service system.

There definitely is a learning curve to switching to electronic medical records, but it is not nearly as steep as many believe. The extra time it takes a clinician to initially make a computer entry rather than write on paper is vastly recouped downstream: the electronic medical record is legible and organized, and it doesn’t get lost or need to be redone. You can bring up a patient record from 6 months before and reuse it as a template.

Dr. Bader: The discussion of cost savings from preoperative clinics usually focuses on savings from avoiding surgery cancellations and delays and from more efficient laboratory testing, but the biggest savings for an institution is better reimbursement through better diagnosis-related groups (DRG) coding. That’s an important reason our institution is funding our clinic. Electronic medical records allow standardization of information so that coders know exactly where to look for the comorbidities and other pertinent information. This increases payments for DRGs, which can be documented for the hospital. This literally runs into millions of dollars a year and more than offsets the costs of the system.

Question from the audience: Dr. Bader, I’m impressed with the number of patients going through your pre­operative clinic. How many patients are seen per nurse practitioner in your clinic?

Dr. Bader: The nurse practitioners have 10-hour shifts and see one patient every 75 minutes. The process of seeing a patient takes a lot less time now than with the old system, in which patients saw an anesthesiologist plus a nurse. Our current system eliminates redundancy: questions need to be asked only once.

Question from the audience: My compliance office says that preoperative assessments for early-morning admission patients are good for only 7 days. Is that true?

Dr. Bader: There are sometimes differences between Joint Commission requirements and those of certain insurance companies. That kind of issue needs to be discussed with your hospital compliance office. We program rules into our scheduling system to accommodate different insurance policies and other requirements so that a patient is not scheduled beyond the allowable period.

Anemia is a potent risk factor for mortality and morbidity in surgical patients, and its management has begun to shift away from allogeneic blood transfusion in recent years. This article reviews the clinical importance of perioperative anemia, the role and shortcomings of blood transfusion, and the pros and cons of alternative approaches to managing perioperative anemia. I conclude with an overview of a program for perioperative blood product use at my institution, Cleveland Clinic.

SIGNIFICANCE OF PERIOPERATIVE ANEMIA

Prevalence depends on many factors

The reported prevalence of anemia in surgical patients varies widely—from 5% to 76%¹—and depends on the patient’s disease and comorbidities, the surgical procedure and associated blood loss, and the definition of anemia used. The prevalence of preoperative anemia increases with patient age and is higher in women than in men.²

A multiplier of risk

Anemia is an important multiplier of mortality risk. For example, the presence of anemia raises the relative risk of 2-year mortality from 2.05 to 3.37 in patients with chronic kidney disease, from 2.86 to 3.78 in patients with heart failure, and from 4.86 to 6.07 in patients with concomitant heart failure and chronic kidney disease.³

Adverse effects of anemia have been demonstrated specifically in the perioperative setting as well. A large retrospective cohort study showed that a preoperative hemoglobin concentration of less than 6 g/dL increases the risk of death 30 days after surgery by a factor of 26 relative to a concentration of 12 g/dL or greater in surgical patients who declined blood transfusion for religious reasons.⁴ The anemia-associated mortality risk was especially pronounced among patients with cardiovascular disease.⁴ Other studies have demonstrated perioperative anemia to be associated with increases in the risk of death,⁵ cardiac events,⁶ pneumonia,⁷ and postoperative delirium.⁸

IS BLOOD TRANSFUSION THE ANSWER

The use of allogeneic blood transfusion to manage anemia and blood loss is a concept that originated several centuries ago and has changed little over the years.

Blood supply challenges

Blood collection has historically lagged demand, resulting in a blood supply insufficient to meet transfusion needs. According to the federal government’s 2007 National Blood Collection and Utilization Survey Report, 6.89% of US hospitals reported that they cancelled elective surgery on 1 or more days in the prior year because of a lack of blood availability, and 13.5% experienced at least 1 day in which nonsurgical blood needs could not be met.⁹ Unless practices are changed to increase blood donation, these unmet tranfusion needs may grow.

Joint Commission set to measure blood management

In response to this challenge, an advisory panel formed by the Joint Commission has identified 17 performance measures related to blood conservation and appropriate transfusion.¹⁰ These measures are currently in development, and we expect to see some types of metrics in the near future. Such metrics are likely to further prioritize blood management for US hospitals.

Safety of the blood supply: Viral transmission down, TRALI risk persists

The safety of the blood supply has improved markedly. Sophisticated testing and public demand have led to a dramatic decline in the risk of transfusion-related transmission of HIV, hepatitis C virus, and hepatitis B virus.¹¹

Despite this progress, the risk of transfusion-related acute lung injury (TRALI) has persisted in recent years. TRALI is characterized by acute onset of noncardiogenic pulmonary edema within 6 hours of blood product transfusion. Believed to be immune-mediated, TRALI is thought to occur as antibodies to human leukocyte antigens develop, inducing capillary leak syndrome.¹² The patients most commonly affected are those who receive plasma from multiparous female donors. A recent evaluation of transfusion-related fatalities reported to the US Food and Drug Administration (FDA) revealed a continual rise in fatal TRALI cases in the United States from 2001 to 2006.^13–15 TRALI was implicated in more than half of all transfusion-related fatalities reported to the FDA in 2006, a higher number than for any other single cause.¹³

At the same time, there is evidence that hemovigilance can reduce TRALI risk. In the United Kingdom, the Serious Hazards of Transfusion Steering Group introduced in late 2003 a policy of using plasma from male donors as much as possible, in view of the association of TRALI with plasma from multiparous female donors. The effort appeared to pay off: whereas TRALI accounted for 6.8% of all transfusion-related adverse events reported in the United Kingdom during the period 1996–2003,¹⁶ this proportion declined to just 1.9% in 2006.¹⁷

Finally, despite the progress in screening blood for more established infections like HIV and the hepatitis viruses, some additional infections now must be considered when assessing blood supply safety. These include diseases newly recognized as being transmissible by blood, or for which blood donor screening is not currently available, or that are newly emergent infections for which the potential for spread by transfusion is unknown. For such diseases—which include malaria and West Nile virus—the risk of transmission through transfusion is low, as they are much more likely to be acquired by other means.

Transfusion and outcomes: Not a strong record

Transfusion has never undergone safety and efficacy evaluation by the FDA. Given the challenges of conducting a randomized study of transfusion in the peri­operative setting, we may never have high-quality data to assess transfusion in this setting.

A few studies merit mention, however. The Transfusion Requirement in Critical Care (TRICC) trial was conducted in 838 critically ill patients in the intensive care setting.¹⁸ Patients were randomized to a strategy of either liberal transfusion (begun when hemoglobin fell below 10 g/dL) or restrictive transfusion (begun when hemoglobin fell below 7 g/dL). Thirty-day mortality was similar between patients in the two strategy groups, but the restrictive strategy was associated with significantly lower mortality in at least two subgroups: patients with myocardial infarction and patients with pulmonary edema. Further subgroup analysis found no benefit of early or aggressive transfusion in patients with coronary artery disease or in those requiring mechanical ventilation.

Rao et al performed a meta-analysis of three large international trials of patients with acute coronary syndromes to determine whether blood transfusion to correct anemia in this setting was associated with improved survival.¹⁹ They found significantly higher mortality among patients who underwent transfusion compared with those who did not, prompting them to urge caution in the use of transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease.

Similarly, a risk-adjusted, propensity-matched analysis of 6,301 patients undergoing noncardiac surgery found that receipt of 4 U of blood or more was a predictor of greater mortality, higher risk of infection, and longer hospital stay.²⁰ Moreover, in an observational cohort study of 11,963 patients who underwent isolated coronary artery bypass graft surgery, each unit of red blood cells transfused was associated with an incrementally increased risk of adverse outcome (eg, mortality, renal injury, need for ventilator support, lengthened hospital stay, infection).²¹ The latter study found that transfusion was the single factor most reliably associated with increased risk of postoperative morbidity.

Additional studies have echoed these findings—ie, that perioperative blood transfusion has been associated with a host of adverse outcomes, including increased morbidity and length of stay, increased rates of post­operative infection, as well as immunosuppression, viral transmission, and acute transfusion reactions.^5,22,23

 

 

Outcomes and duration of blood storage

An interesting factor in the relation between transfusion and outcomes is the shelf life of the blood being transfused. The FDA currently allows storage of blood for a maximum of 42 days, but a recent study of patients who received red blood cell transfusions during cardiac surgery found that those who received “older blood” (stored for > 14 days) had significantly higher rates of sepsis, prolonged intubation, renal failure, in-hospital mortality, and 1-year mortality compared with those who received “newer blood” (stored for ≤ 14 days).²⁴

These differing outcomes are generally attributed to the so-called storage defect: as blood gets older, it loses components such as 2,3-DPG and adenosine disphosphate, its red cells lose deformability, and it undergoes buildup of cytokines and free hemoglobin. Increased demand for newer blood in light of the storage defect could further intensify pressures on the blood supply.

MANAGEMENT OF PERIOPERATIVE ANEMIA

In light of these shortcomings of blood transfusion, how should anemia be managed perioperatively to reduce or avoid the need for transfusion?

Preoperative evaluation

Vigilance for anemia and related issues in the preoperative evaluation is fundamental. The evaluation should elicit a history of bleeding tendencies, previous transfusions, and symptoms of anemia. Medications should be reviewed with an eye toward any that may predispose to perioperative bleeding and anemia, such as aspirin, clopidogrel, and anticoagulants. During the physical examination, alertness for pallor and petechiae is key, as is attentiveness to symptoms of anemia such as shortness of breath and fatigue.

The laboratory work-up begins with a measure of hemoglobin: anemia is defined as hemoglobin less than 13 g/dL in males and less than 12 g/dL in females. If anemia is present and is associated with another hematologic abnormality, the patient should be referred to a hematologist for bone marrow examination. If no other hematologic abnormality exists, the ensuing work-up relies on red blood cell indices as detailed in Figure 1.²⁵ The goal is to identify those conditions for which intervention in the short term is possible—namely, anemia of chronic disease, iron deficiency, and vitamin B₁₂ deficiency. Findings suggestive of other conditions require further evaluation at a preoperative center.

Overview of management options

Once the cause of anemia is identified, the choice for optimal medical management can be made. Choices broadly consist of pharmacologic and technological options. The former include iron supplements and erythropoiesis-stimulating agents. Among other pharmacologic options are thrombin, collagen, fibrin glue, tranexamic acid, and aminocaproic acid, but these agents are less well studied and will not be discussed here. Technological options include preoperative autologous blood donation, cell salvage, and acute normovolemic hemodilution.

In addition to these options, careful management of anticoagulant and antiplatelet medications should be provided, including discontinuation or substitution of drugs that could hamper clotting perioperatively.

PHARMACOLOGIC OPTIONS

Iron supplementation

Oral iron is available in four preparations: ferrous sulfate, ferrous gluconate, ferrous fumarate, and iron polysaccharide. Gastrointestinal side effects may limit these preparations’ tolerability. Iron supplements with a high elemental value will require fewer pills and fewer doses, reducing the risk or frequency of side effects.

Intravenous (IV) iron preparations are much safer now than they were years ago, when anaphylactic reactions were a concern. The ones generally used in the perioperative setting are iron sucrose and iron gluconate. Unlike the older IV preparations, the use of iron sucrose and iron gluconate often requires a second dose. The effect on hemoglobin levels usually occurs starting at 1 week, with the maximum effect achieved at 2 weeks. Hypotension, arthralgia, abdominal discomfort, and back pain are potential side effects of IV iron.

Efficacy and safety of iron supplementation. Evidence of the efficacy of preoperative iron supplementation is mounting. A study of 569 patients undergoing colorectal cancer surgery found that among the 116 patients who were anemic, intraoperative transfusion was needed in a significantly lower proportion of those who received 2 weeks of preoperative oral iron supplementation (200 mg) compared with those who received no iron therapy (9.4% vs 27.4%; P < .05).²⁶ Similarly, in an uncontrolled study, 10 days of IV iron sucrose starting 4 weeks preoperatively significantly increased hemoglobin levels in 20 patients with iron-deficiency anemia prior to elective orthopedic surgery.²⁷

Risks of infection and cancer progression have been concerns with IV iron therapy. However, no significant association between IV iron therapy and bacteremia was identified in a prospective study of 985 patients receiving chronic hemodialysis.²⁸ The effect of IV iron administration on tumor progression has not been prospectively studied.

In general, IV iron, especially the newer forms, is a safer alternative to blood transfusion. Death occurs at a much lower rate with iron than with blood transfusion (0.4 per million vs 4 per million, respectively), as do life-threatening adverse events (4 per million vs 10 per million, respectively), according to a systematic review by the Network for Advancement of Transfusion Alternatives.²⁹

Erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) include epoetin alfa (erythropoietin), first approved by the FDA in 1989, and the more recently introduced darbe­poetin alfa. They are approved to treat anemia in several patient populations, but only epoetin alfa is approved by the FDA explicitly for use in patients undergoing major surgery (to reduce the need for blood transfusions). The ESAs have come under intense scrutiny in recent years over their risk-to-benefit ratio, as detailed below.

The preoperative dosing schedule for epoetin alfa is usually three weekly doses (plus a fourth dose on the day of surgery) if the surgery is scheduled 3 or more weeks in advance. However, daily dosing can be used effectively if the preoperative period is less than 3 weeks, provided that it is continued until 4 days after surgery. Oral iron is necessary throughout the course of epoetin alfa therapy.

Efficacy in reducing transfusions. In a systematic review published in 1998, epoetin alfa was shown to minimize perioperative exposure to allogeneic blood transfusion in patients undergoing orthopedic or cardiac surgery.³⁰ Its benefit was greatest in patients at the highest risk of requiring transfusion. It was effective whether given daily or weekly, and did not significantly increase the risk of thrombotic events when used in surgical patients, although some studies did find an excess of thrombotic events with its use.

In three randomized trials conducted in patients undergoing joint arthroplasty (hip or knee), epoetin alfa was associated with substantial and significant reductions in perioperative blood transfusion compared with placebo or preoperative autologous blood donation.^31–33 Rates of deep vein thrombosis (DVT) did not differ significantly between the epoetin alfa and placebo groups.

Concerns over perioperative thromboembolic risk. In early 2007, the FDA was made aware of preliminary results of an open-label study in which 681 patients undergoing elective spinal surgery who did not receive prophylactic anticoagulation were randomized to epoetin alfa plus standard-of-care therapy (pneumatic compression) or standard-of-care therapy alone.^34,35 The incidence of DVT was 4.7% in patients treated with epoetin alfa compared with 2.1% in those not receiving epoetin alfa. It is important to note that the available ESAs are prothrombotic and increase thrombotic risk significantly, especially in populations like this one in which pharmacologic DVT prophylaxis is not routinely used.

Based in part on this study, the FDA in 2007 required a boxed warning to be added to the ESAs’ package inserts to specify the increased risk of DVT with their use in surgical patients not receiving prophylactic anticoagulation. The warning urges consideration of the use of DVT prophylaxis in surgical patients receiving an ESA.^34,35

 

 

TECHNOLOGICAL OPTIONS AND OTHER STRATEGIES

Autologous blood donation: A practice in decline

In cases of elective surgery, autologous blood donation can be used to protect against disease transmission and overcome the challenge of blood type compatibility. Preoperative autologous donation of blood has been a prevalent practice, but its use is declining. One reason is that waste is high (approximately 50% at Cleveland Clinic), which makes this practice more costly than is often realized. Also, autologous blood donation increases the likelihood that the patient will be anemic on the day of surgery, so that he or she may still need allogeneic blood after all, defeating the initial purpose. Despite these limitations, preoperative autologous blood donation remains a useful option for a subset of patients with multiple antibodies for whom donor blood may be difficult to obtain.

Cell salvage

Cell salvage is an innovative technology that recovers the patient’s own blood (after being shed from the surgical incision) for transfusion after filtering and washing. It is particularly well suited to procedures that involve massive blood loss. Cell savage requires technical expertise, however, and involves costs associated with both the machine and disposables.

Restricted postoperative phlebotomy

Phlebotomy accounts for a significant amount of blood loss, especially in intensive care patients with arterial lines. The equivalent of 30% of total blood transfused has been reported to be lost to phlebotomy during an intensive care unit stay.³⁶ Triggers for transfusion cannot be assigned universally based on blood loss from phlebotomy but must consider the patient’s hemodynamic status, cardiac reserve, and other clinical characteristics.

PROMOTING RESPONSIBLE BLOOD PRODUCT USE

Blood is expensive, and in recent years hospitals have experienced increases in the cost of blood and blood products. To promote responsible blood use, we have developed a multipronged approach to blood management at Cleveland Clinic. The program’s cornerstone is increased awareness of the risks associated with blood transfusions. The emphasis is on educating staff physicians and other caregivers about the appropriate use of blood products. We also have implemented a new policy requiring staff authorization for all blood requested in nonemergency situations. Additionally, requests for blood components require adherence to an indication-based ordering process. Finally, data about blood use are shared transparently among physicians, encouraging good clinical practice.

Our program has also involved development and implementation of a preoperative anemia protocol to explicitly define the indications for use of ESAs, iron therapy, and vitamin B₁₂ therapy in patients undergoing joint arthroplasty (Figure 2).

In the first 7 months of the program, we observed decreased utilization of blood products in the inpatient setting. Notably, the reduction in blood use was significantly greater in the surgical population than in the medical population.

CONCULSIONS

Anemia is associated with increased morbidity and mortality in the perioperative setting. Perioperative blood transfusion is one method of raising hemoglobin levels in anemic surgical patients, but it increases perioperative morbidity in the form of acute transfusion reactions, immunosuppression, postoperative infection, and longer hospital stays. Moreover, blood collection continues to lag blood demand. For these reasons, most relevant major medical organizations—including the Association of Blood Banks, the American Red Cross, and the FDA—advise that red blood cell–containing components should not be used to treat anemias that can be corrected with medications. These medical alternatives—all of which can be used in the perioperative setting—include iron supplementation, vitamin B₁₂, and ESAs in select patient groups.

