User login
The Progression of Prehypertension to Hypertension Among Beneficiaries of the Military Health System
The Best Reason Ever to Stop Smoking?
Arthritis and Stress: How Does Race Factor In?
Grand Rounds: Man, 82, With New-Onset Headaches
An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.
The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.
The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.
His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.
The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.
On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.
The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.
CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.
Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.
Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.
Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.
Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.6 Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.4
Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al8 found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.
In addition, excessive anticoagulation has been associated with increased morbidity and mortality.5,9,10 Pieracci et al9 found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.
Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.
Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.11 For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.
Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.11 Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.
Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.
Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.13
Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.13 The mortality rate for SDH is 31% to 36%.14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.16 Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.16,17
Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.4,12,18,19
The risk factors for CSDH are listed in Table 1.4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.4,14
Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.
Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.9,22-24 The choice of agents depends on the timing of intervention.
Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.25
Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al26 found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.
In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.27
Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al14 found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.
Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.20,28 Merlicco et al29 found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.
Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.
Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.
Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.
Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.
1. Pullicino P, Thompson JL. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2003;348(3): 256-257.
2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974.
3. DeSilvey DL. Clinical trials: advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Am J Geriatr Cardiol. 2005;14(2):98-99.
4. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745-752.
5. Koo S, Kucher N, Nguyen PL, et al. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med. 2004;164(14):1557-1560.
6. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma. 2002;53(4):668-672.
7. Pieracci FM, Eachempati SR, Shou J, et al. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma. 2007;63(3):525-530.
8. Fanikos J, Grasso-Correnti N, Shah R, et al. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol. 2005;96(4):595-598.
9. Pieracci FM, Eachempati SR, Shou J, et al. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma. 2007;63(3):519-524.
10. Franko J, Kish KJ, O’Connell BG, et al. Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma. J Trauma. 2006; 61(1):107-110.
11. Drapkin AJ. Chronic subdural hematoma: pathophysiological basis for treatment. Br J Neurosurg. 1991; 5(5):467-473.
12. Yamamoto H, Hirashima Y, Hamada H, et al. Independent predictors of recurrence of chronic subdural hematoma: results of multivariate analysis performed using a logistic regression model. J Neurosurg. 2003;98(6):1217-1221.
13. Iantosca MR, Simon RH. Chronic subdural hematoma in adult and elderly patients. Neurosurg Clin N Am. 2000;11(3):447-454.
14. Rozzelle CJ, Wofford JL, Branch CL. Predictors of hospital mortality in older patients with subdural hematoma. J Am Geriatr Soc. 1995;43(3):240-244.
15. Wintzen AR, Tijssen JG. Subdural hematoma and oral anticoagulant therapy. Arch Neurol. 1982;39(2): 69-72.
16. Ramachandran R, Hegde T. Chronic subdural hematomas: causes of morbidity and mortality. Surg Neurol. 2007;67(4):367-372.
17. Amirjamshidi A, Eftekhar B, Abouzari M, Rashidi A. The relationship between Glasgow coma/outcome scores and abnormal CT scan findings in chronic subdural hematoma. Clin Neurol Neurosurg. 2007;109(2): 152-157.
18. Lee JY, Ebel H, Ernestus RI, Klug N. Various surgical treatments of chronic subdural hematoma and outcome in 172 patients: is membranectomy necessary? Surg Neurol. 2004;61(6):523-527.
19. Gelabert-González M, Iglesias-Pais M, García-Allut A, Martínez-Rumbo R. Chronic subdural haematoma: surgical treatment and outcome in 1000 cases. Clin Neurol Neurosurg. 2005;107(3):223-229.
20. Mattle H, Kohler S, Huber P, et al. Anticoagulation-related intracranial extracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1989;52(7):829-837.
21. Sambasivan M. An overview of chronic subdural hematoma: experience with 2300 cases. Surg Neurol. 1997;47(5):418-422.
22. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg. 2003;98(4):737-740.
23. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79(12):1495-1500.
24. Dager WE, King JH, Regalia RC, et al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006;26(8): 1091-1098.
25. Denas G, Marzot F, Offelli P, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J Thromb Thrombolysis. 2008 Mar 13; [Epub ahead of print].
26. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5):1113-1118.
27. Kissela BM, Eckman MH. Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage. BMC Neurol. 2008;8:17.
28. Ernestus RI, Beldzinski P, Lanfermann H, Klug N. Chronic subdural hematoma: surgical treatment and outcome in 104 patients. Surg Neurol. 1997;48(3): 220-225.
29. Merlicco G, Pierangeli E, di Padova PL. Chronic subdural hematomas in adults: prognostic factors: analysis of 70 cases. Neurosurg Rev. 1995;18(4):247-251.
An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.
The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.
The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.
His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.
The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.
On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.
The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.
CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.
Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.
Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.
Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.
Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.6 Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.4
Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al8 found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.
In addition, excessive anticoagulation has been associated with increased morbidity and mortality.5,9,10 Pieracci et al9 found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.
Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.
Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.11 For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.
Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.11 Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.
Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.
Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.13
Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.13 The mortality rate for SDH is 31% to 36%.14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.16 Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.16,17
Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.4,12,18,19
The risk factors for CSDH are listed in Table 1.4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.4,14
Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.
Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.9,22-24 The choice of agents depends on the timing of intervention.
Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.25
Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al26 found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.
In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.27
Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al14 found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.
Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.20,28 Merlicco et al29 found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.
Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.
Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.
Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.
Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.
An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.
The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.
The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.
His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.
The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.
On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.
The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.
CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.
Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.
Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.
Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.
Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.6 Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.4
Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al8 found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.
In addition, excessive anticoagulation has been associated with increased morbidity and mortality.5,9,10 Pieracci et al9 found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.
Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.
Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.11 For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.
Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.11 Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.
Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.
Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.13
Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.13 The mortality rate for SDH is 31% to 36%.14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.16 Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.16,17
Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.4,12,18,19
The risk factors for CSDH are listed in Table 1.4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.4,14
Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.
Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.9,22-24 The choice of agents depends on the timing of intervention.
Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.25
Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al26 found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.
In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.27
Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al14 found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.
Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.20,28 Merlicco et al29 found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.
Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.
Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.
Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.
Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.
1. Pullicino P, Thompson JL. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2003;348(3): 256-257.
2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974.
3. DeSilvey DL. Clinical trials: advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Am J Geriatr Cardiol. 2005;14(2):98-99.
4. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745-752.
5. Koo S, Kucher N, Nguyen PL, et al. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med. 2004;164(14):1557-1560.
6. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma. 2002;53(4):668-672.
7. Pieracci FM, Eachempati SR, Shou J, et al. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma. 2007;63(3):525-530.
8. Fanikos J, Grasso-Correnti N, Shah R, et al. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol. 2005;96(4):595-598.
9. Pieracci FM, Eachempati SR, Shou J, et al. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma. 2007;63(3):519-524.
10. Franko J, Kish KJ, O’Connell BG, et al. Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma. J Trauma. 2006; 61(1):107-110.
11. Drapkin AJ. Chronic subdural hematoma: pathophysiological basis for treatment. Br J Neurosurg. 1991; 5(5):467-473.
12. Yamamoto H, Hirashima Y, Hamada H, et al. Independent predictors of recurrence of chronic subdural hematoma: results of multivariate analysis performed using a logistic regression model. J Neurosurg. 2003;98(6):1217-1221.
13. Iantosca MR, Simon RH. Chronic subdural hematoma in adult and elderly patients. Neurosurg Clin N Am. 2000;11(3):447-454.
14. Rozzelle CJ, Wofford JL, Branch CL. Predictors of hospital mortality in older patients with subdural hematoma. J Am Geriatr Soc. 1995;43(3):240-244.
15. Wintzen AR, Tijssen JG. Subdural hematoma and oral anticoagulant therapy. Arch Neurol. 1982;39(2): 69-72.
16. Ramachandran R, Hegde T. Chronic subdural hematomas: causes of morbidity and mortality. Surg Neurol. 2007;67(4):367-372.
17. Amirjamshidi A, Eftekhar B, Abouzari M, Rashidi A. The relationship between Glasgow coma/outcome scores and abnormal CT scan findings in chronic subdural hematoma. Clin Neurol Neurosurg. 2007;109(2): 152-157.
18. Lee JY, Ebel H, Ernestus RI, Klug N. Various surgical treatments of chronic subdural hematoma and outcome in 172 patients: is membranectomy necessary? Surg Neurol. 2004;61(6):523-527.
19. Gelabert-González M, Iglesias-Pais M, García-Allut A, Martínez-Rumbo R. Chronic subdural haematoma: surgical treatment and outcome in 1000 cases. Clin Neurol Neurosurg. 2005;107(3):223-229.
20. Mattle H, Kohler S, Huber P, et al. Anticoagulation-related intracranial extracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1989;52(7):829-837.
21. Sambasivan M. An overview of chronic subdural hematoma: experience with 2300 cases. Surg Neurol. 1997;47(5):418-422.
22. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg. 2003;98(4):737-740.
23. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79(12):1495-1500.
24. Dager WE, King JH, Regalia RC, et al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006;26(8): 1091-1098.
25. Denas G, Marzot F, Offelli P, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J Thromb Thrombolysis. 2008 Mar 13; [Epub ahead of print].
26. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5):1113-1118.
27. Kissela BM, Eckman MH. Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage. BMC Neurol. 2008;8:17.
28. Ernestus RI, Beldzinski P, Lanfermann H, Klug N. Chronic subdural hematoma: surgical treatment and outcome in 104 patients. Surg Neurol. 1997;48(3): 220-225.
29. Merlicco G, Pierangeli E, di Padova PL. Chronic subdural hematomas in adults: prognostic factors: analysis of 70 cases. Neurosurg Rev. 1995;18(4):247-251.
1. Pullicino P, Thompson JL. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2003;348(3): 256-257.
2. Hurlen M, Abdelnoor M, Smith P, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974.
3. DeSilvey DL. Clinical trials: advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Am J Geriatr Cardiol. 2005;14(2):98-99.
4. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745-752.
5. Koo S, Kucher N, Nguyen PL, et al. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med. 2004;164(14):1557-1560.
6. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma. 2002;53(4):668-672.
7. Pieracci FM, Eachempati SR, Shou J, et al. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma. 2007;63(3):525-530.
8. Fanikos J, Grasso-Correnti N, Shah R, et al. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol. 2005;96(4):595-598.
9. Pieracci FM, Eachempati SR, Shou J, et al. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma. 2007;63(3):519-524.
10. Franko J, Kish KJ, O’Connell BG, et al. Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma. J Trauma. 2006; 61(1):107-110.