DISCUSSION

Question from the audience: Are there risks involved with autologous blood donation? Are different hemoglobin thresholds used when a patient’s own blood is used?

Dr. Kumar: As I mentioned, preoperative autologous donation is a technique that is less frequently used in our hospital. Autologous transfusion is considered safe only for patients who come to the clinic with normal hemoglobin values. Some patients may not have recovered from their blood loss by the time they come to surgery, so you end up needing to give them more blood because they started out anemic.

Question from the audience: Is there risk to giving patients back their own blood? Do you have to worry about transfusion-induced lung injury, sepsis, or other complications?

Dr. Kumar: As with allogeneic blood, the risk of clerical or clinical error exists with autologous blood: it too needs to be kept on the shelf, taken out, and infused, and the risk of sepsis remains the same.

Anemia is a potent risk factor for mortality and morbidity in surgical patients, and its management has begun to shift away from allogeneic blood transfusion in recent years. This article reviews the clinical importance of perioperative anemia, the role and shortcomings of blood transfusion, and the pros and cons of alternative approaches to managing perioperative anemia. I conclude with an overview of a program for perioperative blood product use at my institution, Cleveland Clinic.

SIGNIFICANCE OF PERIOPERATIVE ANEMIA

Prevalence depends on many factors

The reported prevalence of anemia in surgical patients varies widely—from 5% to 76%¹—and depends on the patient’s disease and comorbidities, the surgical procedure and associated blood loss, and the definition of anemia used. The prevalence of preoperative anemia increases with patient age and is higher in women than in men.²

A multiplier of risk

Anemia is an important multiplier of mortality risk. For example, the presence of anemia raises the relative risk of 2-year mortality from 2.05 to 3.37 in patients with chronic kidney disease, from 2.86 to 3.78 in patients with heart failure, and from 4.86 to 6.07 in patients with concomitant heart failure and chronic kidney disease.³

Adverse effects of anemia have been demonstrated specifically in the perioperative setting as well. A large retrospective cohort study showed that a preoperative hemoglobin concentration of less than 6 g/dL increases the risk of death 30 days after surgery by a factor of 26 relative to a concentration of 12 g/dL or greater in surgical patients who declined blood transfusion for religious reasons.⁴ The anemia-associated mortality risk was especially pronounced among patients with cardiovascular disease.⁴ Other studies have demonstrated perioperative anemia to be associated with increases in the risk of death,⁵ cardiac events,⁶ pneumonia,⁷ and postoperative delirium.⁸

IS BLOOD TRANSFUSION THE ANSWER

The use of allogeneic blood transfusion to manage anemia and blood loss is a concept that originated several centuries ago and has changed little over the years.

Blood supply challenges

Blood collection has historically lagged demand, resulting in a blood supply insufficient to meet transfusion needs. According to the federal government’s 2007 National Blood Collection and Utilization Survey Report, 6.89% of US hospitals reported that they cancelled elective surgery on 1 or more days in the prior year because of a lack of blood availability, and 13.5% experienced at least 1 day in which nonsurgical blood needs could not be met.⁹ Unless practices are changed to increase blood donation, these unmet tranfusion needs may grow.

Joint Commission set to measure blood management

In response to this challenge, an advisory panel formed by the Joint Commission has identified 17 performance measures related to blood conservation and appropriate transfusion.¹⁰ These measures are currently in development, and we expect to see some types of metrics in the near future. Such metrics are likely to further prioritize blood management for US hospitals.

Safety of the blood supply: Viral transmission down, TRALI risk persists

The safety of the blood supply has improved markedly. Sophisticated testing and public demand have led to a dramatic decline in the risk of transfusion-related transmission of HIV, hepatitis C virus, and hepatitis B virus.¹¹

Despite this progress, the risk of transfusion-related acute lung injury (TRALI) has persisted in recent years. TRALI is characterized by acute onset of noncardiogenic pulmonary edema within 6 hours of blood product transfusion. Believed to be immune-mediated, TRALI is thought to occur as antibodies to human leukocyte antigens develop, inducing capillary leak syndrome.¹² The patients most commonly affected are those who receive plasma from multiparous female donors. A recent evaluation of transfusion-related fatalities reported to the US Food and Drug Administration (FDA) revealed a continual rise in fatal TRALI cases in the United States from 2001 to 2006.^13–15 TRALI was implicated in more than half of all transfusion-related fatalities reported to the FDA in 2006, a higher number than for any other single cause.¹³

At the same time, there is evidence that hemovigilance can reduce TRALI risk. In the United Kingdom, the Serious Hazards of Transfusion Steering Group introduced in late 2003 a policy of using plasma from male donors as much as possible, in view of the association of TRALI with plasma from multiparous female donors. The effort appeared to pay off: whereas TRALI accounted for 6.8% of all transfusion-related adverse events reported in the United Kingdom during the period 1996–2003,¹⁶ this proportion declined to just 1.9% in 2006.¹⁷

Finally, despite the progress in screening blood for more established infections like HIV and the hepatitis viruses, some additional infections now must be considered when assessing blood supply safety. These include diseases newly recognized as being transmissible by blood, or for which blood donor screening is not currently available, or that are newly emergent infections for which the potential for spread by transfusion is unknown. For such diseases—which include malaria and West Nile virus—the risk of transmission through transfusion is low, as they are much more likely to be acquired by other means.

Transfusion and outcomes: Not a strong record

Transfusion has never undergone safety and efficacy evaluation by the FDA. Given the challenges of conducting a randomized study of transfusion in the peri­operative setting, we may never have high-quality data to assess transfusion in this setting.

A few studies merit mention, however. The Transfusion Requirement in Critical Care (TRICC) trial was conducted in 838 critically ill patients in the intensive care setting.¹⁸ Patients were randomized to a strategy of either liberal transfusion (begun when hemoglobin fell below 10 g/dL) or restrictive transfusion (begun when hemoglobin fell below 7 g/dL). Thirty-day mortality was similar between patients in the two strategy groups, but the restrictive strategy was associated with significantly lower mortality in at least two subgroups: patients with myocardial infarction and patients with pulmonary edema. Further subgroup analysis found no benefit of early or aggressive transfusion in patients with coronary artery disease or in those requiring mechanical ventilation.

Rao et al performed a meta-analysis of three large international trials of patients with acute coronary syndromes to determine whether blood transfusion to correct anemia in this setting was associated with improved survival.¹⁹ They found significantly higher mortality among patients who underwent transfusion compared with those who did not, prompting them to urge caution in the use of transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease.

Similarly, a risk-adjusted, propensity-matched analysis of 6,301 patients undergoing noncardiac surgery found that receipt of 4 U of blood or more was a predictor of greater mortality, higher risk of infection, and longer hospital stay.²⁰ Moreover, in an observational cohort study of 11,963 patients who underwent isolated coronary artery bypass graft surgery, each unit of red blood cells transfused was associated with an incrementally increased risk of adverse outcome (eg, mortality, renal injury, need for ventilator support, lengthened hospital stay, infection).²¹ The latter study found that transfusion was the single factor most reliably associated with increased risk of postoperative morbidity.

Additional studies have echoed these findings—ie, that perioperative blood transfusion has been associated with a host of adverse outcomes, including increased morbidity and length of stay, increased rates of post­operative infection, as well as immunosuppression, viral transmission, and acute transfusion reactions.^5,22,23

 

 

Outcomes and duration of blood storage

An interesting factor in the relation between transfusion and outcomes is the shelf life of the blood being transfused. The FDA currently allows storage of blood for a maximum of 42 days, but a recent study of patients who received red blood cell transfusions during cardiac surgery found that those who received “older blood” (stored for > 14 days) had significantly higher rates of sepsis, prolonged intubation, renal failure, in-hospital mortality, and 1-year mortality compared with those who received “newer blood” (stored for ≤ 14 days).²⁴

These differing outcomes are generally attributed to the so-called storage defect: as blood gets older, it loses components such as 2,3-DPG and adenosine disphosphate, its red cells lose deformability, and it undergoes buildup of cytokines and free hemoglobin. Increased demand for newer blood in light of the storage defect could further intensify pressures on the blood supply.

MANAGEMENT OF PERIOPERATIVE ANEMIA

In light of these shortcomings of blood transfusion, how should anemia be managed perioperatively to reduce or avoid the need for transfusion?

Preoperative evaluation

Vigilance for anemia and related issues in the preoperative evaluation is fundamental. The evaluation should elicit a history of bleeding tendencies, previous transfusions, and symptoms of anemia. Medications should be reviewed with an eye toward any that may predispose to perioperative bleeding and anemia, such as aspirin, clopidogrel, and anticoagulants. During the physical examination, alertness for pallor and petechiae is key, as is attentiveness to symptoms of anemia such as shortness of breath and fatigue.

The laboratory work-up begins with a measure of hemoglobin: anemia is defined as hemoglobin less than 13 g/dL in males and less than 12 g/dL in females. If anemia is present and is associated with another hematologic abnormality, the patient should be referred to a hematologist for bone marrow examination. If no other hematologic abnormality exists, the ensuing work-up relies on red blood cell indices as detailed in Figure 1.²⁵ The goal is to identify those conditions for which intervention in the short term is possible—namely, anemia of chronic disease, iron deficiency, and vitamin B₁₂ deficiency. Findings suggestive of other conditions require further evaluation at a preoperative center.

Overview of management options

Once the cause of anemia is identified, the choice for optimal medical management can be made. Choices broadly consist of pharmacologic and technological options. The former include iron supplements and erythropoiesis-stimulating agents. Among other pharmacologic options are thrombin, collagen, fibrin glue, tranexamic acid, and aminocaproic acid, but these agents are less well studied and will not be discussed here. Technological options include preoperative autologous blood donation, cell salvage, and acute normovolemic hemodilution.

In addition to these options, careful management of anticoagulant and antiplatelet medications should be provided, including discontinuation or substitution of drugs that could hamper clotting perioperatively.

PHARMACOLOGIC OPTIONS

Iron supplementation

Oral iron is available in four preparations: ferrous sulfate, ferrous gluconate, ferrous fumarate, and iron polysaccharide. Gastrointestinal side effects may limit these preparations’ tolerability. Iron supplements with a high elemental value will require fewer pills and fewer doses, reducing the risk or frequency of side effects.

Intravenous (IV) iron preparations are much safer now than they were years ago, when anaphylactic reactions were a concern. The ones generally used in the perioperative setting are iron sucrose and iron gluconate. Unlike the older IV preparations, the use of iron sucrose and iron gluconate often requires a second dose. The effect on hemoglobin levels usually occurs starting at 1 week, with the maximum effect achieved at 2 weeks. Hypotension, arthralgia, abdominal discomfort, and back pain are potential side effects of IV iron.

Efficacy and safety of iron supplementation. Evidence of the efficacy of preoperative iron supplementation is mounting. A study of 569 patients undergoing colorectal cancer surgery found that among the 116 patients who were anemic, intraoperative transfusion was needed in a significantly lower proportion of those who received 2 weeks of preoperative oral iron supplementation (200 mg) compared with those who received no iron therapy (9.4% vs 27.4%; P < .05).²⁶ Similarly, in an uncontrolled study, 10 days of IV iron sucrose starting 4 weeks preoperatively significantly increased hemoglobin levels in 20 patients with iron-deficiency anemia prior to elective orthopedic surgery.²⁷

Risks of infection and cancer progression have been concerns with IV iron therapy. However, no significant association between IV iron therapy and bacteremia was identified in a prospective study of 985 patients receiving chronic hemodialysis.²⁸ The effect of IV iron administration on tumor progression has not been prospectively studied.

In general, IV iron, especially the newer forms, is a safer alternative to blood transfusion. Death occurs at a much lower rate with iron than with blood transfusion (0.4 per million vs 4 per million, respectively), as do life-threatening adverse events (4 per million vs 10 per million, respectively), according to a systematic review by the Network for Advancement of Transfusion Alternatives.²⁹

Erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) include epoetin alfa (erythropoietin), first approved by the FDA in 1989, and the more recently introduced darbe­poetin alfa. They are approved to treat anemia in several patient populations, but only epoetin alfa is approved by the FDA explicitly for use in patients undergoing major surgery (to reduce the need for blood transfusions). The ESAs have come under intense scrutiny in recent years over their risk-to-benefit ratio, as detailed below.

The preoperative dosing schedule for epoetin alfa is usually three weekly doses (plus a fourth dose on the day of surgery) if the surgery is scheduled 3 or more weeks in advance. However, daily dosing can be used effectively if the preoperative period is less than 3 weeks, provided that it is continued until 4 days after surgery. Oral iron is necessary throughout the course of epoetin alfa therapy.

Efficacy in reducing transfusions. In a systematic review published in 1998, epoetin alfa was shown to minimize perioperative exposure to allogeneic blood transfusion in patients undergoing orthopedic or cardiac surgery.³⁰ Its benefit was greatest in patients at the highest risk of requiring transfusion. It was effective whether given daily or weekly, and did not significantly increase the risk of thrombotic events when used in surgical patients, although some studies did find an excess of thrombotic events with its use.

In three randomized trials conducted in patients undergoing joint arthroplasty (hip or knee), epoetin alfa was associated with substantial and significant reductions in perioperative blood transfusion compared with placebo or preoperative autologous blood donation.^31–33 Rates of deep vein thrombosis (DVT) did not differ significantly between the epoetin alfa and placebo groups.

Concerns over perioperative thromboembolic risk. In early 2007, the FDA was made aware of preliminary results of an open-label study in which 681 patients undergoing elective spinal surgery who did not receive prophylactic anticoagulation were randomized to epoetin alfa plus standard-of-care therapy (pneumatic compression) or standard-of-care therapy alone.^34,35 The incidence of DVT was 4.7% in patients treated with epoetin alfa compared with 2.1% in those not receiving epoetin alfa. It is important to note that the available ESAs are prothrombotic and increase thrombotic risk significantly, especially in populations like this one in which pharmacologic DVT prophylaxis is not routinely used.

Based in part on this study, the FDA in 2007 required a boxed warning to be added to the ESAs’ package inserts to specify the increased risk of DVT with their use in surgical patients not receiving prophylactic anticoagulation. The warning urges consideration of the use of DVT prophylaxis in surgical patients receiving an ESA.^34,35

 

 

TECHNOLOGICAL OPTIONS AND OTHER STRATEGIES

Autologous blood donation: A practice in decline

In cases of elective surgery, autologous blood donation can be used to protect against disease transmission and overcome the challenge of blood type compatibility. Preoperative autologous donation of blood has been a prevalent practice, but its use is declining. One reason is that waste is high (approximately 50% at Cleveland Clinic), which makes this practice more costly than is often realized. Also, autologous blood donation increases the likelihood that the patient will be anemic on the day of surgery, so that he or she may still need allogeneic blood after all, defeating the initial purpose. Despite these limitations, preoperative autologous blood donation remains a useful option for a subset of patients with multiple antibodies for whom donor blood may be difficult to obtain.

Cell salvage

Cell salvage is an innovative technology that recovers the patient’s own blood (after being shed from the surgical incision) for transfusion after filtering and washing. It is particularly well suited to procedures that involve massive blood loss. Cell savage requires technical expertise, however, and involves costs associated with both the machine and disposables.

Restricted postoperative phlebotomy

Phlebotomy accounts for a significant amount of blood loss, especially in intensive care patients with arterial lines. The equivalent of 30% of total blood transfused has been reported to be lost to phlebotomy during an intensive care unit stay.³⁶ Triggers for transfusion cannot be assigned universally based on blood loss from phlebotomy but must consider the patient’s hemodynamic status, cardiac reserve, and other clinical characteristics.

PROMOTING RESPONSIBLE BLOOD PRODUCT USE

Blood is expensive, and in recent years hospitals have experienced increases in the cost of blood and blood products. To promote responsible blood use, we have developed a multipronged approach to blood management at Cleveland Clinic. The program’s cornerstone is increased awareness of the risks associated with blood transfusions. The emphasis is on educating staff physicians and other caregivers about the appropriate use of blood products. We also have implemented a new policy requiring staff authorization for all blood requested in nonemergency situations. Additionally, requests for blood components require adherence to an indication-based ordering process. Finally, data about blood use are shared transparently among physicians, encouraging good clinical practice.

Our program has also involved development and implementation of a preoperative anemia protocol to explicitly define the indications for use of ESAs, iron therapy, and vitamin B₁₂ therapy in patients undergoing joint arthroplasty (Figure 2).

In the first 7 months of the program, we observed decreased utilization of blood products in the inpatient setting. Notably, the reduction in blood use was significantly greater in the surgical population than in the medical population.

CONCULSIONS

Anemia is associated with increased morbidity and mortality in the perioperative setting. Perioperative blood transfusion is one method of raising hemoglobin levels in anemic surgical patients, but it increases perioperative morbidity in the form of acute transfusion reactions, immunosuppression, postoperative infection, and longer hospital stays. Moreover, blood collection continues to lag blood demand. For these reasons, most relevant major medical organizations—including the Association of Blood Banks, the American Red Cross, and the FDA—advise that red blood cell–containing components should not be used to treat anemias that can be corrected with medications. These medical alternatives—all of which can be used in the perioperative setting—include iron supplementation, vitamin B₁₂, and ESAs in select patient groups.

DISCUSSION

Question from the audience: Are there risks involved with autologous blood donation? Are different hemoglobin thresholds used when a patient’s own blood is used?

Dr. Kumar: As I mentioned, preoperative autologous donation is a technique that is less frequently used in our hospital. Autologous transfusion is considered safe only for patients who come to the clinic with normal hemoglobin values. Some patients may not have recovered from their blood loss by the time they come to surgery, so you end up needing to give them more blood because they started out anemic.

Question from the audience: Is there risk to giving patients back their own blood? Do you have to worry about transfusion-induced lung injury, sepsis, or other complications?

Dr. Kumar: As with allogeneic blood, the risk of clerical or clinical error exists with autologous blood: it too needs to be kept on the shelf, taken out, and infused, and the risk of sepsis remains the same.

Anemia is a potent risk factor for mortality and morbidity in surgical patients, and its management has begun to shift away from allogeneic blood transfusion in recent years. This article reviews the clinical importance of perioperative anemia, the role and shortcomings of blood transfusion, and the pros and cons of alternative approaches to managing perioperative anemia. I conclude with an overview of a program for perioperative blood product use at my institution, Cleveland Clinic.

SIGNIFICANCE OF PERIOPERATIVE ANEMIA

Prevalence depends on many factors

The reported prevalence of anemia in surgical patients varies widely—from 5% to 76%¹—and depends on the patient’s disease and comorbidities, the surgical procedure and associated blood loss, and the definition of anemia used. The prevalence of preoperative anemia increases with patient age and is higher in women than in men.²

A multiplier of risk

Anemia is an important multiplier of mortality risk. For example, the presence of anemia raises the relative risk of 2-year mortality from 2.05 to 3.37 in patients with chronic kidney disease, from 2.86 to 3.78 in patients with heart failure, and from 4.86 to 6.07 in patients with concomitant heart failure and chronic kidney disease.³

Adverse effects of anemia have been demonstrated specifically in the perioperative setting as well. A large retrospective cohort study showed that a preoperative hemoglobin concentration of less than 6 g/dL increases the risk of death 30 days after surgery by a factor of 26 relative to a concentration of 12 g/dL or greater in surgical patients who declined blood transfusion for religious reasons.⁴ The anemia-associated mortality risk was especially pronounced among patients with cardiovascular disease.⁴ Other studies have demonstrated perioperative anemia to be associated with increases in the risk of death,⁵ cardiac events,⁶ pneumonia,⁷ and postoperative delirium.⁸

IS BLOOD TRANSFUSION THE ANSWER

The use of allogeneic blood transfusion to manage anemia and blood loss is a concept that originated several centuries ago and has changed little over the years.

Blood supply challenges

Blood collection has historically lagged demand, resulting in a blood supply insufficient to meet transfusion needs. According to the federal government’s 2007 National Blood Collection and Utilization Survey Report, 6.89% of US hospitals reported that they cancelled elective surgery on 1 or more days in the prior year because of a lack of blood availability, and 13.5% experienced at least 1 day in which nonsurgical blood needs could not be met.⁹ Unless practices are changed to increase blood donation, these unmet tranfusion needs may grow.

Joint Commission set to measure blood management

In response to this challenge, an advisory panel formed by the Joint Commission has identified 17 performance measures related to blood conservation and appropriate transfusion.¹⁰ These measures are currently in development, and we expect to see some types of metrics in the near future. Such metrics are likely to further prioritize blood management for US hospitals.

Safety of the blood supply: Viral transmission down, TRALI risk persists

The safety of the blood supply has improved markedly. Sophisticated testing and public demand have led to a dramatic decline in the risk of transfusion-related transmission of HIV, hepatitis C virus, and hepatitis B virus.¹¹

Despite this progress, the risk of transfusion-related acute lung injury (TRALI) has persisted in recent years. TRALI is characterized by acute onset of noncardiogenic pulmonary edema within 6 hours of blood product transfusion. Believed to be immune-mediated, TRALI is thought to occur as antibodies to human leukocyte antigens develop, inducing capillary leak syndrome.¹² The patients most commonly affected are those who receive plasma from multiparous female donors. A recent evaluation of transfusion-related fatalities reported to the US Food and Drug Administration (FDA) revealed a continual rise in fatal TRALI cases in the United States from 2001 to 2006.^13–15 TRALI was implicated in more than half of all transfusion-related fatalities reported to the FDA in 2006, a higher number than for any other single cause.¹³

At the same time, there is evidence that hemovigilance can reduce TRALI risk. In the United Kingdom, the Serious Hazards of Transfusion Steering Group introduced in late 2003 a policy of using plasma from male donors as much as possible, in view of the association of TRALI with plasma from multiparous female donors. The effort appeared to pay off: whereas TRALI accounted for 6.8% of all transfusion-related adverse events reported in the United Kingdom during the period 1996–2003,¹⁶ this proportion declined to just 1.9% in 2006.¹⁷

Finally, despite the progress in screening blood for more established infections like HIV and the hepatitis viruses, some additional infections now must be considered when assessing blood supply safety. These include diseases newly recognized as being transmissible by blood, or for which blood donor screening is not currently available, or that are newly emergent infections for which the potential for spread by transfusion is unknown. For such diseases—which include malaria and West Nile virus—the risk of transmission through transfusion is low, as they are much more likely to be acquired by other means.

Transfusion and outcomes: Not a strong record

Transfusion has never undergone safety and efficacy evaluation by the FDA. Given the challenges of conducting a randomized study of transfusion in the peri­operative setting, we may never have high-quality data to assess transfusion in this setting.

A few studies merit mention, however. The Transfusion Requirement in Critical Care (TRICC) trial was conducted in 838 critically ill patients in the intensive care setting.¹⁸ Patients were randomized to a strategy of either liberal transfusion (begun when hemoglobin fell below 10 g/dL) or restrictive transfusion (begun when hemoglobin fell below 7 g/dL). Thirty-day mortality was similar between patients in the two strategy groups, but the restrictive strategy was associated with significantly lower mortality in at least two subgroups: patients with myocardial infarction and patients with pulmonary edema. Further subgroup analysis found no benefit of early or aggressive transfusion in patients with coronary artery disease or in those requiring mechanical ventilation.

Rao et al performed a meta-analysis of three large international trials of patients with acute coronary syndromes to determine whether blood transfusion to correct anemia in this setting was associated with improved survival.¹⁹ They found significantly higher mortality among patients who underwent transfusion compared with those who did not, prompting them to urge caution in the use of transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease.

Similarly, a risk-adjusted, propensity-matched analysis of 6,301 patients undergoing noncardiac surgery found that receipt of 4 U of blood or more was a predictor of greater mortality, higher risk of infection, and longer hospital stay.²⁰ Moreover, in an observational cohort study of 11,963 patients who underwent isolated coronary artery bypass graft surgery, each unit of red blood cells transfused was associated with an incrementally increased risk of adverse outcome (eg, mortality, renal injury, need for ventilator support, lengthened hospital stay, infection).²¹ The latter study found that transfusion was the single factor most reliably associated with increased risk of postoperative morbidity.

Additional studies have echoed these findings—ie, that perioperative blood transfusion has been associated with a host of adverse outcomes, including increased morbidity and length of stay, increased rates of post­operative infection, as well as immunosuppression, viral transmission, and acute transfusion reactions.^5,22,23

 

 

Outcomes and duration of blood storage

An interesting factor in the relation between transfusion and outcomes is the shelf life of the blood being transfused. The FDA currently allows storage of blood for a maximum of 42 days, but a recent study of patients who received red blood cell transfusions during cardiac surgery found that those who received “older blood” (stored for > 14 days) had significantly higher rates of sepsis, prolonged intubation, renal failure, in-hospital mortality, and 1-year mortality compared with those who received “newer blood” (stored for ≤ 14 days).²⁴

These differing outcomes are generally attributed to the so-called storage defect: as blood gets older, it loses components such as 2,3-DPG and adenosine disphosphate, its red cells lose deformability, and it undergoes buildup of cytokines and free hemoglobin. Increased demand for newer blood in light of the storage defect could further intensify pressures on the blood supply.

MANAGEMENT OF PERIOPERATIVE ANEMIA

In light of these shortcomings of blood transfusion, how should anemia be managed perioperatively to reduce or avoid the need for transfusion?

Preoperative evaluation

Vigilance for anemia and related issues in the preoperative evaluation is fundamental. The evaluation should elicit a history of bleeding tendencies, previous transfusions, and symptoms of anemia. Medications should be reviewed with an eye toward any that may predispose to perioperative bleeding and anemia, such as aspirin, clopidogrel, and anticoagulants. During the physical examination, alertness for pallor and petechiae is key, as is attentiveness to symptoms of anemia such as shortness of breath and fatigue.

The laboratory work-up begins with a measure of hemoglobin: anemia is defined as hemoglobin less than 13 g/dL in males and less than 12 g/dL in females. If anemia is present and is associated with another hematologic abnormality, the patient should be referred to a hematologist for bone marrow examination. If no other hematologic abnormality exists, the ensuing work-up relies on red blood cell indices as detailed in Figure 1.²⁵ The goal is to identify those conditions for which intervention in the short term is possible—namely, anemia of chronic disease, iron deficiency, and vitamin B₁₂ deficiency. Findings suggestive of other conditions require further evaluation at a preoperative center.

Overview of management options

Once the cause of anemia is identified, the choice for optimal medical management can be made. Choices broadly consist of pharmacologic and technological options. The former include iron supplements and erythropoiesis-stimulating agents. Among other pharmacologic options are thrombin, collagen, fibrin glue, tranexamic acid, and aminocaproic acid, but these agents are less well studied and will not be discussed here. Technological options include preoperative autologous blood donation, cell salvage, and acute normovolemic hemodilution.

In addition to these options, careful management of anticoagulant and antiplatelet medications should be provided, including discontinuation or substitution of drugs that could hamper clotting perioperatively.

PHARMACOLOGIC OPTIONS

Iron supplementation

Oral iron is available in four preparations: ferrous sulfate, ferrous gluconate, ferrous fumarate, and iron polysaccharide. Gastrointestinal side effects may limit these preparations’ tolerability. Iron supplements with a high elemental value will require fewer pills and fewer doses, reducing the risk or frequency of side effects.

Intravenous (IV) iron preparations are much safer now than they were years ago, when anaphylactic reactions were a concern. The ones generally used in the perioperative setting are iron sucrose and iron gluconate. Unlike the older IV preparations, the use of iron sucrose and iron gluconate often requires a second dose. The effect on hemoglobin levels usually occurs starting at 1 week, with the maximum effect achieved at 2 weeks. Hypotension, arthralgia, abdominal discomfort, and back pain are potential side effects of IV iron.

Efficacy and safety of iron supplementation. Evidence of the efficacy of preoperative iron supplementation is mounting. A study of 569 patients undergoing colorectal cancer surgery found that among the 116 patients who were anemic, intraoperative transfusion was needed in a significantly lower proportion of those who received 2 weeks of preoperative oral iron supplementation (200 mg) compared with those who received no iron therapy (9.4% vs 27.4%; P < .05).²⁶ Similarly, in an uncontrolled study, 10 days of IV iron sucrose starting 4 weeks preoperatively significantly increased hemoglobin levels in 20 patients with iron-deficiency anemia prior to elective orthopedic surgery.²⁷

Risks of infection and cancer progression have been concerns with IV iron therapy. However, no significant association between IV iron therapy and bacteremia was identified in a prospective study of 985 patients receiving chronic hemodialysis.²⁸ The effect of IV iron administration on tumor progression has not been prospectively studied.

In general, IV iron, especially the newer forms, is a safer alternative to blood transfusion. Death occurs at a much lower rate with iron than with blood transfusion (0.4 per million vs 4 per million, respectively), as do life-threatening adverse events (4 per million vs 10 per million, respectively), according to a systematic review by the Network for Advancement of Transfusion Alternatives.²⁹

Erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) include epoetin alfa (erythropoietin), first approved by the FDA in 1989, and the more recently introduced darbe­poetin alfa. They are approved to treat anemia in several patient populations, but only epoetin alfa is approved by the FDA explicitly for use in patients undergoing major surgery (to reduce the need for blood transfusions). The ESAs have come under intense scrutiny in recent years over their risk-to-benefit ratio, as detailed below.

The preoperative dosing schedule for epoetin alfa is usually three weekly doses (plus a fourth dose on the day of surgery) if the surgery is scheduled 3 or more weeks in advance. However, daily dosing can be used effectively if the preoperative period is less than 3 weeks, provided that it is continued until 4 days after surgery. Oral iron is necessary throughout the course of epoetin alfa therapy.

Efficacy in reducing transfusions. In a systematic review published in 1998, epoetin alfa was shown to minimize perioperative exposure to allogeneic blood transfusion in patients undergoing orthopedic or cardiac surgery.³⁰ Its benefit was greatest in patients at the highest risk of requiring transfusion. It was effective whether given daily or weekly, and did not significantly increase the risk of thrombotic events when used in surgical patients, although some studies did find an excess of thrombotic events with its use.

In three randomized trials conducted in patients undergoing joint arthroplasty (hip or knee), epoetin alfa was associated with substantial and significant reductions in perioperative blood transfusion compared with placebo or preoperative autologous blood donation.^31–33 Rates of deep vein thrombosis (DVT) did not differ significantly between the epoetin alfa and placebo groups.

Concerns over perioperative thromboembolic risk. In early 2007, the FDA was made aware of preliminary results of an open-label study in which 681 patients undergoing elective spinal surgery who did not receive prophylactic anticoagulation were randomized to epoetin alfa plus standard-of-care therapy (pneumatic compression) or standard-of-care therapy alone.^34,35 The incidence of DVT was 4.7% in patients treated with epoetin alfa compared with 2.1% in those not receiving epoetin alfa. It is important to note that the available ESAs are prothrombotic and increase thrombotic risk significantly, especially in populations like this one in which pharmacologic DVT prophylaxis is not routinely used.

Based in part on this study, the FDA in 2007 required a boxed warning to be added to the ESAs’ package inserts to specify the increased risk of DVT with their use in surgical patients not receiving prophylactic anticoagulation. The warning urges consideration of the use of DVT prophylaxis in surgical patients receiving an ESA.^34,35

 

 

TECHNOLOGICAL OPTIONS AND OTHER STRATEGIES

Autologous blood donation: A practice in decline

In cases of elective surgery, autologous blood donation can be used to protect against disease transmission and overcome the challenge of blood type compatibility. Preoperative autologous donation of blood has been a prevalent practice, but its use is declining. One reason is that waste is high (approximately 50% at Cleveland Clinic), which makes this practice more costly than is often realized. Also, autologous blood donation increases the likelihood that the patient will be anemic on the day of surgery, so that he or she may still need allogeneic blood after all, defeating the initial purpose. Despite these limitations, preoperative autologous blood donation remains a useful option for a subset of patients with multiple antibodies for whom donor blood may be difficult to obtain.

Cell salvage

Cell salvage is an innovative technology that recovers the patient’s own blood (after being shed from the surgical incision) for transfusion after filtering and washing. It is particularly well suited to procedures that involve massive blood loss. Cell savage requires technical expertise, however, and involves costs associated with both the machine and disposables.

Restricted postoperative phlebotomy

Phlebotomy accounts for a significant amount of blood loss, especially in intensive care patients with arterial lines. The equivalent of 30% of total blood transfused has been reported to be lost to phlebotomy during an intensive care unit stay.³⁶ Triggers for transfusion cannot be assigned universally based on blood loss from phlebotomy but must consider the patient’s hemodynamic status, cardiac reserve, and other clinical characteristics.

PROMOTING RESPONSIBLE BLOOD PRODUCT USE

Blood is expensive, and in recent years hospitals have experienced increases in the cost of blood and blood products. To promote responsible blood use, we have developed a multipronged approach to blood management at Cleveland Clinic. The program’s cornerstone is increased awareness of the risks associated with blood transfusions. The emphasis is on educating staff physicians and other caregivers about the appropriate use of blood products. We also have implemented a new policy requiring staff authorization for all blood requested in nonemergency situations. Additionally, requests for blood components require adherence to an indication-based ordering process. Finally, data about blood use are shared transparently among physicians, encouraging good clinical practice.

Our program has also involved development and implementation of a preoperative anemia protocol to explicitly define the indications for use of ESAs, iron therapy, and vitamin B₁₂ therapy in patients undergoing joint arthroplasty (Figure 2).

In the first 7 months of the program, we observed decreased utilization of blood products in the inpatient setting. Notably, the reduction in blood use was significantly greater in the surgical population than in the medical population.

CONCULSIONS

Anemia is associated with increased morbidity and mortality in the perioperative setting. Perioperative blood transfusion is one method of raising hemoglobin levels in anemic surgical patients, but it increases perioperative morbidity in the form of acute transfusion reactions, immunosuppression, postoperative infection, and longer hospital stays. Moreover, blood collection continues to lag blood demand. For these reasons, most relevant major medical organizations—including the Association of Blood Banks, the American Red Cross, and the FDA—advise that red blood cell–containing components should not be used to treat anemias that can be corrected with medications. These medical alternatives—all of which can be used in the perioperative setting—include iron supplementation, vitamin B₁₂, and ESAs in select patient groups.

DISCUSSION

Question from the audience: Are there risks involved with autologous blood donation? Are different hemoglobin thresholds used when a patient’s own blood is used?

Dr. Kumar: As I mentioned, preoperative autologous donation is a technique that is less frequently used in our hospital. Autologous transfusion is considered safe only for patients who come to the clinic with normal hemoglobin values. Some patients may not have recovered from their blood loss by the time they come to surgery, so you end up needing to give them more blood because they started out anemic.

Question from the audience: Is there risk to giving patients back their own blood? Do you have to worry about transfusion-induced lung injury, sepsis, or other complications?

Dr. Kumar: As with allogeneic blood, the risk of clerical or clinical error exists with autologous blood: it too needs to be kept on the shelf, taken out, and infused, and the risk of sepsis remains the same.