11. Drapkin AJ. Chronic subdural hematoma: pathophysiological basis for treatment. Br J Neurosurg. 1991; 5(5):467-473.
12. Yamamoto H, Hirashima Y, Hamada H, et al. Independent predictors of recurrence of chronic subdural hematoma: results of multivariate analysis performed using a logistic regression model. J Neurosurg. 2003;98(6):1217-1221.
13. Iantosca MR, Simon RH. Chronic subdural hematoma in adult and elderly patients. Neurosurg Clin N Am. 2000;11(3):447-454.
14. Rozzelle CJ, Wofford JL, Branch CL. Predictors of hospital mortality in older patients with subdural hematoma. J Am Geriatr Soc. 1995;43(3):240-244.
15. Wintzen AR, Tijssen JG. Subdural hematoma and oral anticoagulant therapy. Arch Neurol. 1982;39(2): 69-72.
16. Ramachandran R, Hegde T. Chronic subdural hematomas: causes of morbidity and mortality. Surg Neurol. 2007;67(4):367-372.
17. Amirjamshidi A, Eftekhar B, Abouzari M, Rashidi A. The relationship between Glasgow coma/outcome scores and abnormal CT scan findings in chronic subdural hematoma. Clin Neurol Neurosurg. 2007;109(2): 152-157.
18. Lee JY, Ebel H, Ernestus RI, Klug N. Various surgical treatments of chronic subdural hematoma and outcome in 172 patients: is membranectomy necessary? Surg Neurol. 2004;61(6):523-527.
19. Gelabert-González M, Iglesias-Pais M, García-Allut A, Martínez-Rumbo R. Chronic subdural haematoma: surgical treatment and outcome in 1000 cases. Clin Neurol Neurosurg. 2005;107(3):223-229.
20. Mattle H, Kohler S, Huber P, et al. Anticoagulation-related intracranial extracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1989;52(7):829-837.
21. Sambasivan M. An overview of chronic subdural hematoma: experience with 2300 cases. Surg Neurol. 1997;47(5):418-422.
22. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg. 2003;98(4):737-740.
23. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79(12):1495-1500.
24. Dager WE, King JH, Regalia RC, et al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006;26(8): 1091-1098.
25. Denas G, Marzot F, Offelli P, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J Thromb Thrombolysis. 2008 Mar 13; [Epub ahead of print].
26. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5):1113-1118.
27. Kissela BM, Eckman MH. Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage. BMC Neurol. 2008;8:17.
28. Ernestus RI, Beldzinski P, Lanfermann H, Klug N. Chronic subdural hematoma: surgical treatment and outcome in 104 patients. Surg Neurol. 1997;48(3): 220-225.
29. Merlicco G, Pierangeli E, di Padova PL. Chronic subdural hematomas in adults: prognostic factors: analysis of 70 cases. Neurosurg Rev. 1995;18(4):247-251.
Acetabular Labral Tears
YOU HAVE A NEW JOB: Monitor the lipid profile
Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.
Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.
This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.
A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.
If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.1
1. Look at the triglyceride (TG) level. If it is >500 mg/dL, treatment is indicated, and TG reduction takes precedence over all other lipid concentrations. If TG is <500 mg/dL, go to Step 2.
2. Look at the low-density lipoprotein cholesterol (LDL-C) level. If it is >190 mg/dL, drug therapy is indicated regardless of other findings. At lower levels, the need for therapy is based on the patient’s overall risk of cardiovascular disease (CVD). Therapeutic lifestyle recommendations are always indicated.
3. Look at high-density lipoprotein cholesterol (HDL-C). Increased risk is present if it is <50 mg/dL, the threshold for women. Do not assume that high HDL-C always means low CVD risk.
4. Calculate the total cholesterol (TC)/HDL-C ratio (a surrogate of apoB/apoA-I ratio). Increased risk is present if it is >4.0.
5. Calculate the non-HDL-C level (TC minus HDL-C). If it is >130 mg/dL (or >100 mg/dL in very-high-risk women), therapy is warranted. Newer data reveal that this calculation is always equal to, or better than, LDL-C at predicting CVD risk. Non-HDL-C is less valuable if TG is >500 mg/dL.
6. Calculate the TG/HDL-C ratio to estimate the size of LDL. If the ratio is >3.8, the likelihood of small LDL is 80%. (Small LDL usually has very high LDL-P.)
Why lipoproteins are important
There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.
Lipids associated with cardiovascular disease (CVD) include:
- cholesterol
- noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
- triacylglycerol, or triglycerides (TG)
- phospholipids.
Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.2
Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.
A new paradigm is on its way
The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.
Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.3 A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.4 Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.5-7
Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)8,9 and the American Heart Association (AHA) CVD Prevention in Women10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).
The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.
TABLE 1
Desirable lipid values for women
| Lipid | Level (mg/dL) |
|---|---|
| Total cholesterol | <200 |
| Low-density lipoprotein (LDL) cholesterol | <100 |
| High-density lipoprotein (HDL) cholesterol | ≥50 |
| Triglycerides | <150 |
| Non-HDL-cholesterol | <130 |
| FOR VERY HIGH-RISK PATIENTS | |
| LDL-C | <70 |
| Non-HDL-C | <100 |
| Source: American Heart Association | |
How lipoproteins are analyzed
Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.13,14
Apolipoprotein content analysis reveals two major categories of particles:
- alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
- beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.15
Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).14
Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:
- elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
- a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.6,13,14
After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.16,17
Lipids and lipoproteins: A glossary
| Variable | What is it? |
|---|---|
| Triglycerides (TG) | The triacylglycerol concentration within all of the TG-trafficking lipoproteins in 100 mL or 1 dL of plasma |
| Total cholesterol (TC) | Cholesterol content of all lipoproteins in 1 dL of plasma |
| Low-density lipoprotein (LDL) cholesterol | Cholesterol content of all intermediate-density lipoprotein (IDL) and LDL particles in 1 dL of plasma |
| High-density lipoprotein (HDL) cholesterol | Cholesterol content of all HDL particles in 1 dL of plasma |
| Very-low-density lipoprotein (VLDL) cholesterol | Cholesterol content of all VLDL particles in 1 dL of plasma |
| Remnant-C | Cholesterol content of all remnants in 1 dL of plasma |
| Lipoprotein (a) [Lp(a)] cholesterol | Cholesterol content of LDL particles that have apo(a) attached |
| Lp(a) concentration | Concentration of apo(a) in 1 dL of plasma |
| Non-HDL cholesterol | Cholesterol within all apoB particles in 1 dL of plasma |
| LDL-P | Number of LDL particles in 1 L of plasma (expressed in nmol/L). This represents LDL particles of all sizes |
| Small LDL-P | Number of small and intermediate LDL particles in 1 L of plasma (nmol/L) |
| HDL-P | Number of HDL particles in 1 L of plasma (μmol/L). HDL-P is also reported as large, intermediate, and small HDL-P (μmol/L) |
| VLDL-P | Number of VLDL particles in 1 L of plasma (nmol/L) |
| IDL-P | Number of IDL particles in 1 L of plasma (nmol/L) |
| LDL size | Diameter of the predominant LDL species:
|
Using lipid measurements to estimate lipoproteins
Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.
VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.
A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.
LDL-C is also an apoB surrogate
Although VLDL-C is a weak apoB surrogate,15 data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.18 However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.
LDL-C is usually a calculated value using the formula:
LDL-C = TC – (HDL-C + VLDL-C)
Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).19 For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .
TABLE 2
How lipid concentrations are determined
| TC = apoA-I-C + apoB-C |
| TC = HDL-C + LDL-C + VLDL-C + IDL-C + Chylomicron-C + Lp(a)-C + Remnant-C |
| In a fasting patient under normal circumstances, there are no chylomicrons and remnants (smaller chylomicrons or VLDL particles) and very few, if any, IDL particles. These are postprandial lipoproteins. Most patients do not have Lp(a) pathology. Therefore, the lipid concentration formula simplifies: |
| TC = HDL-C + LDL-C + VLDL-C |
| VLDL-C is estimated by TG/5 (assumes that all TG is in VLDL and that VLDL TG:cholesterol composition is 5:1). Therefore: |
| TC = HDL-C + LDL-C + TG/5 |
| LDL-C = TC – (HDL-C + TG/5) |
| Non-HDL-C = TC – HDL-C |
| In actuality, the calculated or directly measured LDL-C values in the standard lipid panel represent LDL-C + IDL-C + Lp(a)-C. However, because labs do not usually separate IDL and Lp(a) particles from LDL (without significant added expense), only total LDL-C is reported. |
FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C
HDL-C, apoA-I are inversely related to cardiovascular risk
The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.6 HDL particles are a heterogenous collection of:
- unlipidated apoA-I
- very small pre-beta HDL
- more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).
NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.14 The smaller HDL species also contain apoA-II.
Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.20 The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.
In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.
Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.20,21
Two premenopausal women undergo assessment of their basic lipid panel, with these results:
| LIPID | PATIENT 1 | PATIENT 2 |
|---|---|---|
| Total cholesterol (TC) | 180 | 180 |
| LDL-C | 100 | 100 |
| HDL-C | 60 | 40 |
| VLDL-C | 20 | 40 |
| Triglycerides (TG) | 100 | 200 |
| Non-HDL-C | 120 | 160 |
| TC/HDL-C ratio | 3.0 | 4.5 |
| TG/HDL-C ratio | 1.6 | 5.0 |
| LDL-C, low-density lipoprotein cholesterol | ||
| HDL-C, high-density lipoprotein cholesterol | ||
| VLDL-C, very-low-density lipoprotein cholesterol | ||
Both patients have the same desirable TC and LDL-C values. However, further analysis reveals an abnormal TC/HDL-C ratio and an abnormal non-HDL-C level in patient 2. This finding indicates a higher risk of CVD.
In addition, the TG/HDL-C ratio of 5.0 in patient 2 is highly suggestive of small-LDL phenotype B. That designation means that this patient will have 40% to 70% more LDL particles to traffic her LDL-C than patient 1, who appears to have LDL of normal size.27 The elevated VLDL-C of patient 2 indicates the presence of VLDL remnants, which predict risk above that conveyed by LDL-C.7
The typical clinician, looking only at TC or LDL-C, would miss the increased risk (high apoB) in patient 2. Obvious clues to her lipoprotein pathology are the elevated TG and reduced HDL-C (TG-HDL axis disorder). Beyond elevated TG and reduced HDL-C, patient 2 is also likely to have increased waist size, subtle hypertension, and possibly impaired fasting glucose—three additional parameters of metabolic syndrome.7,10,25
Focus on lipoprotein particle concentrations
To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).
TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.18 If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.
Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.15 Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.8 In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.15,24
NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.18
The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.10 Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).9,11
Insulin resistance diminishes accuracy of lipid profile
The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.25
As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.
In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.
Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).26,27
Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.1
LDL-C and LDL-P do not always correlate
Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr3),14 a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.28 This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.8,11 (See the case studies.)
In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).8,9
TABLE 3
Lipid markers of small low-density lipoproteins
| High-density lipoprotein cholesterol (HDL-C) <50 mg/dL |
| Triglyceride (TG) >130–150 mg/dL |
| Total cholesterol/HDL-C ratio >4.0 with normal low-density lipoprotein cholesterol (LDL-C) |
| TG/HDL-C ratio >3.8 in women |
| Unremarkable LDL-C but elevated non-HDL-C |
TABLE 4
Lipid markers of remnant lipoproteins
| Triglyceride (TG) >150–200 mg/dL |
| Very-low-density lipoprotein cholesterol >30 mg/dL |
| Unremarkable low-density lipoprotein cholesterol with elevated non-high-density lipoprotein cholesterol (HDL-C) |
| Low HDL-C in insulin-resistant patients |
| Elevated total cholesterol/HDL-C ratio and TG >150 mg/dL |
A few words of advice
The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.
The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:
- TC (unless HDL-C is very high)
- LDL-C
- Non-HDL-C
- TC/HDL-C ratio
- TG/HDL-C ratio.
Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).7,15
Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.
1. Lloyd-Jones DM, O’Donnell CJ, D’Agostino RB, et al. Applicability of cholesterol-lowering primary prevention trials to a general population. The Framingham Heart Study. Arch Intern Med. 2001;161:949-954.
2. Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Educ. 2004;28:105-106.
3. Nordestgaard BG, Wooten R, Lewis B. Selective retention of VLDL, IDL and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534-542.
4. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.
5. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med. 2006;259:247-258.
6. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033.
7. Mudd JO, Borlaug BA, Johnson PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.
8. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
9. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.
10. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
11. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481.-
12. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol. And the winner is… Circulation. 2005;112:3366-3367.
13. Sniderman AD, Marcovina SM. Apolipoprotein A-I and B. Clin Lab Med. 2006;26:733-750.
14. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847-870.
15. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Off spring Study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.
16. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547-553.
17. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211-217.
18. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their predictive risk values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.
19. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. National Institutes of Health. National Heart, Lung, and Blood Institute. NIH Publication No. 95-3044. Bethesda, Md: September 1995.
20. Dayspring T. High density lipoproteins: emerging knowledge. J Cardiometabol Syndr. 2007;2:59-62.
21. Cromwell WC. High-density lipoprotein associations with coronary heart disease: does measurement of cholesterol content give the best result? J Clin Lipidol. 2007;1:57-64.
22. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326.-
23. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-1937.
24. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-785.
25. Szapary PO, Rader DJ. The triglyceride-high-density lipoprotein axis: an important target of therapy. Am Heart J. 2004;148:211-221.
26. Davidson MH, Yannicelli D. New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord. 2006;4:299-314.
27. Hanak V, Munoz J, Teague J, Stanley A, Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004;94:219-222.
28. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20-29.
Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.
Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.
This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.
A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.
If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.1
1. Look at the triglyceride (TG) level. If it is >500 mg/dL, treatment is indicated, and TG reduction takes precedence over all other lipid concentrations. If TG is <500 mg/dL, go to Step 2.
2. Look at the low-density lipoprotein cholesterol (LDL-C) level. If it is >190 mg/dL, drug therapy is indicated regardless of other findings. At lower levels, the need for therapy is based on the patient’s overall risk of cardiovascular disease (CVD). Therapeutic lifestyle recommendations are always indicated.
3. Look at high-density lipoprotein cholesterol (HDL-C). Increased risk is present if it is <50 mg/dL, the threshold for women. Do not assume that high HDL-C always means low CVD risk.
4. Calculate the total cholesterol (TC)/HDL-C ratio (a surrogate of apoB/apoA-I ratio). Increased risk is present if it is >4.0.
5. Calculate the non-HDL-C level (TC minus HDL-C). If it is >130 mg/dL (or >100 mg/dL in very-high-risk women), therapy is warranted. Newer data reveal that this calculation is always equal to, or better than, LDL-C at predicting CVD risk. Non-HDL-C is less valuable if TG is >500 mg/dL.
6. Calculate the TG/HDL-C ratio to estimate the size of LDL. If the ratio is >3.8, the likelihood of small LDL is 80%. (Small LDL usually has very high LDL-P.)
Why lipoproteins are important
There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.
Lipids associated with cardiovascular disease (CVD) include:
- cholesterol
- noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
- triacylglycerol, or triglycerides (TG)
- phospholipids.
Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.2
Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.
A new paradigm is on its way
The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.
Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.3 A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.4 Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.5-7
Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)8,9 and the American Heart Association (AHA) CVD Prevention in Women10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).
The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.
TABLE 1
Desirable lipid values for women
| Lipid | Level (mg/dL) |
|---|---|
| Total cholesterol | <200 |
| Low-density lipoprotein (LDL) cholesterol | <100 |
| High-density lipoprotein (HDL) cholesterol | ≥50 |
| Triglycerides | <150 |
| Non-HDL-cholesterol | <130 |
| FOR VERY HIGH-RISK PATIENTS | |
| LDL-C | <70 |
| Non-HDL-C | <100 |
| Source: American Heart Association | |
How lipoproteins are analyzed
Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.13,14
Apolipoprotein content analysis reveals two major categories of particles:
- alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
- beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.15
Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).14
Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:
- elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
- a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.6,13,14
After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.16,17
Lipids and lipoproteins: A glossary
| Variable | What is it? |
|---|---|
| Triglycerides (TG) | The triacylglycerol concentration within all of the TG-trafficking lipoproteins in 100 mL or 1 dL of plasma |
| Total cholesterol (TC) | Cholesterol content of all lipoproteins in 1 dL of plasma |
| Low-density lipoprotein (LDL) cholesterol | Cholesterol content of all intermediate-density lipoprotein (IDL) and LDL particles in 1 dL of plasma |
| High-density lipoprotein (HDL) cholesterol | Cholesterol content of all HDL particles in 1 dL of plasma |
| Very-low-density lipoprotein (VLDL) cholesterol | Cholesterol content of all VLDL particles in 1 dL of plasma |
| Remnant-C | Cholesterol content of all remnants in 1 dL of plasma |
| Lipoprotein (a) [Lp(a)] cholesterol | Cholesterol content of LDL particles that have apo(a) attached |
| Lp(a) concentration | Concentration of apo(a) in 1 dL of plasma |
| Non-HDL cholesterol | Cholesterol within all apoB particles in 1 dL of plasma |
| LDL-P | Number of LDL particles in 1 L of plasma (expressed in nmol/L). This represents LDL particles of all sizes |
| Small LDL-P | Number of small and intermediate LDL particles in 1 L of plasma (nmol/L) |
| HDL-P | Number of HDL particles in 1 L of plasma (μmol/L). HDL-P is also reported as large, intermediate, and small HDL-P (μmol/L) |
| VLDL-P | Number of VLDL particles in 1 L of plasma (nmol/L) |
| IDL-P | Number of IDL particles in 1 L of plasma (nmol/L) |
| LDL size | Diameter of the predominant LDL species:
|
Using lipid measurements to estimate lipoproteins
Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.
VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.
A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.
LDL-C is also an apoB surrogate
Although VLDL-C is a weak apoB surrogate,15 data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.18 However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.
LDL-C is usually a calculated value using the formula:
LDL-C = TC – (HDL-C + VLDL-C)
Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).19 For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .
TABLE 2
How lipid concentrations are determined
| TC = apoA-I-C + apoB-C |
| TC = HDL-C + LDL-C + VLDL-C + IDL-C + Chylomicron-C + Lp(a)-C + Remnant-C |
| In a fasting patient under normal circumstances, there are no chylomicrons and remnants (smaller chylomicrons or VLDL particles) and very few, if any, IDL particles. These are postprandial lipoproteins. Most patients do not have Lp(a) pathology. Therefore, the lipid concentration formula simplifies: |
| TC = HDL-C + LDL-C + VLDL-C |
| VLDL-C is estimated by TG/5 (assumes that all TG is in VLDL and that VLDL TG:cholesterol composition is 5:1). Therefore: |
| TC = HDL-C + LDL-C + TG/5 |
| LDL-C = TC – (HDL-C + TG/5) |
| Non-HDL-C = TC – HDL-C |
| In actuality, the calculated or directly measured LDL-C values in the standard lipid panel represent LDL-C + IDL-C + Lp(a)-C. However, because labs do not usually separate IDL and Lp(a) particles from LDL (without significant added expense), only total LDL-C is reported. |
FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C
HDL-C, apoA-I are inversely related to cardiovascular risk
The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.6 HDL particles are a heterogenous collection of:
- unlipidated apoA-I
- very small pre-beta HDL
- more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).
NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.14 The smaller HDL species also contain apoA-II.
Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.20 The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.
In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.
Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.20,21
Two premenopausal women undergo assessment of their basic lipid panel, with these results:
| LIPID | PATIENT 1 | PATIENT 2 |
|---|---|---|
| Total cholesterol (TC) | 180 | 180 |
| LDL-C | 100 | 100 |
| HDL-C | 60 | 40 |
| VLDL-C | 20 | 40 |
| Triglycerides (TG) | 100 | 200 |
| Non-HDL-C | 120 | 160 |
| TC/HDL-C ratio | 3.0 | 4.5 |
| TG/HDL-C ratio | 1.6 | 5.0 |
| LDL-C, low-density lipoprotein cholesterol | ||
| HDL-C, high-density lipoprotein cholesterol | ||
| VLDL-C, very-low-density lipoprotein cholesterol | ||
Both patients have the same desirable TC and LDL-C values. However, further analysis reveals an abnormal TC/HDL-C ratio and an abnormal non-HDL-C level in patient 2. This finding indicates a higher risk of CVD.
In addition, the TG/HDL-C ratio of 5.0 in patient 2 is highly suggestive of small-LDL phenotype B. That designation means that this patient will have 40% to 70% more LDL particles to traffic her LDL-C than patient 1, who appears to have LDL of normal size.27 The elevated VLDL-C of patient 2 indicates the presence of VLDL remnants, which predict risk above that conveyed by LDL-C.7
The typical clinician, looking only at TC or LDL-C, would miss the increased risk (high apoB) in patient 2. Obvious clues to her lipoprotein pathology are the elevated TG and reduced HDL-C (TG-HDL axis disorder). Beyond elevated TG and reduced HDL-C, patient 2 is also likely to have increased waist size, subtle hypertension, and possibly impaired fasting glucose—three additional parameters of metabolic syndrome.7,10,25
Focus on lipoprotein particle concentrations
To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).
TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.18 If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.
Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.15 Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.8 In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.15,24
NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.18
The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.10 Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).9,11
Insulin resistance diminishes accuracy of lipid profile
The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.25
As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.
In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.
Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).26,27
Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.1
LDL-C and LDL-P do not always correlate
Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr3),14 a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.28 This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.8,11 (See the case studies.)
In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).8,9
TABLE 3
Lipid markers of small low-density lipoproteins
| High-density lipoprotein cholesterol (HDL-C) <50 mg/dL |
| Triglyceride (TG) >130–150 mg/dL |
| Total cholesterol/HDL-C ratio >4.0 with normal low-density lipoprotein cholesterol (LDL-C) |
| TG/HDL-C ratio >3.8 in women |
| Unremarkable LDL-C but elevated non-HDL-C |
TABLE 4
Lipid markers of remnant lipoproteins
| Triglyceride (TG) >150–200 mg/dL |
| Very-low-density lipoprotein cholesterol >30 mg/dL |
| Unremarkable low-density lipoprotein cholesterol with elevated non-high-density lipoprotein cholesterol (HDL-C) |
| Low HDL-C in insulin-resistant patients |
| Elevated total cholesterol/HDL-C ratio and TG >150 mg/dL |
A few words of advice
The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.
The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:
- TC (unless HDL-C is very high)
- LDL-C
- Non-HDL-C
- TC/HDL-C ratio
- TG/HDL-C ratio.
Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).7,15
Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.
Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.
Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.
This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.
A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.
If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.1
1. Look at the triglyceride (TG) level. If it is >500 mg/dL, treatment is indicated, and TG reduction takes precedence over all other lipid concentrations. If TG is <500 mg/dL, go to Step 2.
2. Look at the low-density lipoprotein cholesterol (LDL-C) level. If it is >190 mg/dL, drug therapy is indicated regardless of other findings. At lower levels, the need for therapy is based on the patient’s overall risk of cardiovascular disease (CVD). Therapeutic lifestyle recommendations are always indicated.
3. Look at high-density lipoprotein cholesterol (HDL-C). Increased risk is present if it is <50 mg/dL, the threshold for women. Do not assume that high HDL-C always means low CVD risk.
4. Calculate the total cholesterol (TC)/HDL-C ratio (a surrogate of apoB/apoA-I ratio). Increased risk is present if it is >4.0.
5. Calculate the non-HDL-C level (TC minus HDL-C). If it is >130 mg/dL (or >100 mg/dL in very-high-risk women), therapy is warranted. Newer data reveal that this calculation is always equal to, or better than, LDL-C at predicting CVD risk. Non-HDL-C is less valuable if TG is >500 mg/dL.
6. Calculate the TG/HDL-C ratio to estimate the size of LDL. If the ratio is >3.8, the likelihood of small LDL is 80%. (Small LDL usually has very high LDL-P.)
Why lipoproteins are important
There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.
Lipids associated with cardiovascular disease (CVD) include:
- cholesterol
- noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
- triacylglycerol, or triglycerides (TG)
- phospholipids.
Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.2
Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.
A new paradigm is on its way
The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.
Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.3 A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.4 Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.5-7
Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)8,9 and the American Heart Association (AHA) CVD Prevention in Women10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).
The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.
TABLE 1
Desirable lipid values for women
| Lipid | Level (mg/dL) |
|---|---|
| Total cholesterol | <200 |
| Low-density lipoprotein (LDL) cholesterol | <100 |
| High-density lipoprotein (HDL) cholesterol | ≥50 |
| Triglycerides | <150 |
| Non-HDL-cholesterol | <130 |
| FOR VERY HIGH-RISK PATIENTS | |
| LDL-C | <70 |
| Non-HDL-C | <100 |
| Source: American Heart Association | |
How lipoproteins are analyzed
Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.13,14
Apolipoprotein content analysis reveals two major categories of particles:
- alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
- beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.15
Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).14
Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:
- elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
- a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.6,13,14
After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.16,17
Lipids and lipoproteins: A glossary
| Variable | What is it? |
|---|---|
| Triglycerides (TG) | The triacylglycerol concentration within all of the TG-trafficking lipoproteins in 100 mL or 1 dL of plasma |
| Total cholesterol (TC) | Cholesterol content of all lipoproteins in 1 dL of plasma |
| Low-density lipoprotein (LDL) cholesterol | Cholesterol content of all intermediate-density lipoprotein (IDL) and LDL particles in 1 dL of plasma |
| High-density lipoprotein (HDL) cholesterol | Cholesterol content of all HDL particles in 1 dL of plasma |
| Very-low-density lipoprotein (VLDL) cholesterol | Cholesterol content of all VLDL particles in 1 dL of plasma |
| Remnant-C | Cholesterol content of all remnants in 1 dL of plasma |
| Lipoprotein (a) [Lp(a)] cholesterol | Cholesterol content of LDL particles that have apo(a) attached |
| Lp(a) concentration | Concentration of apo(a) in 1 dL of plasma |
| Non-HDL cholesterol | Cholesterol within all apoB particles in 1 dL of plasma |
| LDL-P | Number of LDL particles in 1 L of plasma (expressed in nmol/L). This represents LDL particles of all sizes |
| Small LDL-P | Number of small and intermediate LDL particles in 1 L of plasma (nmol/L) |
| HDL-P | Number of HDL particles in 1 L of plasma (μmol/L). HDL-P is also reported as large, intermediate, and small HDL-P (μmol/L) |
| VLDL-P | Number of VLDL particles in 1 L of plasma (nmol/L) |
| IDL-P | Number of IDL particles in 1 L of plasma (nmol/L) |
| LDL size | Diameter of the predominant LDL species:
|
Using lipid measurements to estimate lipoproteins
Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.
VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.
A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.
LDL-C is also an apoB surrogate
Although VLDL-C is a weak apoB surrogate,15 data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.18 However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.
LDL-C is usually a calculated value using the formula:
LDL-C = TC – (HDL-C + VLDL-C)
Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).19 For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .
TABLE 2
How lipid concentrations are determined
| TC = apoA-I-C + apoB-C |
| TC = HDL-C + LDL-C + VLDL-C + IDL-C + Chylomicron-C + Lp(a)-C + Remnant-C |
| In a fasting patient under normal circumstances, there are no chylomicrons and remnants (smaller chylomicrons or VLDL particles) and very few, if any, IDL particles. These are postprandial lipoproteins. Most patients do not have Lp(a) pathology. Therefore, the lipid concentration formula simplifies: |
| TC = HDL-C + LDL-C + VLDL-C |
| VLDL-C is estimated by TG/5 (assumes that all TG is in VLDL and that VLDL TG:cholesterol composition is 5:1). Therefore: |
| TC = HDL-C + LDL-C + TG/5 |
| LDL-C = TC – (HDL-C + TG/5) |
| Non-HDL-C = TC – HDL-C |
| In actuality, the calculated or directly measured LDL-C values in the standard lipid panel represent LDL-C + IDL-C + Lp(a)-C. However, because labs do not usually separate IDL and Lp(a) particles from LDL (without significant added expense), only total LDL-C is reported. |
FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C
HDL-C, apoA-I are inversely related to cardiovascular risk
The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.6 HDL particles are a heterogenous collection of:
- unlipidated apoA-I
- very small pre-beta HDL
- more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).
NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.14 The smaller HDL species also contain apoA-II.
Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.20 The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.
In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.
Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.20,21
Two premenopausal women undergo assessment of their basic lipid panel, with these results:
| LIPID | PATIENT 1 | PATIENT 2 |
|---|---|---|
| Total cholesterol (TC) | 180 | 180 |
| LDL-C | 100 | 100 |
| HDL-C | 60 | 40 |
| VLDL-C | 20 | 40 |
| Triglycerides (TG) | 100 | 200 |
| Non-HDL-C | 120 | 160 |
| TC/HDL-C ratio | 3.0 | 4.5 |
| TG/HDL-C ratio | 1.6 | 5.0 |
| LDL-C, low-density lipoprotein cholesterol | ||
| HDL-C, high-density lipoprotein cholesterol | ||
| VLDL-C, very-low-density lipoprotein cholesterol | ||
Both patients have the same desirable TC and LDL-C values. However, further analysis reveals an abnormal TC/HDL-C ratio and an abnormal non-HDL-C level in patient 2. This finding indicates a higher risk of CVD.
In addition, the TG/HDL-C ratio of 5.0 in patient 2 is highly suggestive of small-LDL phenotype B. That designation means that this patient will have 40% to 70% more LDL particles to traffic her LDL-C than patient 1, who appears to have LDL of normal size.27 The elevated VLDL-C of patient 2 indicates the presence of VLDL remnants, which predict risk above that conveyed by LDL-C.7
The typical clinician, looking only at TC or LDL-C, would miss the increased risk (high apoB) in patient 2. Obvious clues to her lipoprotein pathology are the elevated TG and reduced HDL-C (TG-HDL axis disorder). Beyond elevated TG and reduced HDL-C, patient 2 is also likely to have increased waist size, subtle hypertension, and possibly impaired fasting glucose—three additional parameters of metabolic syndrome.7,10,25
Focus on lipoprotein particle concentrations
To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).
TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.18 If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.
Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.15 Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.8 In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.15,24
NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.18
The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.10 Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).9,11
Insulin resistance diminishes accuracy of lipid profile
The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.25
As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.
In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.
Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).26,27
Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.1
LDL-C and LDL-P do not always correlate
Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr3),14 a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.28 This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.8,11 (See the case studies.)
In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).8,9
TABLE 3
Lipid markers of small low-density lipoproteins
| High-density lipoprotein cholesterol (HDL-C) <50 mg/dL |
| Triglyceride (TG) >130–150 mg/dL |
| Total cholesterol/HDL-C ratio >4.0 with normal low-density lipoprotein cholesterol (LDL-C) |
| TG/HDL-C ratio >3.8 in women |
| Unremarkable LDL-C but elevated non-HDL-C |
TABLE 4
Lipid markers of remnant lipoproteins
| Triglyceride (TG) >150–200 mg/dL |
| Very-low-density lipoprotein cholesterol >30 mg/dL |
| Unremarkable low-density lipoprotein cholesterol with elevated non-high-density lipoprotein cholesterol (HDL-C) |
| Low HDL-C in insulin-resistant patients |
| Elevated total cholesterol/HDL-C ratio and TG >150 mg/dL |
A few words of advice
The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.
The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:
- TC (unless HDL-C is very high)
- LDL-C
- Non-HDL-C
- TC/HDL-C ratio
- TG/HDL-C ratio.
Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).7,15
Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.
1. Lloyd-Jones DM, O’Donnell CJ, D’Agostino RB, et al. Applicability of cholesterol-lowering primary prevention trials to a general population. The Framingham Heart Study. Arch Intern Med. 2001;161:949-954.
2. Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Educ. 2004;28:105-106.
3. Nordestgaard BG, Wooten R, Lewis B. Selective retention of VLDL, IDL and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534-542.
4. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.
5. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med. 2006;259:247-258.
6. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033.
7. Mudd JO, Borlaug BA, Johnson PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.
8. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
9. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.
10. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
11. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481.-
12. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol. And the winner is… Circulation. 2005;112:3366-3367.
13. Sniderman AD, Marcovina SM. Apolipoprotein A-I and B. Clin Lab Med. 2006;26:733-750.
14. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847-870.
15. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Off spring Study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.
16. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547-553.
17. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211-217.
18. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their predictive risk values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.
19. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. National Institutes of Health. National Heart, Lung, and Blood Institute. NIH Publication No. 95-3044. Bethesda, Md: September 1995.
20. Dayspring T. High density lipoproteins: emerging knowledge. J Cardiometabol Syndr. 2007;2:59-62.
21. Cromwell WC. High-density lipoprotein associations with coronary heart disease: does measurement of cholesterol content give the best result? J Clin Lipidol. 2007;1:57-64.
22. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326.-
23. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-1937.
24. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-785.
25. Szapary PO, Rader DJ. The triglyceride-high-density lipoprotein axis: an important target of therapy. Am Heart J. 2004;148:211-221.
26. Davidson MH, Yannicelli D. New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord. 2006;4:299-314.
27. Hanak V, Munoz J, Teague J, Stanley A, Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004;94:219-222.
28. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20-29.
1. Lloyd-Jones DM, O’Donnell CJ, D’Agostino RB, et al. Applicability of cholesterol-lowering primary prevention trials to a general population. The Framingham Heart Study. Arch Intern Med. 2001;161:949-954.
2. Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Educ. 2004;28:105-106.
3. Nordestgaard BG, Wooten R, Lewis B. Selective retention of VLDL, IDL and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534-542.
4. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.
5. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med. 2006;259:247-258.
6. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033.
7. Mudd JO, Borlaug BA, Johnson PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.
8. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
9. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.
10. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
11. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481.-
12. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol. And the winner is… Circulation. 2005;112:3366-3367.
13. Sniderman AD, Marcovina SM. Apolipoprotein A-I and B. Clin Lab Med. 2006;26:733-750.
14. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847-870.
15. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Off spring Study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.
16. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547-553.
17. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211-217.
18. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their predictive risk values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.
19. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. National Institutes of Health. National Heart, Lung, and Blood Institute. NIH Publication No. 95-3044. Bethesda, Md: September 1995.
20. Dayspring T. High density lipoproteins: emerging knowledge. J Cardiometabol Syndr. 2007;2:59-62.
21. Cromwell WC. High-density lipoprotein associations with coronary heart disease: does measurement of cholesterol content give the best result? J Clin Lipidol. 2007;1:57-64.
22. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326.-
23. Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-1937.
24. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-785.
25. Szapary PO, Rader DJ. The triglyceride-high-density lipoprotein axis: an important target of therapy. Am Heart J. 2004;148:211-221.
26. Davidson MH, Yannicelli D. New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord. 2006;4:299-314.
27. Hanak V, Munoz J, Teague J, Stanley A, Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004;94:219-222.
28. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20-29.
The unbearable unhappiness of the ObGyn: A crisis looms
Dr. Weinstein has no financial relationships relevant to this article.
“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965
“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964
The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.
Why the decline in work satisfaction? Many reasons have been cited, including:
- loss of autonomy
- economic pressures
- an increasing degree of government and insurer control over practice
- the liability crisis
- a divergence between professional and personal expectations
- physicians’ own high career expectations
- a desire for more time for family and self.1
The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.
In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.
Ultimate effect of dissatisfaction? Loss of a physician
An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.4 And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.
Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.4 However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.
It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.
Does gender influence the satisfaction rate?
The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.
This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.7 A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.8
Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.9 Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.10
That said, there are some gender-related differences in medical workforce characteristics:
- Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do4
- In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are11
- Among surgeons, 90% of women live in dual-career households, compared with 50% of men9
- When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households9
- Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.12
Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.
After much talk of an impending physician shortage, many medical schools have increased class size, and a number of new medical schools recently opened or are on their way to opening. The Association of American Medical Colleges recommends that medical school class size increase 30% by 2015.32
Some experts believe that there will be a dearth of generalist physicians; others think that specialists will be in short supply.
Possible causes of the shortage
The coming physician shortage has been attributed to a number of variables, including:
- an aging population, which will require a greater level of health care
- aging physicians, with as many as 30% of the current workforce expected to retire during the next 5 to 10 years
- an increase in the number of female physicians who work fewer hours than their male counterparts
- an increase in physicians from Generations X and Y, who place greater emphasis on lifestyle and personal time.33
Cooper, who has written extensively on physician workforce numbers, believes that placement of the Medicare-funded graduate medical education (GME) position cap approximately 10 years ago has been the major driver of the physician shortage. Improvement will come, he says, only when this cap is lifted or altered.34
Are there enough doctors?
The number of physicians per capita is at its highest point in 50 years in the United States, yet the Council of Graduate Medical Education predicts a 10% shortfall by 2020.35 When regions with a high supply of physicians are compared with regions with a low supply, outcomes are the same, and patients do not perceive any physician shortfall.36,37 It is interesting that, in regions where there is a high supply of physicians, physicians perceive there to be greater difficulty in providing the quality of care they desire for their patients.38
A greater supply of physicians leads to more tests and procedures and higher costs.37 Goodman and Fisher believe that having more specialists decreases the flexibility of the physician workforce. They also believe that the GME cap should be maintained, funding should be reallocated to the more cognitive specialties, and the current payment system should be reformed.35 (Any physician who has attended a hospital medical executive committee meeting knows that reallocation of resources to cognitive specialties will never happen: Hospitals want more surgical procedures to boost their bottom line.)
A review of the many studies and opinions published about current work-force numbers and future needs makes it obvious that very little evidence exists to support any of the recommendations made by experts. Almost all studies mention adding to the workforce with minimal discussion about how to keep the current workforce from leaving—a much better use of resources.
Age is the determining factor
The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.13
These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.13
Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.
However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.14 In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.15
For Generations X and Y, time is the overarching issue
Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.16 These issues have also contributed to rising dissatisfaction among Baby Boomers.
Enter, the 80-hour workweek
In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.
Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.17 Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.18 Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.19
There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.20 By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.
If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.4
The profession must understand that burnout is common and directly related to increasing dissatisfaction.21
Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:
- emotional exhaustion
- feelings of inadequacy in terms of personal accomplishment
- depersonalization
- increasing cynicism in personal interactions.21
This is an accurate description of the current state of medical practice.
Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.22-24
Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.
Ways to reduce dissatisfaction
Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”25
I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.
Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.
Recommendations—for practitioners, academic and private
- Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.26 For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
- Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.27 Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
- Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
- Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.28 Job sharing will also facilitate recruitment and retention of the current workforce.29
- Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
- In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.30 Similar changes are recommended for the private practitioner under consideration for partnership.
Recommendations—for physicians in training
- Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.31 No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
- Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
- Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
- Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
- Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
- Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.
We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”
1. Holsinger JW, Jr, Beaton B. Physician professionalism for a new century. Clin Anat. 2006;19:473-479.
2. Buchbinder SB, Wilson M, Melick CF, Powe NR. Primary care physician job satisfaction and turnover. Am J Manag Care. 2001;7:701-713.
3. Leigh JP, Kravitz RL, Schembri M, Samuels SJ, Mobley S. Physician career satisfaction across specialties. Arch Intern Med. 2002;162:1577-1584.
4. Landon BE, Reschovsky JD, Pham HH, Blumenthal D. Leaving medicine: the consequences of physician dissatisfaction. Med Care. 2006;44:234-242.
5. Berger JE, Boyle RL, Jr. How to avoid the high costs of physician turnover. Med Group Manage J. 1992;39:80-91.
6. Buchbinder SB, Wilson M, Melick CF, Powe NR. Estimates of costs of primary care physician turnover. Am J Manag Care. 1999;5:1431-1438.
7. Carr PL, Ash AS, Friedman RH, et al. Relation of family responsibilities and gender to the productivity and career satisfaction of medical faculty. Ann Intern Med. 1998;129:532-538.
8. Jovic E, Wallace JE, Lemaire J. The generation and gender shifts in medicine: an exploratory survey of internal medicine physicians. BMC Health Serv Res. 2006;6:55-71.
9. Schroen AT, Brownstein MR, Sheldon GF. Women in academic general surgery. Acad Med. 2004;79:310-318.
10. Helliger PJ, Hingstman L. Career p and the work-family balance in medicine: gender differences among medical specialists. Soc Sci Med. 2000;50:1235-1246.
11. Pearse WH, Haffner WHJ, Primack A. Effect of gender on the obstetric-gynecologic work force. Obstet Gynecol. 2001;97:794-797.
12. Grandis JR, Gooding WF, Zamboni BA, et al. The gender gap in a surgical subspecialty. Arch Otolaryngol Head Neck Surg. 2004;130:695-702.
13. Schwartz RW, Jarecky RK, Strodel WE, Haley JV, Young B, Griffen WO, Jr. Controllable lifestyle: a new focus in career choice by medical students. Acad Med. 1989;64:606-609.
14. Pathman DE, Konrad TR, Williams ES, et al. Physician job satisfaction, dissatisfaction, and turnover. J Fam Pract. 2002;51:593.-
15. Rittenhouse DR, Mertz E, Keane D, Grumbach K. No exit: an evaluation of measures of physician attrition. Health Serv Res. 2004;39:1572-1588.
16. Weinstein L, Wolfe H. The downward spiral of physician satisfaction: an attempt to avert a crisis within the medical profession. Obstet Gynecol. 2007;109:1181-1183.
17. Zaré SM, Galanko JA, Behrns KE, et al. Psychologic well-being of surgery residents after inception of the 80-hour workweek: a multi-institutional study. Surgery. 2005;138:150-157.