If this is a typical audience of physicians involved in perioperative care, about 35% to 40% of you have been sued for malpractice and have learned the hard way some of the lessons we will discuss today. This session will begin with an overview of malpractice law and medicolegal principles, after which we will review three real-life malpractice cases and open the floor to the audience for discussion of the lessons these cases can offer.

MALPRACTICE LAWSUITS ARE COMMON, EXPENSIVE, DAMAGING

If a physician practices long enough, lawsuits are nearly inevitable, especially in certain specialties. Surgeons and anesthesiologists are sued about once every 4 to 5 years; internists generally are sued less, averaging once every 7 to 10 years,¹ but hospitalists and others who practice a good deal of perioperative care probably constitute a higher risk pool among internists.

At the same time, it is estimated that only one in eight preventable medical errors committed in hospitals results in a malpractice claim.² From 1995 to 2000, the number of new malpractice claims actually declined by approximately 4%.³

Jury awards can be huge

Fewer than half (42%) of verdicts in malpractice cases are won by plaintiffs.⁴ But when plaintiffs succeed, the awards can be costly: the mean amount of physician malpractice payments in the United States in 2006 (the most recent data available) was $311,965, according to the National Practitioner Data Bank.⁵ Cases that involve a death result in substantially higher payments, averaging $1.4 million.⁴

Lawsuits are traumatic

Even if a physician is covered by good malpractice insurance, a malpractice lawsuit typically changes his or her life. It causes major disruption to the physician’s practice and may damage his or her reputation. Lawsuits cause considerable emotional distress, including a loss of self-esteem, particularly if the physician feels that a mistake was made in the delivery of care.

CATEGORIES OF CLAIMS IN MALPRACTICE LAW

Malpractice law involves torts, which are civil wrongs causing injury to a person or property for which the plaintiff may seek redress through the courts. In general, the plaintiff seeks financial compensation. Practitioners do not go to jail for committing malpractice unless a district attorney decides that the harm was committed intentionally, in which case criminal charges may be brought.

There are many different categories of claims in malpractice law. The most common pertaining to perioperative medicine involve issues surrounding informed consent and medical negligence (the worst form being wrongful death).

Informed consent

Although everyone is familiar with informed consent, details of the process are called into question when something goes wrong. Informed consent is based on the right of patient autonomy: each person has a right to determine what will be done to his or her body, which includes the right to consent to or refuse treatment.

For any procedure, treatment, or medication, patients should be informed about the following:

• The nature of the intervention
• The benefits of the intervention (why it is being recommended)
• Significant risks reasonably expected to exist
• Available alternatives (including “no treatment”).

If possible, it is important that the patient’s family understand the risks involved, because if the patient dies or becomes incapacitated, a family that is surprised by the outcome is more likely to sue.

The standard to which physicians are held in malpractice suits is that of a “reasonable physician” dealing with a “reasonable patient.” Often, a plaintiff claims that he or she did not know that a specific risk was involved, and the doctor claims that he or she spent a “typical” amount of time explaining all the risks. If that amount of time was only a few seconds, that may not pass the “reasonable physician” test, as a jury might conclude that more time may have been necessary.

Negligence and wrongful death

Negligence, including wrongful death, is a very common category of claim. The plaintiff generally must demonstrate four elements in negligence claims:

• The provider had a duty to the patient
• The duty was breached
• An injury occurred
• The breach of duty was a “proximate cause” of the injury.

Duty arises from the physician-patient relationship: any person whose name is on the medical chart essentially has a duty to the patient and can be brought into the case, even if the involvement was only peripheral.

Breach of duty. Determining whether a breach of duty occurred often involves a battle of medical experts. The standard of care is defined as what a reasonable practitioner would do under the same or similar circumstances, assuming similar training and background. The jury decides whether the physician met the standard of care based on testimony from experts.

The Latin phrase res ipsa loquitur means “the thing speaks for itself.” In surgery, the classic example is if an instrument or a towel were accidentally left in a patient. In such a situation, the breach of duty is obvious, so the strategy of the defense generally must be to show that the patient was not harmed by the breach.

Injury. The concept of injury can be broad and often depends on distinguishing bad practice from a bad or unfortunate outcome. For instance, a patient who suffered multisystem trauma but whose life was saved by medical intervention could sue if he ended up with paresthesia in the foot afterwards. An expert may be called to help determine whether or not the complication is reasonable for the particular medical situation. Patient expectations usually factor prominently into questions of injury.

Proximate cause often enters into situations involving wrongful death. A clear understanding of the cause of death or evidence from an autopsy is not necessarily required for a plaintiff to argue that malpractice was a proximate cause of death. A plaintiff’s attorney will often speculate why a patient died, and because the plaintiff’s burden of proof is so low (see next paragraph), it may not help the defense to argue that it is pure speculation that a particular event was related to the death. 

A low burden of proof

In a civil tort, the burden of proof is established by a “preponderance of the evidence,” meaning that the allegation is “more likely than not.” This is a much lower standard than the “beyond a reasonable doubt” threshold used for criminal proceedings. In other words, the plaintiff has to show only that the chance that malpractice occurred was greater than 50%. 

Three types of damages

Potential damages (financial compensation) in malpractice suits fall into three categories:

• Economic, or the monetary costs of an injury (eg, medical bills or loss of income)
• Noneconomic (eg, pain and suffering, loss of ability to have sex)
• Punitive, or damages to punish a defendant for willful and wanton conduct.

Punitive damages are generally not covered by malpractice insurance policies and are only rarely involved in cases against an individual physician. They are more often awarded when deep pockets are perceived to be involved, such as in a case against a hospital system or an insurance company, and when the jury wants to punish the entity for doing something that was believed to be willful.

 

 

REDUCING THE RISK OF BEING SUED

Physicians tend to get sued when a bad outcome occurs that can be associated with substandard care or poor communication. Steps can be taken to reduce the risk of being sued, which can be simplified to the “four Cs”: competence, communication, compassion, and charting (Table 1).

Regardless of the circumstances, communication is probably the most important factor determining whether a physician will be sued. Sometimes a doctor does everything right medically but gets sued because of lack of communication with the patient. Conversely, many of us know of veteran physicians who still practice medicine as they did 35 years ago but are never sued because they have a great rapport with their patients and their patients love them for it.

The importance of careful charting also cannot be overemphasized. In malpractice cases, experts for the plaintiff will comb through the medical records and be sure to notice if something is missing. The plaintiff also benefits enormously if, for instance, nurses documented that they paged the doctor many times over a 3-day period and got no response.

CASE 1: PATIENT DIES DURING PREOPERATIVE STRESS TEST FOR KNEE SURGERY

A 65-year-old man with New York Heart Association class III cardiac disease (marked limitation of physical activity) is scheduled for a total knee arthroplasty and is seen at the preoperative testing center. His past medical history includes coronary artery disease, chronic obstructive pulmonary disease, hypertension, and prior repair of an abdominal aortic aneurysm. He is referred for a preoperative stress test.

Dobutamine stress echocardiography is performed. His target heart rate is reached at 132 beats per minute with sporadic premature ventricular contractions. Toward the end of the test, he complains of shortness of breath and chest pain. The test is terminated, and the patient goes into ventricular tachycardia and then ventricular fibrillation. Despite resuscitative efforts, he dies.

Dr. Michota: From the family’s perspective, this patient had come for quality-of-life–enhancing surgery. They were looking forward to him getting a new knee so he could play golf again when he retired. The doctor convinced them that he needed a stress test first, which ends up killing him. Mr. Donnelly, as a lawyer, would you want to be the plaintiff’s attorney in this case?

Mr. Donnelly: Very much so. The family never contemplated that their loved one would die from this procedure. The first issue would be whether or not the possibility of complications or death from the stress test had been discussed with the patient or his family.

Consent must be truly ‘informed’ and documented

Dr. Michota: How many of our audience members who do preoperative assessments and refer patients for stress testing can recall a conversation with a patient that included the comment, “You may die from getting this test”? Before this case occurred, I never brought up this possibility, but I do now. This case illustrates how important expectations are.

Comment from the audience: I think you have to be careful of your own bias about risks. You might say to the patient, “There’s a risk that you’ll have an arrhythmia and die,” but if you also tell him, “I’ve never seen that happen during a stress test in my 10 years of practice,” you’ve biased the informed consent. The family can say, “Well, he basically told us that it wasn’t going to happen; he’d never seen a case of it.”

Dr. Michota: Are there certain things we shouldn’t say? Surely you should never promise somebody a good outcome by saying that certain rare events never happen.

Mr. Donnelly: That’s true. You can give percentages. You might say, “I’m letting you know there’s a possibility that you could die from this, but it’s a low percentage risk.” That way, you are informing the patient. This relates to the “reasonable physician” and “reasonable patient” standard. You are expected to do what is reasonable.

Is a signed consent form adequate defense?

Dr. Michota: What should the defense team do now? Let’s say informed consent was obtained and documented at the stress lab. The patient signed a form that listed death as a risk, but no family members were present. Is this an adequate defense?

Mr. Donnelly: It depends on whether the patient understood what was on the form and had the opportunity to ask questions.

Dr. Michota: So the form means nothing?

Mr. Donnelly: If he didn’t understand it, that is correct.

Dr. Michota: We thought he understood it. Can’t we just say, “Of course he understood it—he signed it.”

Mr. Donnelly: No. Keep in mind that most jurors have been patients at one time or another. There may be a perception that physicians are rushed or don’t have time to answer questions. Communication is really important here.

Dr. Michota: But surely there’s a physician on the jury who can help talk to the other jurors about how it really works.

Mr. Donnelly: No, a “jury of peers” is not a jury box of physicians. The plaintiff’s attorneys tend to exclude scientists and other educated professionals from the jury; they don’t want jurors who are accustomed to holding people to certain standards. They prefer young, impressionable people who wouldn’t think twice about awarding somebody $20 million.

 

 

Who should be obtaining informed consent?

Question from the audience: Who should have obtained informed consent for this patient—the doctor who referred him for the stress test or the cardiologist who conducted the test? Sometimes I have to get informed consent for specialty procedures that I myself do not understand very well. Could I be considered culpable even though I’m not the one doing the procedure? I can imagine an attorney asking, “Doctor, are you a cardiologist? How many of these tests do you do? Why are you the one doing the informed consent? Did the patient really understand the effects of the test? Do you really understand them?”

Dr. Michota: That question is even more pertinent if the patient is referred to another institution covered under different malpractice insurance. You can bet the other provider will try to blame you if something goes wrong.

Mr. Donnelly: In an ideal world, both the referring physician and the physician who does the test discuss the risks, benefits, and alternatives, and answer all questions that the patient and family have. The discussion is properly documented in the medical record.

Question from the audience: Can you address the issue of supervision? What is the liability of a resident or intern in doing the informed consent?

Mr. Donnelly: The attending physician is usually responsible for everything that a resident does. I would prefer that the attending obtain the informed consent.

Dr. Michota: But our fellows and second-year postgraduate residents are independent licensed practitioners in Ohio. Does letting them handle informed consent pose a danger to a defense team’s legal case?

Mr. Donnelly: It’s not necessarily a danger medically, but it gives the plaintiff something to talk about. They will ignore the fact that an independent licensed practitioner obtained the informed consent. They will simply focus on the fact that the physician was a resident or fellow. They will claim, “They had this young, inexperienced doctor give the informed consent when there were staff physicians with 20 years of experience who should have done it.” Plaintiffs will attempt to get a lot of mileage out of these minor issues.

Question from the audience: At our institution, the physician is present with the technician, so that when the physician obtains consent, the technician signs as a witness. The bottom of the long form basically says, “By signing this form, I attest that the physician performing the test has informed me of the benefits and risks of this test, and I agree to go ahead. I fully understand the implications of the test.” Does that have value in the eyes of the law?

Mr. Donnelly: That’s a great informed consent process and will have great value. That said, you can still get sued, because you can get sued for anything. But the jury ultimately decides, and odds are that with a process like yours they will conclude that the patient knew all the risks and benefits and alternatives because he or she signed the form and the doctor documented that everything was discussed.

Confidentiality vs family involvement

Comment from the audience: I’m struck by the comments that informed consent is supposed to be with the family so that there will be living witnesses in case the patient dies. According to Health Insurance Portability and Accountability Act (HIPAA) regulations, we have to be very careful to maintain confidentiality. For a competent patient, medical discussions are private unless specific permission has been obtained to involve the family.

Mr. Donnelly: Yes, we’ve assumed that the patient gave permission to discuss these issues with his family. If the patient does not want that, obviously you can’t include the family because of HIPAA regulations.

Question from the audience: Should we routinely ask a patient to involve the family in an informed consent in case something goes wrong?

Mr. Donnelly: No. In general, it’s appropriate only if the family is already present.

Dr. Michota: Keep in mind that there’s nothing you can do to completely prevent being sued. You can do everything right and still get sued. If you’re following good clinical practice and a patient doesn’t want to involve the family, all you can do is document your discussion and that you believed the patient understood the risks of the procedure.

Question from the audience: Do you consider a patient’s decision-making capacity for informed consent? Should physicians document it prior to obtaining consent? A plaintiff can always claim that an elderly patient did not understand.

Mr. Donnelly: I have never seen specific documentation that a patient had capacity to consent, but it’s a good idea for a borderline case. For such a case, it’s especially important to involve the family and document, “I discussed the matter with this elderly patient and her husband and three daughters.” You could also get a psychiatric consult or a social worker to help determine whether a patient has the capacity to make legal and medical decisions.

CASE 2: FATAL POSTSURGICAL MI RAISES QUESTIONS ABOUT THE PREOP EVALUATION

A 75-year-old man with rectal cancer presents for colorectal surgery. He has a remote cardiac history but exercises regularly and has a good functional classification without symptoms. The surgery is uneventful, but the patient develops hypotension in the postanesthesia care unit. He improves the next morning and goes to the colorectal surgery ward. Internal bleeding occurs but initially goes unrecognized; on postoperative day 2, his hemoglobin is found to be 2 g/dL and he is transferred to the intensive care unit, then back to the operating room, where he suffers cardiac arrest. He is revived but dies 2 weeks later. Autopsy reveals that he died of a myocardial infarction (MI).

Dr. Michota: The complaint in this case is that the patient did not receive a proper preoperative evaluation because no cardiac workup was done. As the hypothetical defense attorney, do you feel this case has merit? The patient most likely had an MI from demand ischemia due to hemorrhage, but does this have anything to do with not having a cardiac workup?

Mr. Donnelly: You as the physician are saying that even if he had an electrocardiogram (ECG), it is likely that nothing would have been determined. The cardiac problems he had prior to the surgery in question were well controlled, occurred in the distant past, and may not have affected the outcome. Maybe his remote cardiac problems were irrelevant and something else caused the MI that killed him. Nevertheless, the fact that the ECG wasn’t done still could be a major issue for the plaintiff’s attorney. After the fact, it seems like a no-brainer that an ECG should have been done in a case like this, and it’s easy for the plaintiff to argue that it might have detected something. The defense has to keep reminding the jury that the case cannot be looked at retrospectively, and that’s a tall order.

Dr. Michota: This case shows that even in the context of high-quality care, such things can happen. We have spent a lot of time at this summit talking about guidelines. But at the end of the day, if somebody dies perioperatively of an MI, the family may start looking for blame and any plaintiff’s attorney will go through the record to see if a preoperative ECG was done. If it wasn’t, a suit will get filed.

 

 

The four Cs offer the best protection

Question from the audience: Even if the physician had done the ECG, how do you know the plaintiff’s attorney wouldn’t attack him for not ordering a stress test? And if he had done a stress test, then they’d ask why he didn’t order a catheterization. Where is it going to end?

Dr. Michota: You make a good point. The best way for physicians to protect themselves is to follow the four Cs mentioned earlier: competent care, communication, compassion, and charting. After I learned about this case, the next time I was in the clinic and didn’t order an ECG, I asked the patient, “Did you expect that we would do an ECG here today?” When he responded that he did, I talked to him about how it wasn’t indicated and probably would not change management. So that level of communication can sometimes prevent a lawsuit that might stem from a patient not feeling informed. I’m not suggesting that you spend hours explaining details with each patient, but it’s good to be aware that cases like this happen and how you can reduce their likelihood.

Battles of the experts

Question from the audience: Exactly what standard is applied when the “standard of care” is determined in a court? For instance, my hospital may routinely order stress tests, whereas the American College of Cardiology and American Heart Association (ACC/AHA) guidelines are more restrictive in recommending when a stress test is indicated. Which standard would apply in court?

Dr. Michota: It’s easy to find a plaintiff’s expert who will say just about anything. If you claim that everybody gets a stress test at your community hospital and a patient dies during the stress test, the plaintiff’s team will find an expert to say, “That was an unnecessary test and posed an unnecessary risk.” If you’re in a setting where stress tests are rarely done for preoperative evaluation, they’ll find an expert to say, “Stress testing was available; it should have been done.”

This is when the battles of the experts occur. If you have a superstar physician on your defense team, the plaintiff will have to find someone of equal pedigree who can argue against him or her. Sometimes cases go away because the defense lines up amazing experts and the plaintiffs lose their stomach for the money it would take to bring the case forward. But usually cases do not involve that caliber of experts; most notables in the field are academic physicians who don’t do this type of work. Usually you get busy physicians who spend 75% of their time in clinical practice and seem smart enough to impress the jury. Although they can say things that aren’t even factual, they can sway the jury. 

Question from the audience: I would not have ordered a preoperative ECG on this healthy 75-year-old, but one of the experts at this summit said that he would get a baseline ECG for such a case. How are differences like these reconciled in the legal context?

Dr. Michota: The standard to which we are held is that of a reasonable physician. Can you show that your approach was a reasonable one? Can you say, “I didn’t order the ECG for the following reasons, and I discussed the issue with the patient”? Or alternately, “An ECG was ordered for the following reasons, and I discussed it with the patient”? The jury will want to know whether the care that was provided was reasonable.