18. Goitein L, Shanafelt TD, Wipf JE, Slatore CG, Back AL. The effects of work-hour limitations on resident well-being, patient care, and education in an internal medicine residency program. Arch Intern Med. 2005;165:2601-2606.
19. Karamanoukian RL, Ku JK, DeLaRosa J, Karamanoukian HL, Evans GR. The effects of restricted work hours on clinical training. Am Surg. 2006;72:19-21.
20. Boex JR, Leahy PJ. Understanding residents’ work: moving beyond counting hours to assessing educational value. Acad Med. 2003;78:939-944.
21. Gabbe SG, Webb LE, Moore DE, Jr, Mandel LS, Melville JL, Spickard WA, Jr. Can mentors prevent and reduce burnout in new chairs of departments of obstetrics and gynecology: results from a prospective, randomized pilot study. Am J Obstet Gynecol. 2008;198:653.e1-653.e7.
22. Cooke M, Irby DM, Sullivan W, Ludmerer KM. American medical education 100 years after the Flexner report. N Engl J Med. 2006;355:1339-1344.
23. Jauhar S. The demise of the physical exam. N Engl J Med. 2006;354:548-551.
24. Arky RA. Shattuck Lecture. The family business—to educate. N Engl J Med. 2006;354:1922-1926.
25. Zuger A. Dissatisfaction with medical practice. N Engl J Med. 2004;350:69-75.
26. Weinstein L, Garite TJ. On call for obstetrics—time for a change. Am J Obstet Gynecol. 2007;196:3.-
27. Weinstein L. The laborist: a new focus of practice for the obstetrician. Am J Obstet Gynecol. 2003;188:310-312.
28. Parkerton PH, Wagner EH, Smith DG, Straley HL. Effect of part-time practice on patient outcome. J Gen Intern Med. 2003;18:717-724.
29. Shields MC, Shields MT. Working with Generation X physicians. Physician Exec. 2003;29:14-18.
30. Williams J. Unbending Gender: Why Family and Work Conflict and What To Do About It. New York: Oxford University Press; 2000.
31. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 398: Fatigue and patient safety. Washington, DC: ACOG; Feb 2008.
32. Association of American Medical Colleges. AAMC statement on the physician workforce, June 2006. Available at: http://www. aamc.org/workforce/workforceposition.pdf. Accessed Oct. 31, 2008.
33. Iglehart JK. Grassroots activism and the pursuit of an expanded physician supply. N Engl J Med. 2008;358:1741-1749.
34. Cooper RA. It’s time to address the problem of physician shortages: graduate medical education is the key. Ann Surg. 2007;246:527-534.
35. Goodman DC, Fisher ES. Physician workforce crisis? Wrong diagnosis, wrong prescription. N Engl J Med. 2008;358:1658-1661.
36. Goodman DC, Fisher ES, Little GA, Stukel TA, Chang CH, Schoendorf KS. The relation between the availability of neonatal intensive care and neonatal mortality. N Engl J Med. 2002;346:1538-1544.
37. Fisher ES, Wennberg DE, Stukel TA, Gottlieb DJ, Lucas FL, Pinder EL. The implications of regional variations in Medicare spending. Ann Intern Med. 2003;138:273-298.
38. Sirovich BE, Gottlieb DJ, Welch HG, Fisher ES. Regional variations in health care intensity and physician perceptions of quality of care. Ann Intern Med. 2006;144:641-649.
Dr. Weinstein has no financial relationships relevant to this article.
“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965
“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964
The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.
Why the decline in work satisfaction? Many reasons have been cited, including:
- loss of autonomy
- economic pressures
- an increasing degree of government and insurer control over practice
- the liability crisis
- a divergence between professional and personal expectations
- physicians’ own high career expectations
- a desire for more time for family and self.1
The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.
In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.
Ultimate effect of dissatisfaction? Loss of a physician
An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.4 And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.
Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.4 However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.
It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.
Does gender influence the satisfaction rate?
The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.
This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.7 A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.8
Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.9 Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.10
That said, there are some gender-related differences in medical workforce characteristics:
- Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do4
- In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are11
- Among surgeons, 90% of women live in dual-career households, compared with 50% of men9
- When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households9
- Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.12
Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.
After much talk of an impending physician shortage, many medical schools have increased class size, and a number of new medical schools recently opened or are on their way to opening. The Association of American Medical Colleges recommends that medical school class size increase 30% by 2015.32
Some experts believe that there will be a dearth of generalist physicians; others think that specialists will be in short supply.
Possible causes of the shortage
The coming physician shortage has been attributed to a number of variables, including:
- an aging population, which will require a greater level of health care
- aging physicians, with as many as 30% of the current workforce expected to retire during the next 5 to 10 years
- an increase in the number of female physicians who work fewer hours than their male counterparts
- an increase in physicians from Generations X and Y, who place greater emphasis on lifestyle and personal time.33
Cooper, who has written extensively on physician workforce numbers, believes that placement of the Medicare-funded graduate medical education (GME) position cap approximately 10 years ago has been the major driver of the physician shortage. Improvement will come, he says, only when this cap is lifted or altered.34
Are there enough doctors?
The number of physicians per capita is at its highest point in 50 years in the United States, yet the Council of Graduate Medical Education predicts a 10% shortfall by 2020.35 When regions with a high supply of physicians are compared with regions with a low supply, outcomes are the same, and patients do not perceive any physician shortfall.36,37 It is interesting that, in regions where there is a high supply of physicians, physicians perceive there to be greater difficulty in providing the quality of care they desire for their patients.38
A greater supply of physicians leads to more tests and procedures and higher costs.37 Goodman and Fisher believe that having more specialists decreases the flexibility of the physician workforce. They also believe that the GME cap should be maintained, funding should be reallocated to the more cognitive specialties, and the current payment system should be reformed.35 (Any physician who has attended a hospital medical executive committee meeting knows that reallocation of resources to cognitive specialties will never happen: Hospitals want more surgical procedures to boost their bottom line.)
A review of the many studies and opinions published about current work-force numbers and future needs makes it obvious that very little evidence exists to support any of the recommendations made by experts. Almost all studies mention adding to the workforce with minimal discussion about how to keep the current workforce from leaving—a much better use of resources.
Age is the determining factor
The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.13
These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.13
Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.
However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.14 In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.15
For Generations X and Y, time is the overarching issue
Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.16 These issues have also contributed to rising dissatisfaction among Baby Boomers.
Enter, the 80-hour workweek
In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.
Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.17 Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.18 Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.19
There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.20 By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.
If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.4
The profession must understand that burnout is common and directly related to increasing dissatisfaction.21
Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:
- emotional exhaustion
- feelings of inadequacy in terms of personal accomplishment
- depersonalization
- increasing cynicism in personal interactions.21
This is an accurate description of the current state of medical practice.
Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.22-24
Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.
Ways to reduce dissatisfaction
Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”25
I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.
Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.
Recommendations—for practitioners, academic and private
- Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.26 For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
- Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.27 Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
- Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
- Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.28 Job sharing will also facilitate recruitment and retention of the current workforce.29
- Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
- In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.30 Similar changes are recommended for the private practitioner under consideration for partnership.
Recommendations—for physicians in training
- Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.31 No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
- Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
- Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
- Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
- Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
- Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.
We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”
Dr. Weinstein has no financial relationships relevant to this article.
“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965
“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964
The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.
Why the decline in work satisfaction? Many reasons have been cited, including:
- loss of autonomy
- economic pressures
- an increasing degree of government and insurer control over practice
- the liability crisis
- a divergence between professional and personal expectations
- physicians’ own high career expectations
- a desire for more time for family and self.1
The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.
In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.
Ultimate effect of dissatisfaction? Loss of a physician
An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.4 And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.
Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.4 However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.
It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.
Does gender influence the satisfaction rate?
The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.
This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.7 A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.8
Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.9 Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.10
That said, there are some gender-related differences in medical workforce characteristics:
- Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do4
- In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are11
- Among surgeons, 90% of women live in dual-career households, compared with 50% of men9
- When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households9
- Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.12
Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.
After much talk of an impending physician shortage, many medical schools have increased class size, and a number of new medical schools recently opened or are on their way to opening. The Association of American Medical Colleges recommends that medical school class size increase 30% by 2015.32
Some experts believe that there will be a dearth of generalist physicians; others think that specialists will be in short supply.
Possible causes of the shortage
The coming physician shortage has been attributed to a number of variables, including:
- an aging population, which will require a greater level of health care
- aging physicians, with as many as 30% of the current workforce expected to retire during the next 5 to 10 years
- an increase in the number of female physicians who work fewer hours than their male counterparts
- an increase in physicians from Generations X and Y, who place greater emphasis on lifestyle and personal time.33
Cooper, who has written extensively on physician workforce numbers, believes that placement of the Medicare-funded graduate medical education (GME) position cap approximately 10 years ago has been the major driver of the physician shortage. Improvement will come, he says, only when this cap is lifted or altered.34
Are there enough doctors?
The number of physicians per capita is at its highest point in 50 years in the United States, yet the Council of Graduate Medical Education predicts a 10% shortfall by 2020.35 When regions with a high supply of physicians are compared with regions with a low supply, outcomes are the same, and patients do not perceive any physician shortfall.36,37 It is interesting that, in regions where there is a high supply of physicians, physicians perceive there to be greater difficulty in providing the quality of care they desire for their patients.38
A greater supply of physicians leads to more tests and procedures and higher costs.37 Goodman and Fisher believe that having more specialists decreases the flexibility of the physician workforce. They also believe that the GME cap should be maintained, funding should be reallocated to the more cognitive specialties, and the current payment system should be reformed.35 (Any physician who has attended a hospital medical executive committee meeting knows that reallocation of resources to cognitive specialties will never happen: Hospitals want more surgical procedures to boost their bottom line.)
A review of the many studies and opinions published about current work-force numbers and future needs makes it obvious that very little evidence exists to support any of the recommendations made by experts. Almost all studies mention adding to the workforce with minimal discussion about how to keep the current workforce from leaving—a much better use of resources.
Age is the determining factor
The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.13
These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.13
Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.
However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.14 In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.15
For Generations X and Y, time is the overarching issue
Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.16 These issues have also contributed to rising dissatisfaction among Baby Boomers.
Enter, the 80-hour workweek
In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.
Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.17 Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.18 Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.19
There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.20 By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.
If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.4
The profession must understand that burnout is common and directly related to increasing dissatisfaction.21
Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:
- emotional exhaustion
- feelings of inadequacy in terms of personal accomplishment
- depersonalization
- increasing cynicism in personal interactions.21
This is an accurate description of the current state of medical practice.
Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.22-24
Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.
Ways to reduce dissatisfaction
Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”25
I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.
Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.