Costs and consequences of being sued

Question from the audience: What does it cost to mount a defense in a malpractice trial?

Mr. Donnelly: You can easily spend more than $100,000 to go through a trial. Plaintiffs typically have three or four experts in various cities across the country, and you have to pay your lawyers to travel to those cities and take the depositions. And delays often occur. Cases get filed, dismissed, and refiled. A lot of the work that the lawyers did to prepare for the trial will have to be redone for a second, third, or fourth time as new dates for the trial are set. There are many unforeseen costs.

Dr. Michota: Let’s say the physician who did the preoperative evaluation in this case was not affiliated with the hospital and wasn’t involved in the surgery or any of the postoperative monitoring and management, which we see may have been questionable. This physician might get pulled into the case anyway because he didn’t order an ECG in the preoperative evaluation. Although an ECG wasn’t recommended in this case by the ACC/AHA guidelines, this doctor is looking at spending considerable time, energy, and money to defend himself. What if his attorney recommends that he settle for a nominal amount—say, $25,000—because it’s cheaper and easier? Are there repercussions for him as a physician when he pays out a settlement under his name?

Mr. Donnelly: Absolutely. He will be reported to the National Practitioner Data Bank, and when he renews his license or applies for a license to practice in another state, he must disclose that he has been sued and paid a settlement. The new consumer-targeted public reporting Web sites will also publicize this information. It is like a black mark against this doctor even though he never admitted any liability.

CASE 3: A CLEAR CASE OF NEGLIGENCE―WHO IS RESPONSIBLE

A 67-year-old man undergoes a laminectomy in the hospital. He develops shortness of breath postoperatively and is seen by the hospitalist team. He is started on full-dose weight-adjusted low-molecular-weight heparin (LMWH) for possible pulmonary embolism or acute coronary syndrome. His symptoms resolve and his workup is negative. It is a holiday weekend. The consultants sign off but do not stop the full-dose LMWH. The patient is discharged to the rehabilitation unit by the surgeon and the surgeon’s assistant, who include all the medications at discharge, including the full-dose LMWH. The patient is admitted to a subacute nursing facility, where the physiatrist transfers to the chart all the medications on which the patient was discharged.

The patient does well until postoperative day 7, when he develops urinary retention and can’t move his legs. At this point, someone finally questions why he is on the LMWH, and it is stopped. The patient undergoes emergency surgery to evacuate a huge spinal hematoma, but his neurologic function never recovers.

Dr. Michota: I think most of us would agree that there was negligence here. I bet a plaintiff’s attorney would love to have this case.

Mr. Donnelly: Absolutely. The patient can no longer walk, so it’s already a high-value case. It would be even more so if we supposed that the patient were only 45 years old and a corporate executive. That would make it a really high-value case.

Dr. Michota: What do you mean? Does a patient’s age or economic means matter to a plaintiff’s attorney?

Mr. Donnelly: Of course. For a plaintiff’s attorney, it’s always nice to have a case like this where there’s negligence, but the high-dollar cases typically involve a likable plaintiff who is a high wage earner with a good family. A plaintiff’s lawyer will take a case that may not be so strong on evidence of negligence if it’s likely that a jury will like the plaintiff and his or her family. Kids always help to sway a jury—jurors will feel sorry for them and want to help them. This case even has two surgeries, so the family’s medical bills will be especially high. It’s a great case for a plaintiff’s attorney.

Who’s at fault?

Dr. Michota: Let’s look at a few more case details. Once the various doctors involved in this case realized what happened, they got nervous and engaged in finger-pointing. The surgeons felt that the hospitalists should have stopped the LMWH. The hospitalists claimed that since they had signed off, the surgeons should have stopped it. The physiatrist said, “Who am I to decide to stop medications? I assumed that the hospital physicians checked the medications before sending the patient to the rehab facility.”

Interestingly, a hospitalist went back and made a chart entry after the second surgery. He wrote, “Late chart entry. Discussion with surgeon regarding LMWH. I told him to stop it.” Does that make him free and clear?

Mr. Donnelly: Actually, the hospitalist just shot his credibility, and now the jury is really angry. The dollar value of the case has just gone up.

Dr. Michota: Okay, suppose the hospitalist wouldn’t do something that obvious. Instead, he goes back to the chart after the fact, finds the same color pen as the entry at the time, and writes, “Patient is okay. Please stop LMWH,” and signs his name. Is there any way anyone is going to be able to figure that out?

Mr. Donnelly: All the other doctors and nurses will testify that the note was not in the chart before. The plaintiff will hire a handwriting expert and look at the different impressions on the paper, the inks, and the style of writing. Now the hospitalist has really escalated the situation and is liable for punitive damages, which will come out of his own pocket, since malpractice insurance doesn’t cover punitive damages. His license may be threatened. The jury will really be angered, and the plaintiff’s lawyer will love stoking the situation.

If this is a typical audience of physicians involved in perioperative care, about 35% to 40% of you have been sued for malpractice and have learned the hard way some of the lessons we will discuss today. This session will begin with an overview of malpractice law and medicolegal principles, after which we will review three real-life malpractice cases and open the floor to the audience for discussion of the lessons these cases can offer.

MALPRACTICE LAWSUITS ARE COMMON, EXPENSIVE, DAMAGING

If a physician practices long enough, lawsuits are nearly inevitable, especially in certain specialties. Surgeons and anesthesiologists are sued about once every 4 to 5 years; internists generally are sued less, averaging once every 7 to 10 years,¹ but hospitalists and others who practice a good deal of perioperative care probably constitute a higher risk pool among internists.

At the same time, it is estimated that only one in eight preventable medical errors committed in hospitals results in a malpractice claim.² From 1995 to 2000, the number of new malpractice claims actually declined by approximately 4%.³

Jury awards can be huge

Fewer than half (42%) of verdicts in malpractice cases are won by plaintiffs.⁴ But when plaintiffs succeed, the awards can be costly: the mean amount of physician malpractice payments in the United States in 2006 (the most recent data available) was $311,965, according to the National Practitioner Data Bank.⁵ Cases that involve a death result in substantially higher payments, averaging $1.4 million.⁴

Lawsuits are traumatic

Even if a physician is covered by good malpractice insurance, a malpractice lawsuit typically changes his or her life. It causes major disruption to the physician’s practice and may damage his or her reputation. Lawsuits cause considerable emotional distress, including a loss of self-esteem, particularly if the physician feels that a mistake was made in the delivery of care.

CATEGORIES OF CLAIMS IN MALPRACTICE LAW

Malpractice law involves torts, which are civil wrongs causing injury to a person or property for which the plaintiff may seek redress through the courts. In general, the plaintiff seeks financial compensation. Practitioners do not go to jail for committing malpractice unless a district attorney decides that the harm was committed intentionally, in which case criminal charges may be brought.

There are many different categories of claims in malpractice law. The most common pertaining to perioperative medicine involve issues surrounding informed consent and medical negligence (the worst form being wrongful death).

Informed consent

Although everyone is familiar with informed consent, details of the process are called into question when something goes wrong. Informed consent is based on the right of patient autonomy: each person has a right to determine what will be done to his or her body, which includes the right to consent to or refuse treatment.

For any procedure, treatment, or medication, patients should be informed about the following:

• The nature of the intervention
• The benefits of the intervention (why it is being recommended)
• Significant risks reasonably expected to exist
• Available alternatives (including “no treatment”).

If possible, it is important that the patient’s family understand the risks involved, because if the patient dies or becomes incapacitated, a family that is surprised by the outcome is more likely to sue.

The standard to which physicians are held in malpractice suits is that of a “reasonable physician” dealing with a “reasonable patient.” Often, a plaintiff claims that he or she did not know that a specific risk was involved, and the doctor claims that he or she spent a “typical” amount of time explaining all the risks. If that amount of time was only a few seconds, that may not pass the “reasonable physician” test, as a jury might conclude that more time may have been necessary.

Negligence and wrongful death

Negligence, including wrongful death, is a very common category of claim. The plaintiff generally must demonstrate four elements in negligence claims:

• The provider had a duty to the patient
• The duty was breached
• An injury occurred
• The breach of duty was a “proximate cause” of the injury.

Duty arises from the physician-patient relationship: any person whose name is on the medical chart essentially has a duty to the patient and can be brought into the case, even if the involvement was only peripheral.

Breach of duty. Determining whether a breach of duty occurred often involves a battle of medical experts. The standard of care is defined as what a reasonable practitioner would do under the same or similar circumstances, assuming similar training and background. The jury decides whether the physician met the standard of care based on testimony from experts.

The Latin phrase res ipsa loquitur means “the thing speaks for itself.” In surgery, the classic example is if an instrument or a towel were accidentally left in a patient. In such a situation, the breach of duty is obvious, so the strategy of the defense generally must be to show that the patient was not harmed by the breach.

Injury. The concept of injury can be broad and often depends on distinguishing bad practice from a bad or unfortunate outcome. For instance, a patient who suffered multisystem trauma but whose life was saved by medical intervention could sue if he ended up with paresthesia in the foot afterwards. An expert may be called to help determine whether or not the complication is reasonable for the particular medical situation. Patient expectations usually factor prominently into questions of injury.

Proximate cause often enters into situations involving wrongful death. A clear understanding of the cause of death or evidence from an autopsy is not necessarily required for a plaintiff to argue that malpractice was a proximate cause of death. A plaintiff’s attorney will often speculate why a patient died, and because the plaintiff’s burden of proof is so low (see next paragraph), it may not help the defense to argue that it is pure speculation that a particular event was related to the death. 

A low burden of proof

In a civil tort, the burden of proof is established by a “preponderance of the evidence,” meaning that the allegation is “more likely than not.” This is a much lower standard than the “beyond a reasonable doubt” threshold used for criminal proceedings. In other words, the plaintiff has to show only that the chance that malpractice occurred was greater than 50%. 

Three types of damages

Potential damages (financial compensation) in malpractice suits fall into three categories:

• Economic, or the monetary costs of an injury (eg, medical bills or loss of income)
• Noneconomic (eg, pain and suffering, loss of ability to have sex)
• Punitive, or damages to punish a defendant for willful and wanton conduct.

Punitive damages are generally not covered by malpractice insurance policies and are only rarely involved in cases against an individual physician. They are more often awarded when deep pockets are perceived to be involved, such as in a case against a hospital system or an insurance company, and when the jury wants to punish the entity for doing something that was believed to be willful.

 

 

REDUCING THE RISK OF BEING SUED

Physicians tend to get sued when a bad outcome occurs that can be associated with substandard care or poor communication. Steps can be taken to reduce the risk of being sued, which can be simplified to the “four Cs”: competence, communication, compassion, and charting (Table 1).

Regardless of the circumstances, communication is probably the most important factor determining whether a physician will be sued. Sometimes a doctor does everything right medically but gets sued because of lack of communication with the patient. Conversely, many of us know of veteran physicians who still practice medicine as they did 35 years ago but are never sued because they have a great rapport with their patients and their patients love them for it.

The importance of careful charting also cannot be overemphasized. In malpractice cases, experts for the plaintiff will comb through the medical records and be sure to notice if something is missing. The plaintiff also benefits enormously if, for instance, nurses documented that they paged the doctor many times over a 3-day period and got no response.

CASE 1: PATIENT DIES DURING PREOPERATIVE STRESS TEST FOR KNEE SURGERY

A 65-year-old man with New York Heart Association class III cardiac disease (marked limitation of physical activity) is scheduled for a total knee arthroplasty and is seen at the preoperative testing center. His past medical history includes coronary artery disease, chronic obstructive pulmonary disease, hypertension, and prior repair of an abdominal aortic aneurysm. He is referred for a preoperative stress test.

Dobutamine stress echocardiography is performed. His target heart rate is reached at 132 beats per minute with sporadic premature ventricular contractions. Toward the end of the test, he complains of shortness of breath and chest pain. The test is terminated, and the patient goes into ventricular tachycardia and then ventricular fibrillation. Despite resuscitative efforts, he dies.

Dr. Michota: From the family’s perspective, this patient had come for quality-of-life–enhancing surgery. They were looking forward to him getting a new knee so he could play golf again when he retired. The doctor convinced them that he needed a stress test first, which ends up killing him. Mr. Donnelly, as a lawyer, would you want to be the plaintiff’s attorney in this case?

Mr. Donnelly: Very much so. The family never contemplated that their loved one would die from this procedure. The first issue would be whether or not the possibility of complications or death from the stress test had been discussed with the patient or his family.

Consent must be truly ‘informed’ and documented

Dr. Michota: How many of our audience members who do preoperative assessments and refer patients for stress testing can recall a conversation with a patient that included the comment, “You may die from getting this test”? Before this case occurred, I never brought up this possibility, but I do now. This case illustrates how important expectations are.

Comment from the audience: I think you have to be careful of your own bias about risks. You might say to the patient, “There’s a risk that you’ll have an arrhythmia and die,” but if you also tell him, “I’ve never seen that happen during a stress test in my 10 years of practice,” you’ve biased the informed consent. The family can say, “Well, he basically told us that it wasn’t going to happen; he’d never seen a case of it.”

Dr. Michota: Are there certain things we shouldn’t say? Surely you should never promise somebody a good outcome by saying that certain rare events never happen.

Mr. Donnelly: That’s true. You can give percentages. You might say, “I’m letting you know there’s a possibility that you could die from this, but it’s a low percentage risk.” That way, you are informing the patient. This relates to the “reasonable physician” and “reasonable patient” standard. You are expected to do what is reasonable.

Is a signed consent form adequate defense?

Dr. Michota: What should the defense team do now? Let’s say informed consent was obtained and documented at the stress lab. The patient signed a form that listed death as a risk, but no family members were present. Is this an adequate defense?

Mr. Donnelly: It depends on whether the patient understood what was on the form and had the opportunity to ask questions.

Dr. Michota: So the form means nothing?

Mr. Donnelly: If he didn’t understand it, that is correct.

Dr. Michota: We thought he understood it. Can’t we just say, “Of course he understood it—he signed it.”

Mr. Donnelly: No. Keep in mind that most jurors have been patients at one time or another. There may be a perception that physicians are rushed or don’t have time to answer questions. Communication is really important here.

Dr. Michota: But surely there’s a physician on the jury who can help talk to the other jurors about how it really works.

Mr. Donnelly: No, a “jury of peers” is not a jury box of physicians. The plaintiff’s attorneys tend to exclude scientists and other educated professionals from the jury; they don’t want jurors who are accustomed to holding people to certain standards. They prefer young, impressionable people who wouldn’t think twice about awarding somebody $20 million.

 

 

Who should be obtaining informed consent?

Question from the audience: Who should have obtained informed consent for this patient—the doctor who referred him for the stress test or the cardiologist who conducted the test? Sometimes I have to get informed consent for specialty procedures that I myself do not understand very well. Could I be considered culpable even though I’m not the one doing the procedure? I can imagine an attorney asking, “Doctor, are you a cardiologist? How many of these tests do you do? Why are you the one doing the informed consent? Did the patient really understand the effects of the test? Do you really understand them?”

Dr. Michota: That question is even more pertinent if the patient is referred to another institution covered under different malpractice insurance. You can bet the other provider will try to blame you if something goes wrong.

Mr. Donnelly: In an ideal world, both the referring physician and the physician who does the test discuss the risks, benefits, and alternatives, and answer all questions that the patient and family have. The discussion is properly documented in the medical record.

Question from the audience: Can you address the issue of supervision? What is the liability of a resident or intern in doing the informed consent?

Mr. Donnelly: The attending physician is usually responsible for everything that a resident does. I would prefer that the attending obtain the informed consent.

Dr. Michota: But our fellows and second-year postgraduate residents are independent licensed practitioners in Ohio. Does letting them handle informed consent pose a danger to a defense team’s legal case?

Mr. Donnelly: It’s not necessarily a danger medically, but it gives the plaintiff something to talk about. They will ignore the fact that an independent licensed practitioner obtained the informed consent. They will simply focus on the fact that the physician was a resident or fellow. They will claim, “They had this young, inexperienced doctor give the informed consent when there were staff physicians with 20 years of experience who should have done it.” Plaintiffs will attempt to get a lot of mileage out of these minor issues.

Question from the audience: At our institution, the physician is present with the technician, so that when the physician obtains consent, the technician signs as a witness. The bottom of the long form basically says, “By signing this form, I attest that the physician performing the test has informed me of the benefits and risks of this test, and I agree to go ahead. I fully understand the implications of the test.” Does that have value in the eyes of the law?

Mr. Donnelly: That’s a great informed consent process and will have great value. That said, you can still get sued, because you can get sued for anything. But the jury ultimately decides, and odds are that with a process like yours they will conclude that the patient knew all the risks and benefits and alternatives because he or she signed the form and the doctor documented that everything was discussed.

Confidentiality vs family involvement

Comment from the audience: I’m struck by the comments that informed consent is supposed to be with the family so that there will be living witnesses in case the patient dies. According to Health Insurance Portability and Accountability Act (HIPAA) regulations, we have to be very careful to maintain confidentiality. For a competent patient, medical discussions are private unless specific permission has been obtained to involve the family.

Mr. Donnelly: Yes, we’ve assumed that the patient gave permission to discuss these issues with his family. If the patient does not want that, obviously you can’t include the family because of HIPAA regulations.

Question from the audience: Should we routinely ask a patient to involve the family in an informed consent in case something goes wrong?

Mr. Donnelly: No. In general, it’s appropriate only if the family is already present.

Dr. Michota: Keep in mind that there’s nothing you can do to completely prevent being sued. You can do everything right and still get sued. If you’re following good clinical practice and a patient doesn’t want to involve the family, all you can do is document your discussion and that you believed the patient understood the risks of the procedure.

Question from the audience: Do you consider a patient’s decision-making capacity for informed consent? Should physicians document it prior to obtaining consent? A plaintiff can always claim that an elderly patient did not understand.

Mr. Donnelly: I have never seen specific documentation that a patient had capacity to consent, but it’s a good idea for a borderline case. For such a case, it’s especially important to involve the family and document, “I discussed the matter with this elderly patient and her husband and three daughters.” You could also get a psychiatric consult or a social worker to help determine whether a patient has the capacity to make legal and medical decisions.

CASE 2: FATAL POSTSURGICAL MI RAISES QUESTIONS ABOUT THE PREOP EVALUATION

A 75-year-old man with rectal cancer presents for colorectal surgery. He has a remote cardiac history but exercises regularly and has a good functional classification without symptoms. The surgery is uneventful, but the patient develops hypotension in the postanesthesia care unit. He improves the next morning and goes to the colorectal surgery ward. Internal bleeding occurs but initially goes unrecognized; on postoperative day 2, his hemoglobin is found to be 2 g/dL and he is transferred to the intensive care unit, then back to the operating room, where he suffers cardiac arrest. He is revived but dies 2 weeks later. Autopsy reveals that he died of a myocardial infarction (MI).

Dr. Michota: The complaint in this case is that the patient did not receive a proper preoperative evaluation because no cardiac workup was done. As the hypothetical defense attorney, do you feel this case has merit? The patient most likely had an MI from demand ischemia due to hemorrhage, but does this have anything to do with not having a cardiac workup?

Mr. Donnelly: You as the physician are saying that even if he had an electrocardiogram (ECG), it is likely that nothing would have been determined. The cardiac problems he had prior to the surgery in question were well controlled, occurred in the distant past, and may not have affected the outcome. Maybe his remote cardiac problems were irrelevant and something else caused the MI that killed him. Nevertheless, the fact that the ECG wasn’t done still could be a major issue for the plaintiff’s attorney. After the fact, it seems like a no-brainer that an ECG should have been done in a case like this, and it’s easy for the plaintiff to argue that it might have detected something. The defense has to keep reminding the jury that the case cannot be looked at retrospectively, and that’s a tall order.

Dr. Michota: This case shows that even in the context of high-quality care, such things can happen. We have spent a lot of time at this summit talking about guidelines. But at the end of the day, if somebody dies perioperatively of an MI, the family may start looking for blame and any plaintiff’s attorney will go through the record to see if a preoperative ECG was done. If it wasn’t, a suit will get filed.

 

 

The four Cs offer the best protection

Question from the audience: Even if the physician had done the ECG, how do you know the plaintiff’s attorney wouldn’t attack him for not ordering a stress test? And if he had done a stress test, then they’d ask why he didn’t order a catheterization. Where is it going to end?

Dr. Michota: You make a good point. The best way for physicians to protect themselves is to follow the four Cs mentioned earlier: competent care, communication, compassion, and charting. After I learned about this case, the next time I was in the clinic and didn’t order an ECG, I asked the patient, “Did you expect that we would do an ECG here today?” When he responded that he did, I talked to him about how it wasn’t indicated and probably would not change management. So that level of communication can sometimes prevent a lawsuit that might stem from a patient not feeling informed. I’m not suggesting that you spend hours explaining details with each patient, but it’s good to be aware that cases like this happen and how you can reduce their likelihood.

Battles of the experts

Question from the audience: Exactly what standard is applied when the “standard of care” is determined in a court? For instance, my hospital may routinely order stress tests, whereas the American College of Cardiology and American Heart Association (ACC/AHA) guidelines are more restrictive in recommending when a stress test is indicated. Which standard would apply in court?

Dr. Michota: It’s easy to find a plaintiff’s expert who will say just about anything. If you claim that everybody gets a stress test at your community hospital and a patient dies during the stress test, the plaintiff’s team will find an expert to say, “That was an unnecessary test and posed an unnecessary risk.” If you’re in a setting where stress tests are rarely done for preoperative evaluation, they’ll find an expert to say, “Stress testing was available; it should have been done.”

This is when the battles of the experts occur. If you have a superstar physician on your defense team, the plaintiff will have to find someone of equal pedigree who can argue against him or her. Sometimes cases go away because the defense lines up amazing experts and the plaintiffs lose their stomach for the money it would take to bring the case forward. But usually cases do not involve that caliber of experts; most notables in the field are academic physicians who don’t do this type of work. Usually you get busy physicians who spend 75% of their time in clinical practice and seem smart enough to impress the jury. Although they can say things that aren’t even factual, they can sway the jury. 

Question from the audience: I would not have ordered a preoperative ECG on this healthy 75-year-old, but one of the experts at this summit said that he would get a baseline ECG for such a case. How are differences like these reconciled in the legal context?

Dr. Michota: The standard to which we are held is that of a reasonable physician. Can you show that your approach was a reasonable one? Can you say, “I didn’t order the ECG for the following reasons, and I discussed the issue with the patient”? Or alternately, “An ECG was ordered for the following reasons, and I discussed it with the patient”? The jury will want to know whether the care that was provided was reasonable.

Costs and consequences of being sued

Question from the audience: What does it cost to mount a defense in a malpractice trial?

Mr. Donnelly: You can easily spend more than $100,000 to go through a trial. Plaintiffs typically have three or four experts in various cities across the country, and you have to pay your lawyers to travel to those cities and take the depositions. And delays often occur. Cases get filed, dismissed, and refiled. A lot of the work that the lawyers did to prepare for the trial will have to be redone for a second, third, or fourth time as new dates for the trial are set. There are many unforeseen costs.

Dr. Michota: Let’s say the physician who did the preoperative evaluation in this case was not affiliated with the hospital and wasn’t involved in the surgery or any of the postoperative monitoring and management, which we see may have been questionable. This physician might get pulled into the case anyway because he didn’t order an ECG in the preoperative evaluation. Although an ECG wasn’t recommended in this case by the ACC/AHA guidelines, this doctor is looking at spending considerable time, energy, and money to defend himself. What if his attorney recommends that he settle for a nominal amount—say, $25,000—because it’s cheaper and easier? Are there repercussions for him as a physician when he pays out a settlement under his name?

Mr. Donnelly: Absolutely. He will be reported to the National Practitioner Data Bank, and when he renews his license or applies for a license to practice in another state, he must disclose that he has been sued and paid a settlement. The new consumer-targeted public reporting Web sites will also publicize this information. It is like a black mark against this doctor even though he never admitted any liability.

CASE 3: A CLEAR CASE OF NEGLIGENCE―WHO IS RESPONSIBLE

A 67-year-old man undergoes a laminectomy in the hospital. He develops shortness of breath postoperatively and is seen by the hospitalist team. He is started on full-dose weight-adjusted low-molecular-weight heparin (LMWH) for possible pulmonary embolism or acute coronary syndrome. His symptoms resolve and his workup is negative. It is a holiday weekend. The consultants sign off but do not stop the full-dose LMWH. The patient is discharged to the rehabilitation unit by the surgeon and the surgeon’s assistant, who include all the medications at discharge, including the full-dose LMWH. The patient is admitted to a subacute nursing facility, where the physiatrist transfers to the chart all the medications on which the patient was discharged.

The patient does well until postoperative day 7, when he develops urinary retention and can’t move his legs. At this point, someone finally questions why he is on the LMWH, and it is stopped. The patient undergoes emergency surgery to evacuate a huge spinal hematoma, but his neurologic function never recovers.

Dr. Michota: I think most of us would agree that there was negligence here. I bet a plaintiff’s attorney would love to have this case.

Mr. Donnelly: Absolutely. The patient can no longer walk, so it’s already a high-value case. It would be even more so if we supposed that the patient were only 45 years old and a corporate executive. That would make it a really high-value case.

Dr. Michota: What do you mean? Does a patient’s age or economic means matter to a plaintiff’s attorney?

Mr. Donnelly: Of course. For a plaintiff’s attorney, it’s always nice to have a case like this where there’s negligence, but the high-dollar cases typically involve a likable plaintiff who is a high wage earner with a good family. A plaintiff’s lawyer will take a case that may not be so strong on evidence of negligence if it’s likely that a jury will like the plaintiff and his or her family. Kids always help to sway a jury—jurors will feel sorry for them and want to help them. This case even has two surgeries, so the family’s medical bills will be especially high. It’s a great case for a plaintiff’s attorney.

Who’s at fault?

Dr. Michota: Let’s look at a few more case details. Once the various doctors involved in this case realized what happened, they got nervous and engaged in finger-pointing. The surgeons felt that the hospitalists should have stopped the LMWH. The hospitalists claimed that since they had signed off, the surgeons should have stopped it. The physiatrist said, “Who am I to decide to stop medications? I assumed that the hospital physicians checked the medications before sending the patient to the rehab facility.”

Interestingly, a hospitalist went back and made a chart entry after the second surgery. He wrote, “Late chart entry. Discussion with surgeon regarding LMWH. I told him to stop it.” Does that make him free and clear?

Mr. Donnelly: Actually, the hospitalist just shot his credibility, and now the jury is really angry. The dollar value of the case has just gone up.

Dr. Michota: Okay, suppose the hospitalist wouldn’t do something that obvious. Instead, he goes back to the chart after the fact, finds the same color pen as the entry at the time, and writes, “Patient is okay. Please stop LMWH,” and signs his name. Is there any way anyone is going to be able to figure that out?

Mr. Donnelly: All the other doctors and nurses will testify that the note was not in the chart before. The plaintiff will hire a handwriting expert and look at the different impressions on the paper, the inks, and the style of writing. Now the hospitalist has really escalated the situation and is liable for punitive damages, which will come out of his own pocket, since malpractice insurance doesn’t cover punitive damages. His license may be threatened. The jury will really be angered, and the plaintiff’s lawyer will love stoking the situation.

If this is a typical audience of physicians involved in perioperative care, about 35% to 40% of you have been sued for malpractice and have learned the hard way some of the lessons we will discuss today. This session will begin with an overview of malpractice law and medicolegal principles, after which we will review three real-life malpractice cases and open the floor to the audience for discussion of the lessons these cases can offer.

MALPRACTICE LAWSUITS ARE COMMON, EXPENSIVE, DAMAGING

If a physician practices long enough, lawsuits are nearly inevitable, especially in certain specialties. Surgeons and anesthesiologists are sued about once every 4 to 5 years; internists generally are sued less, averaging once every 7 to 10 years,¹ but hospitalists and others who practice a good deal of perioperative care probably constitute a higher risk pool among internists.

At the same time, it is estimated that only one in eight preventable medical errors committed in hospitals results in a malpractice claim.² From 1995 to 2000, the number of new malpractice claims actually declined by approximately 4%.³

Jury awards can be huge

Fewer than half (42%) of verdicts in malpractice cases are won by plaintiffs.⁴ But when plaintiffs succeed, the awards can be costly: the mean amount of physician malpractice payments in the United States in 2006 (the most recent data available) was $311,965, according to the National Practitioner Data Bank.⁵ Cases that involve a death result in substantially higher payments, averaging $1.4 million.⁴

Lawsuits are traumatic

Even if a physician is covered by good malpractice insurance, a malpractice lawsuit typically changes his or her life. It causes major disruption to the physician’s practice and may damage his or her reputation. Lawsuits cause considerable emotional distress, including a loss of self-esteem, particularly if the physician feels that a mistake was made in the delivery of care.

CATEGORIES OF CLAIMS IN MALPRACTICE LAW

Malpractice law involves torts, which are civil wrongs causing injury to a person or property for which the plaintiff may seek redress through the courts. In general, the plaintiff seeks financial compensation. Practitioners do not go to jail for committing malpractice unless a district attorney decides that the harm was committed intentionally, in which case criminal charges may be brought.

There are many different categories of claims in malpractice law. The most common pertaining to perioperative medicine involve issues surrounding informed consent and medical negligence (the worst form being wrongful death).

Informed consent

Although everyone is familiar with informed consent, details of the process are called into question when something goes wrong. Informed consent is based on the right of patient autonomy: each person has a right to determine what will be done to his or her body, which includes the right to consent to or refuse treatment.

For any procedure, treatment, or medication, patients should be informed about the following:

• The nature of the intervention
• The benefits of the intervention (why it is being recommended)
• Significant risks reasonably expected to exist
• Available alternatives (including “no treatment”).

If possible, it is important that the patient’s family understand the risks involved, because if the patient dies or becomes incapacitated, a family that is surprised by the outcome is more likely to sue.

The standard to which physicians are held in malpractice suits is that of a “reasonable physician” dealing with a “reasonable patient.” Often, a plaintiff claims that he or she did not know that a specific risk was involved, and the doctor claims that he or she spent a “typical” amount of time explaining all the risks. If that amount of time was only a few seconds, that may not pass the “reasonable physician” test, as a jury might conclude that more time may have been necessary.

Negligence and wrongful death

Negligence, including wrongful death, is a very common category of claim. The plaintiff generally must demonstrate four elements in negligence claims:

• The provider had a duty to the patient
• The duty was breached
• An injury occurred
• The breach of duty was a “proximate cause” of the injury.

Duty arises from the physician-patient relationship: any person whose name is on the medical chart essentially has a duty to the patient and can be brought into the case, even if the involvement was only peripheral.

Breach of duty. Determining whether a breach of duty occurred often involves a battle of medical experts. The standard of care is defined as what a reasonable practitioner would do under the same or similar circumstances, assuming similar training and background. The jury decides whether the physician met the standard of care based on testimony from experts.

The Latin phrase res ipsa loquitur means “the thing speaks for itself.” In surgery, the classic example is if an instrument or a towel were accidentally left in a patient. In such a situation, the breach of duty is obvious, so the strategy of the defense generally must be to show that the patient was not harmed by the breach.

Injury. The concept of injury can be broad and often depends on distinguishing bad practice from a bad or unfortunate outcome. For instance, a patient who suffered multisystem trauma but whose life was saved by medical intervention could sue if he ended up with paresthesia in the foot afterwards. An expert may be called to help determine whether or not the complication is reasonable for the particular medical situation. Patient expectations usually factor prominently into questions of injury.

Proximate cause often enters into situations involving wrongful death. A clear understanding of the cause of death or evidence from an autopsy is not necessarily required for a plaintiff to argue that malpractice was a proximate cause of death. A plaintiff’s attorney will often speculate why a patient died, and because the plaintiff’s burden of proof is so low (see next paragraph), it may not help the defense to argue that it is pure speculation that a particular event was related to the death. 

A low burden of proof

In a civil tort, the burden of proof is established by a “preponderance of the evidence,” meaning that the allegation is “more likely than not.” This is a much lower standard than the “beyond a reasonable doubt” threshold used for criminal proceedings. In other words, the plaintiff has to show only that the chance that malpractice occurred was greater than 50%. 

Three types of damages

Potential damages (financial compensation) in malpractice suits fall into three categories:

• Economic, or the monetary costs of an injury (eg, medical bills or loss of income)
• Noneconomic (eg, pain and suffering, loss of ability to have sex)
• Punitive, or damages to punish a defendant for willful and wanton conduct.

Punitive damages are generally not covered by malpractice insurance policies and are only rarely involved in cases against an individual physician. They are more often awarded when deep pockets are perceived to be involved, such as in a case against a hospital system or an insurance company, and when the jury wants to punish the entity for doing something that was believed to be willful.

 

 

REDUCING THE RISK OF BEING SUED

Physicians tend to get sued when a bad outcome occurs that can be associated with substandard care or poor communication. Steps can be taken to reduce the risk of being sued, which can be simplified to the “four Cs”: competence, communication, compassion, and charting (Table 1).

Regardless of the circumstances, communication is probably the most important factor determining whether a physician will be sued. Sometimes a doctor does everything right medically but gets sued because of lack of communication with the patient. Conversely, many of us know of veteran physicians who still practice medicine as they did 35 years ago but are never sued because they have a great rapport with their patients and their patients love them for it.

The importance of careful charting also cannot be overemphasized. In malpractice cases, experts for the plaintiff will comb through the medical records and be sure to notice if something is missing. The plaintiff also benefits enormously if, for instance, nurses documented that they paged the doctor many times over a 3-day period and got no response.

CASE 1: PATIENT DIES DURING PREOPERATIVE STRESS TEST FOR KNEE SURGERY

A 65-year-old man with New York Heart Association class III cardiac disease (marked limitation of physical activity) is scheduled for a total knee arthroplasty and is seen at the preoperative testing center. His past medical history includes coronary artery disease, chronic obstructive pulmonary disease, hypertension, and prior repair of an abdominal aortic aneurysm. He is referred for a preoperative stress test.

Dobutamine stress echocardiography is performed. His target heart rate is reached at 132 beats per minute with sporadic premature ventricular contractions. Toward the end of the test, he complains of shortness of breath and chest pain. The test is terminated, and the patient goes into ventricular tachycardia and then ventricular fibrillation. Despite resuscitative efforts, he dies.

Dr. Michota: From the family’s perspective, this patient had come for quality-of-life–enhancing surgery. They were looking forward to him getting a new knee so he could play golf again when he retired. The doctor convinced them that he needed a stress test first, which ends up killing him. Mr. Donnelly, as a lawyer, would you want to be the plaintiff’s attorney in this case?

Mr. Donnelly: Very much so. The family never contemplated that their loved one would die from this procedure. The first issue would be whether or not the possibility of complications or death from the stress test had been discussed with the patient or his family.

Consent must be truly ‘informed’ and documented

Dr. Michota: How many of our audience members who do preoperative assessments and refer patients for stress testing can recall a conversation with a patient that included the comment, “You may die from getting this test”? Before this case occurred, I never brought up this possibility, but I do now. This case illustrates how important expectations are.