Recommendations—for practitioners, academic and private
- Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.26 For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
- Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.27 Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
- Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
- Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.28 Job sharing will also facilitate recruitment and retention of the current workforce.29
- Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
- In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.30 Similar changes are recommended for the private practitioner under consideration for partnership.
Recommendations—for physicians in training
- Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.31 No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
- Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
- Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
- Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
- Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
- Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.
We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”
1. Holsinger JW, Jr, Beaton B. Physician professionalism for a new century. Clin Anat. 2006;19:473-479.
2. Buchbinder SB, Wilson M, Melick CF, Powe NR. Primary care physician job satisfaction and turnover. Am J Manag Care. 2001;7:701-713.
3. Leigh JP, Kravitz RL, Schembri M, Samuels SJ, Mobley S. Physician career satisfaction across specialties. Arch Intern Med. 2002;162:1577-1584.
4. Landon BE, Reschovsky JD, Pham HH, Blumenthal D. Leaving medicine: the consequences of physician dissatisfaction. Med Care. 2006;44:234-242.
5. Berger JE, Boyle RL, Jr. How to avoid the high costs of physician turnover. Med Group Manage J. 1992;39:80-91.
6. Buchbinder SB, Wilson M, Melick CF, Powe NR. Estimates of costs of primary care physician turnover. Am J Manag Care. 1999;5:1431-1438.
7. Carr PL, Ash AS, Friedman RH, et al. Relation of family responsibilities and gender to the productivity and career satisfaction of medical faculty. Ann Intern Med. 1998;129:532-538.
8. Jovic E, Wallace JE, Lemaire J. The generation and gender shifts in medicine: an exploratory survey of internal medicine physicians. BMC Health Serv Res. 2006;6:55-71.
9. Schroen AT, Brownstein MR, Sheldon GF. Women in academic general surgery. Acad Med. 2004;79:310-318.
10. Helliger PJ, Hingstman L. Career p and the work-family balance in medicine: gender differences among medical specialists. Soc Sci Med. 2000;50:1235-1246.
11. Pearse WH, Haffner WHJ, Primack A. Effect of gender on the obstetric-gynecologic work force. Obstet Gynecol. 2001;97:794-797.
12. Grandis JR, Gooding WF, Zamboni BA, et al. The gender gap in a surgical subspecialty. Arch Otolaryngol Head Neck Surg. 2004;130:695-702.
13. Schwartz RW, Jarecky RK, Strodel WE, Haley JV, Young B, Griffen WO, Jr. Controllable lifestyle: a new focus in career choice by medical students. Acad Med. 1989;64:606-609.
14. Pathman DE, Konrad TR, Williams ES, et al. Physician job satisfaction, dissatisfaction, and turnover. J Fam Pract. 2002;51:593.-
15. Rittenhouse DR, Mertz E, Keane D, Grumbach K. No exit: an evaluation of measures of physician attrition. Health Serv Res. 2004;39:1572-1588.
16. Weinstein L, Wolfe H. The downward spiral of physician satisfaction: an attempt to avert a crisis within the medical profession. Obstet Gynecol. 2007;109:1181-1183.
17. Zaré SM, Galanko JA, Behrns KE, et al. Psychologic well-being of surgery residents after inception of the 80-hour workweek: a multi-institutional study. Surgery. 2005;138:150-157.
18. Goitein L, Shanafelt TD, Wipf JE, Slatore CG, Back AL. The effects of work-hour limitations on resident well-being, patient care, and education in an internal medicine residency program. Arch Intern Med. 2005;165:2601-2606.
19. Karamanoukian RL, Ku JK, DeLaRosa J, Karamanoukian HL, Evans GR. The effects of restricted work hours on clinical training. Am Surg. 2006;72:19-21.
20. Boex JR, Leahy PJ. Understanding residents’ work: moving beyond counting hours to assessing educational value. Acad Med. 2003;78:939-944.
21. Gabbe SG, Webb LE, Moore DE, Jr, Mandel LS, Melville JL, Spickard WA, Jr. Can mentors prevent and reduce burnout in new chairs of departments of obstetrics and gynecology: results from a prospective, randomized pilot study. Am J Obstet Gynecol. 2008;198:653.e1-653.e7.
22. Cooke M, Irby DM, Sullivan W, Ludmerer KM. American medical education 100 years after the Flexner report. N Engl J Med. 2006;355:1339-1344.
23. Jauhar S. The demise of the physical exam. N Engl J Med. 2006;354:548-551.
24. Arky RA. Shattuck Lecture. The family business—to educate. N Engl J Med. 2006;354:1922-1926.
25. Zuger A. Dissatisfaction with medical practice. N Engl J Med. 2004;350:69-75.
26. Weinstein L, Garite TJ. On call for obstetrics—time for a change. Am J Obstet Gynecol. 2007;196:3.-
27. Weinstein L. The laborist: a new focus of practice for the obstetrician. Am J Obstet Gynecol. 2003;188:310-312.
28. Parkerton PH, Wagner EH, Smith DG, Straley HL. Effect of part-time practice on patient outcome. J Gen Intern Med. 2003;18:717-724.
29. Shields MC, Shields MT. Working with Generation X physicians. Physician Exec. 2003;29:14-18.
30. Williams J. Unbending Gender: Why Family and Work Conflict and What To Do About It. New York: Oxford University Press; 2000.
31. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 398: Fatigue and patient safety. Washington, DC: ACOG; Feb 2008.
32. Association of American Medical Colleges. AAMC statement on the physician workforce, June 2006. Available at: http://www. aamc.org/workforce/workforceposition.pdf. Accessed Oct. 31, 2008.
33. Iglehart JK. Grassroots activism and the pursuit of an expanded physician supply. N Engl J Med. 2008;358:1741-1749.
34. Cooper RA. It’s time to address the problem of physician shortages: graduate medical education is the key. Ann Surg. 2007;246:527-534.
35. Goodman DC, Fisher ES. Physician workforce crisis? Wrong diagnosis, wrong prescription. N Engl J Med. 2008;358:1658-1661.
36. Goodman DC, Fisher ES, Little GA, Stukel TA, Chang CH, Schoendorf KS. The relation between the availability of neonatal intensive care and neonatal mortality. N Engl J Med. 2002;346:1538-1544.
37. Fisher ES, Wennberg DE, Stukel TA, Gottlieb DJ, Lucas FL, Pinder EL. The implications of regional variations in Medicare spending. Ann Intern Med. 2003;138:273-298.
38. Sirovich BE, Gottlieb DJ, Welch HG, Fisher ES. Regional variations in health care intensity and physician perceptions of quality of care. Ann Intern Med. 2006;144:641-649.
1. Holsinger JW, Jr, Beaton B. Physician professionalism for a new century. Clin Anat. 2006;19:473-479.
2. Buchbinder SB, Wilson M, Melick CF, Powe NR. Primary care physician job satisfaction and turnover. Am J Manag Care. 2001;7:701-713.
3. Leigh JP, Kravitz RL, Schembri M, Samuels SJ, Mobley S. Physician career satisfaction across specialties. Arch Intern Med. 2002;162:1577-1584.
4. Landon BE, Reschovsky JD, Pham HH, Blumenthal D. Leaving medicine: the consequences of physician dissatisfaction. Med Care. 2006;44:234-242.
5. Berger JE, Boyle RL, Jr. How to avoid the high costs of physician turnover. Med Group Manage J. 1992;39:80-91.
6. Buchbinder SB, Wilson M, Melick CF, Powe NR. Estimates of costs of primary care physician turnover. Am J Manag Care. 1999;5:1431-1438.
7. Carr PL, Ash AS, Friedman RH, et al. Relation of family responsibilities and gender to the productivity and career satisfaction of medical faculty. Ann Intern Med. 1998;129:532-538.
8. Jovic E, Wallace JE, Lemaire J. The generation and gender shifts in medicine: an exploratory survey of internal medicine physicians. BMC Health Serv Res. 2006;6:55-71.
9. Schroen AT, Brownstein MR, Sheldon GF. Women in academic general surgery. Acad Med. 2004;79:310-318.
10. Helliger PJ, Hingstman L. Career p and the work-family balance in medicine: gender differences among medical specialists. Soc Sci Med. 2000;50:1235-1246.
11. Pearse WH, Haffner WHJ, Primack A. Effect of gender on the obstetric-gynecologic work force. Obstet Gynecol. 2001;97:794-797.
12. Grandis JR, Gooding WF, Zamboni BA, et al. The gender gap in a surgical subspecialty. Arch Otolaryngol Head Neck Surg. 2004;130:695-702.
13. Schwartz RW, Jarecky RK, Strodel WE, Haley JV, Young B, Griffen WO, Jr. Controllable lifestyle: a new focus in career choice by medical students. Acad Med. 1989;64:606-609.
14. Pathman DE, Konrad TR, Williams ES, et al. Physician job satisfaction, dissatisfaction, and turnover. J Fam Pract. 2002;51:593.-
15. Rittenhouse DR, Mertz E, Keane D, Grumbach K. No exit: an evaluation of measures of physician attrition. Health Serv Res. 2004;39:1572-1588.
16. Weinstein L, Wolfe H. The downward spiral of physician satisfaction: an attempt to avert a crisis within the medical profession. Obstet Gynecol. 2007;109:1181-1183.
17. Zaré SM, Galanko JA, Behrns KE, et al. Psychologic well-being of surgery residents after inception of the 80-hour workweek: a multi-institutional study. Surgery. 2005;138:150-157.
18. Goitein L, Shanafelt TD, Wipf JE, Slatore CG, Back AL. The effects of work-hour limitations on resident well-being, patient care, and education in an internal medicine residency program. Arch Intern Med. 2005;165:2601-2606.
19. Karamanoukian RL, Ku JK, DeLaRosa J, Karamanoukian HL, Evans GR. The effects of restricted work hours on clinical training. Am Surg. 2006;72:19-21.
20. Boex JR, Leahy PJ. Understanding residents’ work: moving beyond counting hours to assessing educational value. Acad Med. 2003;78:939-944.
21. Gabbe SG, Webb LE, Moore DE, Jr, Mandel LS, Melville JL, Spickard WA, Jr. Can mentors prevent and reduce burnout in new chairs of departments of obstetrics and gynecology: results from a prospective, randomized pilot study. Am J Obstet Gynecol. 2008;198:653.e1-653.e7.
22. Cooke M, Irby DM, Sullivan W, Ludmerer KM. American medical education 100 years after the Flexner report. N Engl J Med. 2006;355:1339-1344.