Comment from the audience: I think you have to be careful of your own bias about risks. You might say to the patient, “There’s a risk that you’ll have an arrhythmia and die,” but if you also tell him, “I’ve never seen that happen during a stress test in my 10 years of practice,” you’ve biased the informed consent. The family can say, “Well, he basically told us that it wasn’t going to happen; he’d never seen a case of it.”

Dr. Michota: Are there certain things we shouldn’t say? Surely you should never promise somebody a good outcome by saying that certain rare events never happen.

Mr. Donnelly: That’s true. You can give percentages. You might say, “I’m letting you know there’s a possibility that you could die from this, but it’s a low percentage risk.” That way, you are informing the patient. This relates to the “reasonable physician” and “reasonable patient” standard. You are expected to do what is reasonable.

Is a signed consent form adequate defense?

Dr. Michota: What should the defense team do now? Let’s say informed consent was obtained and documented at the stress lab. The patient signed a form that listed death as a risk, but no family members were present. Is this an adequate defense?

Mr. Donnelly: It depends on whether the patient understood what was on the form and had the opportunity to ask questions.

Dr. Michota: So the form means nothing?

Mr. Donnelly: If he didn’t understand it, that is correct.

Dr. Michota: We thought he understood it. Can’t we just say, “Of course he understood it—he signed it.”

Mr. Donnelly: No. Keep in mind that most jurors have been patients at one time or another. There may be a perception that physicians are rushed or don’t have time to answer questions. Communication is really important here.

Dr. Michota: But surely there’s a physician on the jury who can help talk to the other jurors about how it really works.

Mr. Donnelly: No, a “jury of peers” is not a jury box of physicians. The plaintiff’s attorneys tend to exclude scientists and other educated professionals from the jury; they don’t want jurors who are accustomed to holding people to certain standards. They prefer young, impressionable people who wouldn’t think twice about awarding somebody $20 million.

 

 

Who should be obtaining informed consent?

Question from the audience: Who should have obtained informed consent for this patient—the doctor who referred him for the stress test or the cardiologist who conducted the test? Sometimes I have to get informed consent for specialty procedures that I myself do not understand very well. Could I be considered culpable even though I’m not the one doing the procedure? I can imagine an attorney asking, “Doctor, are you a cardiologist? How many of these tests do you do? Why are you the one doing the informed consent? Did the patient really understand the effects of the test? Do you really understand them?”

Dr. Michota: That question is even more pertinent if the patient is referred to another institution covered under different malpractice insurance. You can bet the other provider will try to blame you if something goes wrong.

Mr. Donnelly: In an ideal world, both the referring physician and the physician who does the test discuss the risks, benefits, and alternatives, and answer all questions that the patient and family have. The discussion is properly documented in the medical record.

Question from the audience: Can you address the issue of supervision? What is the liability of a resident or intern in doing the informed consent?

Mr. Donnelly: The attending physician is usually responsible for everything that a resident does. I would prefer that the attending obtain the informed consent.

Dr. Michota: But our fellows and second-year postgraduate residents are independent licensed practitioners in Ohio. Does letting them handle informed consent pose a danger to a defense team’s legal case?

Mr. Donnelly: It’s not necessarily a danger medically, but it gives the plaintiff something to talk about. They will ignore the fact that an independent licensed practitioner obtained the informed consent. They will simply focus on the fact that the physician was a resident or fellow. They will claim, “They had this young, inexperienced doctor give the informed consent when there were staff physicians with 20 years of experience who should have done it.” Plaintiffs will attempt to get a lot of mileage out of these minor issues.

Question from the audience: At our institution, the physician is present with the technician, so that when the physician obtains consent, the technician signs as a witness. The bottom of the long form basically says, “By signing this form, I attest that the physician performing the test has informed me of the benefits and risks of this test, and I agree to go ahead. I fully understand the implications of the test.” Does that have value in the eyes of the law?

Mr. Donnelly: That’s a great informed consent process and will have great value. That said, you can still get sued, because you can get sued for anything. But the jury ultimately decides, and odds are that with a process like yours they will conclude that the patient knew all the risks and benefits and alternatives because he or she signed the form and the doctor documented that everything was discussed.

Confidentiality vs family involvement

Comment from the audience: I’m struck by the comments that informed consent is supposed to be with the family so that there will be living witnesses in case the patient dies. According to Health Insurance Portability and Accountability Act (HIPAA) regulations, we have to be very careful to maintain confidentiality. For a competent patient, medical discussions are private unless specific permission has been obtained to involve the family.

Mr. Donnelly: Yes, we’ve assumed that the patient gave permission to discuss these issues with his family. If the patient does not want that, obviously you can’t include the family because of HIPAA regulations.

Question from the audience: Should we routinely ask a patient to involve the family in an informed consent in case something goes wrong?

Mr. Donnelly: No. In general, it’s appropriate only if the family is already present.

Dr. Michota: Keep in mind that there’s nothing you can do to completely prevent being sued. You can do everything right and still get sued. If you’re following good clinical practice and a patient doesn’t want to involve the family, all you can do is document your discussion and that you believed the patient understood the risks of the procedure.

Question from the audience: Do you consider a patient’s decision-making capacity for informed consent? Should physicians document it prior to obtaining consent? A plaintiff can always claim that an elderly patient did not understand.

Mr. Donnelly: I have never seen specific documentation that a patient had capacity to consent, but it’s a good idea for a borderline case. For such a case, it’s especially important to involve the family and document, “I discussed the matter with this elderly patient and her husband and three daughters.” You could also get a psychiatric consult or a social worker to help determine whether a patient has the capacity to make legal and medical decisions.

CASE 2: FATAL POSTSURGICAL MI RAISES QUESTIONS ABOUT THE PREOP EVALUATION

A 75-year-old man with rectal cancer presents for colorectal surgery. He has a remote cardiac history but exercises regularly and has a good functional classification without symptoms. The surgery is uneventful, but the patient develops hypotension in the postanesthesia care unit. He improves the next morning and goes to the colorectal surgery ward. Internal bleeding occurs but initially goes unrecognized; on postoperative day 2, his hemoglobin is found to be 2 g/dL and he is transferred to the intensive care unit, then back to the operating room, where he suffers cardiac arrest. He is revived but dies 2 weeks later. Autopsy reveals that he died of a myocardial infarction (MI).

Dr. Michota: The complaint in this case is that the patient did not receive a proper preoperative evaluation because no cardiac workup was done. As the hypothetical defense attorney, do you feel this case has merit? The patient most likely had an MI from demand ischemia due to hemorrhage, but does this have anything to do with not having a cardiac workup?

Mr. Donnelly: You as the physician are saying that even if he had an electrocardiogram (ECG), it is likely that nothing would have been determined. The cardiac problems he had prior to the surgery in question were well controlled, occurred in the distant past, and may not have affected the outcome. Maybe his remote cardiac problems were irrelevant and something else caused the MI that killed him. Nevertheless, the fact that the ECG wasn’t done still could be a major issue for the plaintiff’s attorney. After the fact, it seems like a no-brainer that an ECG should have been done in a case like this, and it’s easy for the plaintiff to argue that it might have detected something. The defense has to keep reminding the jury that the case cannot be looked at retrospectively, and that’s a tall order.

Dr. Michota: This case shows that even in the context of high-quality care, such things can happen. We have spent a lot of time at this summit talking about guidelines. But at the end of the day, if somebody dies perioperatively of an MI, the family may start looking for blame and any plaintiff’s attorney will go through the record to see if a preoperative ECG was done. If it wasn’t, a suit will get filed.

 

 

The four Cs offer the best protection

Question from the audience: Even if the physician had done the ECG, how do you know the plaintiff’s attorney wouldn’t attack him for not ordering a stress test? And if he had done a stress test, then they’d ask why he didn’t order a catheterization. Where is it going to end?

Dr. Michota: You make a good point. The best way for physicians to protect themselves is to follow the four Cs mentioned earlier: competent care, communication, compassion, and charting. After I learned about this case, the next time I was in the clinic and didn’t order an ECG, I asked the patient, “Did you expect that we would do an ECG here today?” When he responded that he did, I talked to him about how it wasn’t indicated and probably would not change management. So that level of communication can sometimes prevent a lawsuit that might stem from a patient not feeling informed. I’m not suggesting that you spend hours explaining details with each patient, but it’s good to be aware that cases like this happen and how you can reduce their likelihood.

Battles of the experts

Question from the audience: Exactly what standard is applied when the “standard of care” is determined in a court? For instance, my hospital may routinely order stress tests, whereas the American College of Cardiology and American Heart Association (ACC/AHA) guidelines are more restrictive in recommending when a stress test is indicated. Which standard would apply in court?

Dr. Michota: It’s easy to find a plaintiff’s expert who will say just about anything. If you claim that everybody gets a stress test at your community hospital and a patient dies during the stress test, the plaintiff’s team will find an expert to say, “That was an unnecessary test and posed an unnecessary risk.” If you’re in a setting where stress tests are rarely done for preoperative evaluation, they’ll find an expert to say, “Stress testing was available; it should have been done.”

This is when the battles of the experts occur. If you have a superstar physician on your defense team, the plaintiff will have to find someone of equal pedigree who can argue against him or her. Sometimes cases go away because the defense lines up amazing experts and the plaintiffs lose their stomach for the money it would take to bring the case forward. But usually cases do not involve that caliber of experts; most notables in the field are academic physicians who don’t do this type of work. Usually you get busy physicians who spend 75% of their time in clinical practice and seem smart enough to impress the jury. Although they can say things that aren’t even factual, they can sway the jury. 

Question from the audience: I would not have ordered a preoperative ECG on this healthy 75-year-old, but one of the experts at this summit said that he would get a baseline ECG for such a case. How are differences like these reconciled in the legal context?

Dr. Michota: The standard to which we are held is that of a reasonable physician. Can you show that your approach was a reasonable one? Can you say, “I didn’t order the ECG for the following reasons, and I discussed the issue with the patient”? Or alternately, “An ECG was ordered for the following reasons, and I discussed it with the patient”? The jury will want to know whether the care that was provided was reasonable.

Costs and consequences of being sued

Question from the audience: What does it cost to mount a defense in a malpractice trial?

Mr. Donnelly: You can easily spend more than $100,000 to go through a trial. Plaintiffs typically have three or four experts in various cities across the country, and you have to pay your lawyers to travel to those cities and take the depositions. And delays often occur. Cases get filed, dismissed, and refiled. A lot of the work that the lawyers did to prepare for the trial will have to be redone for a second, third, or fourth time as new dates for the trial are set. There are many unforeseen costs.

Dr. Michota: Let’s say the physician who did the preoperative evaluation in this case was not affiliated with the hospital and wasn’t involved in the surgery or any of the postoperative monitoring and management, which we see may have been questionable. This physician might get pulled into the case anyway because he didn’t order an ECG in the preoperative evaluation. Although an ECG wasn’t recommended in this case by the ACC/AHA guidelines, this doctor is looking at spending considerable time, energy, and money to defend himself. What if his attorney recommends that he settle for a nominal amount—say, $25,000—because it’s cheaper and easier? Are there repercussions for him as a physician when he pays out a settlement under his name?

Mr. Donnelly: Absolutely. He will be reported to the National Practitioner Data Bank, and when he renews his license or applies for a license to practice in another state, he must disclose that he has been sued and paid a settlement. The new consumer-targeted public reporting Web sites will also publicize this information. It is like a black mark against this doctor even though he never admitted any liability.

CASE 3: A CLEAR CASE OF NEGLIGENCE―WHO IS RESPONSIBLE

A 67-year-old man undergoes a laminectomy in the hospital. He develops shortness of breath postoperatively and is seen by the hospitalist team. He is started on full-dose weight-adjusted low-molecular-weight heparin (LMWH) for possible pulmonary embolism or acute coronary syndrome. His symptoms resolve and his workup is negative. It is a holiday weekend. The consultants sign off but do not stop the full-dose LMWH. The patient is discharged to the rehabilitation unit by the surgeon and the surgeon’s assistant, who include all the medications at discharge, including the full-dose LMWH. The patient is admitted to a subacute nursing facility, where the physiatrist transfers to the chart all the medications on which the patient was discharged.

The patient does well until postoperative day 7, when he develops urinary retention and can’t move his legs. At this point, someone finally questions why he is on the LMWH, and it is stopped. The patient undergoes emergency surgery to evacuate a huge spinal hematoma, but his neurologic function never recovers.

Dr. Michota: I think most of us would agree that there was negligence here. I bet a plaintiff’s attorney would love to have this case.

Mr. Donnelly: Absolutely. The patient can no longer walk, so it’s already a high-value case. It would be even more so if we supposed that the patient were only 45 years old and a corporate executive. That would make it a really high-value case.

Dr. Michota: What do you mean? Does a patient’s age or economic means matter to a plaintiff’s attorney?

Mr. Donnelly: Of course. For a plaintiff’s attorney, it’s always nice to have a case like this where there’s negligence, but the high-dollar cases typically involve a likable plaintiff who is a high wage earner with a good family. A plaintiff’s lawyer will take a case that may not be so strong on evidence of negligence if it’s likely that a jury will like the plaintiff and his or her family. Kids always help to sway a jury—jurors will feel sorry for them and want to help them. This case even has two surgeries, so the family’s medical bills will be especially high. It’s a great case for a plaintiff’s attorney.

Who’s at fault?

Dr. Michota: Let’s look at a few more case details. Once the various doctors involved in this case realized what happened, they got nervous and engaged in finger-pointing. The surgeons felt that the hospitalists should have stopped the LMWH. The hospitalists claimed that since they had signed off, the surgeons should have stopped it. The physiatrist said, “Who am I to decide to stop medications? I assumed that the hospital physicians checked the medications before sending the patient to the rehab facility.”

Interestingly, a hospitalist went back and made a chart entry after the second surgery. He wrote, “Late chart entry. Discussion with surgeon regarding LMWH. I told him to stop it.” Does that make him free and clear?

Mr. Donnelly: Actually, the hospitalist just shot his credibility, and now the jury is really angry. The dollar value of the case has just gone up.

Dr. Michota: Okay, suppose the hospitalist wouldn’t do something that obvious. Instead, he goes back to the chart after the fact, finds the same color pen as the entry at the time, and writes, “Patient is okay. Please stop LMWH,” and signs his name. Is there any way anyone is going to be able to figure that out?

Mr. Donnelly: All the other doctors and nurses will testify that the note was not in the chart before. The plaintiff will hire a handwriting expert and look at the different impressions on the paper, the inks, and the style of writing. Now the hospitalist has really escalated the situation and is liable for punitive damages, which will come out of his own pocket, since malpractice insurance doesn’t cover punitive damages. His license may be threatened. The jury will really be angered, and the plaintiff’s lawyer will love stoking the situation.

As a hospitalist who practices in a perioperative clinic, I probably spend more of my time with patients reviewing and discussing the medications they are taking than on any other single subject. Surgical patients—many of whom are elderly—commonly are on multiple medications, have renal or hepatic disease that can alter drug metabolism, and may not be adequately educated about their medication regimens.

Patient safety is the overriding concern behind perioperative medication management, consistent with the medication-related objectives in the Joint Commission’s 2009 National Patient Safety Goals.¹ The increasing surgical burden that comes with an aging population, along with rising expectations for functional recovery, has likewise elevated the importance of perioperative medication management.

Despite these demands, there is scant evidence from randomized controlled trials to directly guide perioperative medication management. For this reason, recommendations in this area rely largely on other forms of evidence, including expert consensus, case reports, in vitro studies, recommendations from pharmaceutical companies, and other known data (pharmacokinetics, drug interactions with anesthetic agents, and effects of the agent on the primary disease and on perioperative risk).

This article reviews general principles of perioperative medication management and then presents four case vignettes to explore perioperative recommendations for a number of common medication classes. It is not intended as a comprehensive review of the perioperative management of all medications, as numerous classes (antiplatelets, beta-blockers, oral hypogycemic agents, insulin, statins) are discussed in detail elsewhere in this proceedings supplement.

GENERAL CONSIDERATIONS IN MEDICATION MANAGEMENT

A comprehensive medication history is fundamental

Effective perioperative management of medications requires an understanding of the patient and his or her comorbidities so that the risk of perioperative decompensation can be gauged. This understanding stems from a thorough medical history that includes a comprehensive medication history to provide a complete inventory of the following:

• All prescription medications
• All over-the-counter (OTC) agents (including nonsteroidal anti-inflammatory drugs [NSAIDs])
• All vitamins
• All herbal medications.

When to stop, when to resume?

Guidance on stopping and resuming medications in the perioperative period is relatively absent from the literature. General considerations include the following:

• The potential for withdrawal when stopping a medication
• The progression of disease with interruption of drug therapy
• The potential for interactions with anesthetic agents if the medication is continued.

Withdrawal potential

Abrupt discontinuation of some drugs may lead to unnecessary complications due to the potential for withdrawal. Common medications that have been associated with withdrawal symptoms are selective serotonin reuptake inhibitors (SSRIs), beta-blockers, clonidine, statins, and corticosteroids.² A recent systematic literature review concluded that continuation of chronic corticosteroid therapy without supplemental (stress) doses of corticosteroids is appropriate unless patients have primary disease of the hypothalamic-pituitary-adrenal axis, in which case perioperative stress dosing is recommended to avoid acute adrenal insufficiency (addisonian crisis).³

Patients on chronic drugs are more likely to have complications

In a medication survey of 1,025 patients admitted to a general surgery unit, Kennedy et al reported that 49% of the patients were taking medications (other than vitamins) unrelated to their surgical procedure.⁴ Even while this percentage is considerably lower than what I observe in my practice, this study showed that medication use has important perioperative consequences⁴:

• The odds ratio for a postoperative complication was 2.7 (95% CI, 1.76–4.04) if patients were taking a drug unrelated to their surgery.
• The risk of a complication was particularly elevated if patients were taking cardiovascular drugs or agents that act on the central nervous system; if patients were on NPO (“nothing by mouth”) orders for more than 24 hours before surgery; and if the operation was more than 1 hour in duration. These findings could reflect destabilization of the disease processes for which the patients were taking chronic medications that required interruption.

Unintended discontinuation of chronic drugs

Stopping a chronic medication for a surgical procedure raises the possibility that its resumption could be overlooked, especially since medical errors are particularly common in the transition between health care settings following hospital discharge. A population-based cohort study among all elderly patients discharged from Ontario, Canada, hospitals over a 5½-year period found that 11.4% of patients undergoing elective surgery did not resume their indicated chronic warfarin therapy within 6 months after its presurgical discontinuation.⁵ Although 6-month rates of unintended failure to resume therapy were lower for statins (4%) and ophthalmic beta-blocker drops (8%),⁵ these findings underscore that drug discontinuation always carries a risk that therapy might not be resumed as indicated.

Additional considerations

Stress response to surgery. Decisions about perioperative drug therapy should always take into account the stress response to surgery and the challenge it presents to homeostasis in the face of increased sympathetic tone and release of pituitary hormones.

Unreliable absorption of oral medications. Surgery and the postoperative state can lead to unreliable absorption of oral drugs for any of a number of reasons: villous atrophy, diminished blood flow to the gut, edema, mucosal ischemia, diminished motility from postoperative ileus, and use of narcotics.⁶

Take-away general principles

The following principles can be applied to guide peri­operative medication management in a general sense⁷:

• Continue medications with withdrawal potential
• Discontinue medications that increase surgical risk and are not essential for short-term quality of life
• Use clinical judgment when neither of the above two principles applies, but be mindful that many other medications are given in the narrow perioperative time window and that metabolism and elimination of chronic drugs may be altered.

 

 

CASE 1: A PATIENT ON A NONPRESCRIPTION NSAID FOR SEVERE ARTHRITIS

A 55-year-old man with severe osteoarthritis is scheduled for total hip arthroplasy in 2 days. He stopped his aspirin (325 mg/day) 1 week ago but continued taking ibuprofen 600 three times daily with food, explaining that “no one told me to stop.” His last dose was yesterday evening.

Question: What should you do?

A. Call the surgeon and cancel the surgery

B. Call the surgeon to notify, and tell the patient to stop the ibuprofen now

C. Check his bleeding time and proceed if normal

D. Just tell the patient to stop the ibuprofen now

E. Proceed to the operating room regardless of the ibuprofen dose

The best approach would be to notify the surgeon and tell the patient to stop the ibuprofen now. NSAIDs such as ibuprofen reversibly inhibit platelet cyclooxygenase (COX), diminish thromboxane A₂ production, diminish platelet aggregation, and can increase bleeding time measurement and overall bleeding risk. They can induce renal failure in combination with other drugs, especially in the setting of hypotension.^8,9 COX-2 inhibitors have less effect on platelet function but retain the potential for renal toxicity and also confer well-known cardio­vascular risks.

In the past, NSAIDs were typically held for 7 days before surgery, but this practice was not supported with much evidence. In vitro assessment indicates that platelet function normalizes within 24 hours after cessation of regular ibuprofen or dexibuprofen in healthy individuals.^10,11

Since NSAIDs vary in their effect on bleeding time, which does not correlate well with elimination half-life, a general recommendation is to stop most NSAIDs at least 3 days before surgery.

CASE 2: A PATIENT ON MULTIPLE CARDIOVASCULAR DRUGS

A 67-year-old man with dilated cardiomyopathy and an ejection fraction of 25% (well compensated) is scheduled for a laparoscopic cholecystectomy tomorrow. He is taking lisinopril (40 mg/day), irbesartan (150 mg/day), and furosemide (80 mg/day).

Question: What is your advice?

A. Call the surgeon and cancel the surgery

B. Call the surgeon to notify, and tell the patient to stop his medications now

C. Hold all of the above medications on the morning of surgery

D. Proceed to the operating room with the usual doses of his medications on the morning of surgery

The best approach is to withhold these medications on the morning of surgery.

Diuretics are typically held on the morning of surgery because of the potential for hypovolemia and electrolyte depletion.

Angiotensin-converting enzyme (ACE) inhibitors intensify the hypotensive effects of anesthesia induction. Because angiotensin II plays a key role in maintaining circulating volume in response to stressors, volume deficits can occur in ACE inhibitor-treated patients as angiotensin II cannot compensate for venous pooling of blood, resulting in diminished cardiac output and arterial hypotension. However, continued renin-angiotensin system suppression may protect regional circulation, as has been demonstrated by reduced release of cardiac enzymes with ACE inhibitor continuation (compared with interruption) in cardiac surgery patients. ACE inhibitors also have a renal protective effect, preserving glomerular filtration rate in patients undergoing aortic abdominal aneurysm repair or coronary artery bypass graft surgery. Hypotension with ACE inhibition is treatable with sympathomimetics, alpha-agonists, and intravenous fluids.^12–15

If a patient’s ACE inhibitor is stopped, be prepared for rebound postoperative hypertension. The probability of postoperative atrial fibrillation is also increased with ACE inhibitor interruption.¹⁴ In patients with left ventricular dysfunction undergoing noncardiac vascular surgery, continued ACE inhibition is associated with reduced mortality.¹⁶ These data argue, at the very least, for prompt resumption of ACE inhibitors after surgery.

Angiotensin receptor blockers (ARBs) have largely the same clinical benefits as do ACE inhibitors. These agents also increase the risk of hypotension upon induction of anesthesia, and this hypotension is not as responsive to conventional vasopressors such as ephedrine and phenylephrine; a better response is achieved with vasopressin.¹⁵ In light of the long half-life of ARBs, current thinking is to withhold them 24 hours before surgery.

Rosenman et al recently published a meta-analysis of five studies assessing the effects of continuing or withholding ACE inhibitors and ARBs in the preoperative period.¹⁷ They found a statistically significant increase in the incidence of perioperative hypotension in patients in whom the drugs were continued compared with those in whom the drugs were withheld (relative risk = 1.50; 95% CI, 1.15–1.96), but there was no significant difference in the rate of perioperative MI between the two groups. Notably, the indication for ACE inhibitor or ARB use in all of the studies was hypertension, not heart failure.

My approach to the perioperative management of ACE inhibitors and ARBs is to withhold them on the morning of surgery (in the case of ARBs, 24 hours prior to surgery) if their only indication is for hypertension and if the patient’s blood pressure is well controlled. If the patient has another indication for these agents or has hypertension that is not well controlled, I am inclined to continue these agents but will first discuss the decision with the anesthesiologist.

 

 

CASE 3: A PATIENT TAKING HERBAL MEDICATIONS

A 68-year-old woman with a history of hypertension, osteoarthritis, and osteoporosis is scheduled for total hip replacement in 7 days. Her medications include atenolol, hydrochlorothiazide, and alendronate. She also reports taking some natural herbal medications. She does not recall their names initially but calls back with the names: ginkgo biloba for her memory and echinacea for her immune system.

Question: What are your recommendations?

A. Stop all medications now except atenolol and proceed to surgery

B. Stop the herbals now but take all other medications on the morning of surgery

C. Stop the herbals now and take only atenolol on the morning of surgery

D. Continue all medications now and take atenolol and the herbals on the morning of surgery

E. Cancel the surgery and call an herbalist for guidance

The best strategy is to stop the herbals now and tell her to take only atenolol (a beta-blocker) on the morning of surgery.

Up to one third of patients scheduled for surgery take herbal medications,¹⁸ and many do not report that they are taking them without prompting, which requires that the consultant specifically ask about herbals. Often this failure to report use of herbals stems from patients’ misperception that herbals are inherently safe because they are “natural.” Yet common herbal medications have been implicated in perioperative complications including MI, stroke, bleeding, prolonged anesthetic action, inadequate anesthetic action, and interference with other medications.¹⁸Table 1 profiles potential perioperative effects specific to eight common herbal medications.

Because the US Food and Drug Administration (FDA) does not regulate herbal products, the contents of these products can vary widely. For example, an analysis using mass spectrometry of 50 commercial ginseng products from 11 countries found that the ginseng content varied from 0% (six preparations) to 9%.¹⁹ Catecholamine-type compounds were found in some of the products.¹⁹

Because of the uncertainty over their actual contents, herbal medications should be stopped at least 7 days prior to surgery. If a patient is still taking herbal supplements on the day before surgery, I typically alert the anesthesiologist and surgeon.

CASE 4: A PATIENT ON MULTIPLE PSYCHOTROPICS

A 38-year-old woman with a history of severe major depression is scheduled for a mastectomy for breast cancer the next day. Her medications include fluoxetine, lorazepam, and phenelzine, all of which she has been taking for many years.

Question: What is your course of action?

A. Call the surgeon and cancel the surgery

B. Call the surgeon and notify the day-of-surgery anesthesiologist that the patient is taking these agents

C. Stop all the medications now and proceed to the operating room

D. Request a psychiatric consult for an alternative drug regimen

E. Proceed and advise the patient to take all of these agents on the morning of surgery

My approach would be to notify the day-of-surgery anesthesiologist, specifically about the phenelzine, which is a monoamine oxidase (MAO) inhibitor (see below). The other two agents can be taken on the morning of surgery, although fluoxetine has a long half-life, so missing a dose should not be problematic, and lorazepam can be given intravenously if needed.

SSRIs, including fluoxetine, are generally safe peri­operatively. Serotonin depletion from platelets, however, increases the risk of bleeding, especially gastrointestinal bleeding, when SSRIs are used with NSAIDs.^20–22 A neurosurgical procedure may therefore be especially risky in patients who have not stopped their SSRI if they are also taking an NSAID or an herbal medication that may increase the risk of bleeding. The caveat to stopping SSRIs is the potential for a minor withdrawal syndrome.

Tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin and may increase the action of sympathomimetics. Although arrhythmias are thought to be a concern with tricyclics, there are no reported cases of association in the literature. In general, I advise continuing triclyclics perioperatively, especially in patients who are on high doses.

Benzodiazepines, including lorazepam, are safe to use perioperatively, and a potential for withdrawal symptoms (hypertension, agitation, delirium, seizures) argues against their discontinuation. Chronic benzodiazepine use may increase anesthetic requirements.

Antipsychotic agents, which include haloperidol, olanzapine, risperidone, and ziprasidone, have multiple routes of administration—intramuscular, oral, sublingual, and intravenous. These agents are generally safe to use in the perioperative period.

MAO inhibitors, including phenelzine, are no longer commonly used and are typically reserved for the treatment of refractory depression. But they merit attention, as their use can cause accumulation of biogenic amines in the central and autonomic nervous systems. There are two types of MAO reactions—excitatory and depressive. Excitatory reactions lead to serotonin syndrome. Depressive reactions induce inhibition of hepatic microsomal enzymes, leading to narcotic accumulation and increased sedation.²³

MAO inhibitors are also of concern because of their many drug interactions. When used with indirect sympathomimetics such as ephedrine, they promote a massive release of stored norepinephrine, leading to severe hypertension. When used with opioids like meperidine and dextromethorphan, MAO inhibitors are associated with a serotonin syndrome characterized by agitation, headache, fever, seizures, coma, and death.

Discontinuing MAO inhibitors before the day of surgery is no longer universally recommended, due to the risk of precipitating an exacerbation of major depression. Safe anesthetic regimens in the setting of MAO inhibitors involve avoidance of meperidine (morphine and fentanyl are safe) and use of only direct-acting sympathomimetics.

 

 

CONCLUSIONS

A good medication history that includes herbal and OTC products is essential for safe induction of anesthesia and optimization of outcomes during and following surgery. In general, medications with the potential to induce withdrawal symptoms should be continued. The use of nonessential medications that can increase surgical risk should be discontinued. If neither of these conditions applies, consider the patient’s risk profile and the risk of the procedure when making perioperative management decisions. Be mindful of withdrawal syndromes and resume medications with the potential for such syndromes as soon as possible.

DISCUSSION

Comment from the audience: In regard to your comment that diuretics are typically held on the morning of surgery, my institution recently completed a randomized placebo-controlled trial (publication is pending) in which we studied the effect of continuing or not continuing furosemide preoperatively. We found no difference in the occurrence of intraoperative hypotension between the two groups. It will be interesting to see if these findings change practice over time.

Dr. Whinney: It’s good to know that hypotension is not a concern with furosemide, but the issue here is not just blood pressure but electrolyte abnormalities that could predispose to arrhythmias. The patients who concern me are those who haven’t been seen by a physician for a while and may be on high doses of furosemide. I would scrutinize such patients closely.

Question from the audience: We see a number of patients on methotrexate and other disease-modifying rheumatologic drugs. Can you comment on the peri­operative management of these medications?

Dr. Whinney: Methotrexate has caused some anxiety over the risk of infection, but the literature does not support such concern.²⁴ In fact, it appears that continuing methotrexate is probably advisable because the risk of decompensation of the disease may be worse than the potential infectious risks. The only caveat is the patient with renal insufficiency, in whom the recommendation is to withhold methotrexate for 2 weeks before surgery. While most rheumatologists favor withholding disease-modifying drugs perioperatively, a recent systematic review showed no increased risk of either total or infectious complications with use of immunomodulators including infliximab, azathioprine, and cyclosporine.²⁵ It is still reasonable and prudent to discuss this issue with the patient’s rheumatologist. Hydroxychloroquine is safe to continue.

Comment from the audience: First, I would like to urge everyone to be mindful of medication-related indications for preoperative testing. There are many psychotropic drugs that prolong the QT interval and thus constitute an indication for a baseline electrocardiogram prior to surgery. Second, I believe there is a mythology in the perioperative community about the bleeding risk associated with omega-3 fatty acids and vitamin E. Can you comment on the bleeding risks associated with each?

Dr. Whinney: There are few data; the fear is based purely on the potential of these compounds to cause bleeding. Neither is beneficial for short-term quality of life or for chronic prevention, and there’s no withdrawal syndrome from either. So I generally withhold them, but if the patient is still taking them up to the day of surgery, it doesn’t merit postponing surgery. I generally let the surgeon or the nurse know, and it tends not to be a big deal.

Question from the audience: Do you stop herbal teas, energy drinks, and diet medications such as phentermine prior to surgery?

Dr. Whinney: You need to know which diet medications the patient is taking. The problem with many of the OTC products is that they may or may not be considered drugs, so they may not be approved by the FDA and thus you don’t know what the patient is actually taking. For the most part, a diet medication does not contribute to short-term quality of life. My aim is to get the patient through surgery as safely as possible, so if a patient is taking an agent with ingredients, known or unknown, with an interaction potential, then I will stop it.

The two types of diet agents are those that block the absorption of fat, which could interact with other oral agents given at the same time, and those that act via the gastrointestinal tract. I generally withhold the fat-absorption blockers the day before surgery. Phentermine has the potential for catecholinergic reactions or sympathomimetic actions. I would put it in the category of herbal-type medicines and withhold it for at least 7 days.

Question from the audience: Can you comment on combination drugs such as losartan/hydrochlorothiazide on the morning of surgery?

Dr. Whinney: The ARB losartan may have more physiologic benefit than the diuretic, so I would prescribe a single dose of losartan the morning of surgery if I had decided to continue this class of medication for uncontrolled hypertension or concern over heart failure decompensation. The same is true for a beta-blocker/diuretic combination product; I will prescribe the beta-blocker component individually and tell the patient to take it the morning of surgery.

Question from the audience: I’m confused by the recommendation to stop hydrochlorothiazide. It’s a far less potent diuretic than furosemide. Does the risk of stopping it, with resulting blood pressure elevation, outweigh the risk of a mild hypotensive response because of a mild diuretic effect? I’m aware of no data on the risk of stopping hydrochlorothiazide—are you?

Dr. Whinney: There are no data. Again, the recommendation is based on the physiology of the drug, as well as on expert consensus and opinion. Since anesthesia has a vasodilatory effect with a hypotensive response, it’s probably reasonable to hold hydrochlorothiazide if its only indication is for hypertension. That’s the logic behind the recommendation. If you continue it the day of surgery, it may not necessarily hurt, but we’re not certain.

Question from the audience: The implication from your third case study was that alendronate should be held. What’s the basis of that recommendation?

Dr. Whinney: First, the patient has to be upright for 30 minutes after taking alendronate, which could be a problem on the morning of surgery. Also, withholding it will not impair short-term quality of life; it’s a weekly medication, so the patient can take her next dose once she’s up and ambulatory.

Question from the audience: What do you for young women on oral contraceptives? I’m lucky if I see them within 7 days of surgery.

Dr. Whinney: You’re bringing up the concern with exogenous hormones and the risk of venous thrombo­embolism (VTE), a risk that clearly is increased with the hypercoagulable milieu of surgery. The recommendation is to stop hormone therapy 30 to 45 days prior to surgery in these patients. As you note, however, we don’t get the chance to see patients during that window of opportunity. So the question is whether stopping hormones within a shorter time period results in an incremental benefit. And that is not necessarily the case. These patients should be seen as being at risk for VTE and be given appropriate VTE prophylaxis. In fact, in the similar context of menopausal hormone therapy, a study among women undergoing orthopedic surgery showed that as long as they received appropriate VTE prophylaxis, there was no significant difference in VTE rates between the women whose hormone therapy was withheld versus those who continued it.²⁶

Question from the audience: Are there concerns about withdrawal in patients with peripheral vascular disease treated with cilostazol or pentoxifylline?

Dr. Whinney: It’s not particularly well studied. Guidelines from the American College of Physicians suggest to hold these agents for elective surgeries.²⁷ With respect to antiplatelet therapies, O’Riordan et al did a systematic review of 99 articles pertaining to antiplatelet agents in the perioperative period and concluded that aspirin should not be stopped in patients going for surgery.²⁸ In vascular surgery, antiplatelet agents may help promote graft patency.