23. Jauhar S. The demise of the physical exam. N Engl J Med. 2006;354:548-551.
24. Arky RA. Shattuck Lecture. The family business—to educate. N Engl J Med. 2006;354:1922-1926.
25. Zuger A. Dissatisfaction with medical practice. N Engl J Med. 2004;350:69-75.
26. Weinstein L, Garite TJ. On call for obstetrics—time for a change. Am J Obstet Gynecol. 2007;196:3.-
27. Weinstein L. The laborist: a new focus of practice for the obstetrician. Am J Obstet Gynecol. 2003;188:310-312.
28. Parkerton PH, Wagner EH, Smith DG, Straley HL. Effect of part-time practice on patient outcome. J Gen Intern Med. 2003;18:717-724.
29. Shields MC, Shields MT. Working with Generation X physicians. Physician Exec. 2003;29:14-18.
30. Williams J. Unbending Gender: Why Family and Work Conflict and What To Do About It. New York: Oxford University Press; 2000.
31. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 398: Fatigue and patient safety. Washington, DC: ACOG; Feb 2008.
32. Association of American Medical Colleges. AAMC statement on the physician workforce, June 2006. Available at: http://www. aamc.org/workforce/workforceposition.pdf. Accessed Oct. 31, 2008.
33. Iglehart JK. Grassroots activism and the pursuit of an expanded physician supply. N Engl J Med. 2008;358:1741-1749.
34. Cooper RA. It’s time to address the problem of physician shortages: graduate medical education is the key. Ann Surg. 2007;246:527-534.
35. Goodman DC, Fisher ES. Physician workforce crisis? Wrong diagnosis, wrong prescription. N Engl J Med. 2008;358:1658-1661.
36. Goodman DC, Fisher ES, Little GA, Stukel TA, Chang CH, Schoendorf KS. The relation between the availability of neonatal intensive care and neonatal mortality. N Engl J Med. 2002;346:1538-1544.
37. Fisher ES, Wennberg DE, Stukel TA, Gottlieb DJ, Lucas FL, Pinder EL. The implications of regional variations in Medicare spending. Ann Intern Med. 2003;138:273-298.
38. Sirovich BE, Gottlieb DJ, Welch HG, Fisher ES. Regional variations in health care intensity and physician perceptions of quality of care. Ann Intern Med. 2006;144:641-649.
Managing community-acquired MRSA lesions: What works?
The author reports no financial disclosure relevant to this article.
- Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) abscesses are best managed surgically; postprocedure antibiotics do not substantially improve outcome. The cure rate with incision and drainage alone is at least 90%.
- If incision and drainage fail to promote healing within 7 days, oral antibiotics of choice are trimethoprim-sulfamethoxazole and tetracycline
- Eradication of nasal carriage of CA-MRSA generally does not help prevent spread of clinical MRSA infection in communities.
CASE: Tender suprapubic lesion
A previously healthy, 22-year-old law school student arrives at your office complaining of “abdominal pain.” She is previously healthy; temperature is normal.
You discover on examination that she has an erythematous, indurated, and tender 3-cm lesion on the suprapubic region. The lesion has no point, but its center is boggy.
Should you prescribe an antibiotic? And should you cover immediately for CA-MRSA? What other factors might influence your decision about treatment?
The incidence of MRSA is increasing in communities across the United States, challenging assumptions about the evaluation and management of skin and soft-tissue infections. In this article, I outline a rational approach to managing patients who have a lesion likely to be caused by CA-MRSA ( TABLE 1 ).
TABLE
Suspect CA-MRSA infection? Consider this treatment scheme
| When a patient meets these criteria… | Provide this management… | And select from these antibiotics |
|---|---|---|
| Lesion nonfluctuant; patient afebrile, healthy (Class 1 infection) | If no drainable abscess, give a common first-line antibiotic for skin and soft-tissue infection; reassess for response | —Semisynthetic penicillin —Oral first- or second-generation cephalosporin —Macrolide —Clindamycin |
| Lesion, fluctuant or pustular, <5 cm in diameter; fever or no fever (Class 2) | Drain abscess surgically if possible; use incision and drainage presumptively for MRSA and monitor closely for response; inpatient management may be indicated | —Trimethoprim sulfamethoxazole —Tetracycline —Clindamycin |
| Lesion, >5 cm in diameter, toxic appearance or at least one unstable comorbidity or a limb-threatening infection (Class 3) | Admit; consider infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Sepsis syndrome or life-threatening infection (necrotizing fasciitis)(Class 4) | Admit; institute aggressive surgical debridement; request infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Source: Eron et al6 and CDC7 . | ||
When to suspect MRSA skin infection
Patients who have a CA-MRSA skin infection often report a “spider bite” because the lesion appears suddenly and unexpectedly in an area where there is no history of trauma.1 Lesions often are pustular with central necrosis; there may be purulent drainage, redness, tenderness, and palpable fluctuance ( FIGURE ).
CA-MRSA skin lesions can occur anywhere on the body, though they appear most often in the axillae or the groin and buttocks. Patients may or may not have a fever.
Persons at increased risk of CA-MRSA disease include users of health clubs, participants in contact sports, men who have sex with men, children younger than 2 years, users of intravenous drugs, military personnel, and prisoners.2,3 Absence of these risk factors in a patient with a skin or soft-tissue infection does not, however, rule out MRSA.4
Regardless of the lesion’s appearance or the patient’s epidemiologic history, consider CA-MRSA if its prevalence in your community has reached 10% to 15%.
CA-MRSA can cause impetigo, but the often-benign nature of this clinical infection makes management decisions less crucial. However, do hospitalize any patient who has a MRSA infection who also exhibits fever or hypothermia, tachycardia >100 bpm, or hypotension with a systolic blood pressure <90 mm Hg or 20 mm Hg below baseline. A skin lesion >5 cm in diameter also likely requires hospitalization and a parenteral antibiotic.5
FIGURE Class-2 CA-MRSA lesion
This raised, red lesion contains a central eschar with dried pus. Such lesions are generally very tender and often fluctuant when palpated.
Incision and drainage are most important
Several management schemes have been proposed to guide the appropriate level of therapy based on presenting characteristics.6,7 If a lesion is clearly fluctuant, incise it and drain the fluid, or refer the patient for surgical consultation. If the lesion is not clearly fluctuant, needle aspiration may help to determine the need for more extensive incision and drainage or to collect a specimen for culture. Although culture of a skin lesion may not have been routine in the past, the advent of CA-MRSA has made it so—particularly given that MRSA lesions may not be clinically distinguishable from those caused by nonresistant S aureus.
Periodic postprocedure follow-up is indicated to ensure resolution of the infection. At the Boston University student health service, CA-MRSA patients return every few days for an appointment with nursing staff for wound irrigation and packing change until the lesion visibly improves. Systemic effects from the infection are monitored as well.
Incision and drainage technique reported. In one study, adult patients were treated with incision and drainage by a surgeon.8 The technique used a#11 blade applied in a “sawing motion” to create a wide opening. The wound cavity was explored for loculations and packed. The identical technique can be used in the office, with one caveat: This study included patients who had an abscess larger than 5 cm in diameter and some whose immune system was compromised—situations not managed routinely in the office.
Are antibiotics indicated after incision and drainage for MRSA?
In the same study,8 the cure rate with incision and drainage alone was just over 90%. The cure rate in the treatment arm of the study, in which patients also received an antibiotic, was 84% (the difference was statistically insignificant), and coverage was inadequate for MRSA. Treatment with cephalexin after incision and drainage resulted in one patient harmed for every 14 treated.
A pediatric study also showed that antibiotics do not affect the outcome of skin lesions following incision and drainage.5 When deciding whether to prescribe postprocedure antibiotics, keep in mind the need to avoid contributing further to bacterial resistance.
Generally, start the patient on trimethoprim (TMP)-sulfamethoxazole (SMX) or tetracycline if incision and drainage fail to promote healing of the MRSA lesion within 7 days. Clindamycin is an option, although resistance is increasingly common. Adjust the choice and dosage of antibiotic as needed once culture and susceptibility testing results are available.
TMP-SMX is generally well tolerated at the recommended dosage of one or two double-strength tablets (160 mg of TMP, 800 mg of SMX) twice daily for adults. If creatinine clearance is 15 to 30 mL/min, halve the dosage. The rate of sulfa allergy with TMP-SMX (3%) is similar to what is seen with other antibiotics.
Tetracycline’s dosing schedule—for adults, 250 or 500 mg, four times daily— makes it difficult to use. Gastrointestinal upset, phototoxicity, and hepatotoxicity can occur. The possibility of tooth discoloration precludes its use in children.
Clindamycin carries a high rate of gastrointestinal-related problems—Clostridium difficile infection in particular (10% incidence, regardless of route). Inducible resistance to clindamycin is 50% in MRSA infections.9 Recent use of antibiotics may increase the likelihood of clindamycin resistance, with erythromycin in particular inducing such resistance. The dosage typically is 150 to 300 mg, every 6 hours.
Doxycycline and minocycline are not recommended. Both carry a 21% failure rate.10
Linezolid is costly and has many drug interactions. In particular, linezolid has the potential to cause serotonin syndrome with agents that affect the serotonergic system. Linezolid may also interact with medications that affect the adrenergic system (pressor agents). Routine use in the community without infectious disease consultation is not advised.
For lesions that are neither fluctuant nor purulent
In such cases, appropriate first-line antibiotics are a semisynthetic penicillin (e.g., dicloxacillin), a first- or second-generation oral cephalosporin, a macrolide, and clindamycin.10 These antibiotics are preferable for group A streptococcal infections, erysipelas (which can be aggressive), and impetigo. Adjustments can be made as culture results become available or if the clinical response is inadequate. There is no particular utility in waiting to administer oral antibiotics in cases of erysipelas or impetigo, although topical antibiotics can often be used for limited cases of impetigo.
CASE RESOLVED
Your patient, who meets criteria for a Class 2 CA-MRSA infection, undergoes incision and drainage of the lesion. No antibiotic is administered.
Two weeks of daily packing of the wound follow—again, without an antibiotic. Subsequently, the wound heals without sign of infection.
Prevention: Simple precautions are the rule
Most CA-MRSA infections result from direct contact with a patient’s wound or from wound drainage on environmental surfaces.
In the medical office. In addition to using sterile technique during incision and drainage, all staff members must wash hands with soap and water or an alcohol-based sanitizer. For the most part, MRSA remains susceptible to triclosan, a topical antiseptic in commercial hand soaps.
Clean equipment as needed with 10% sodium hypochlorite solution or another agent effective against MRSA. Surgical instruments should be disposable or sterilized after each use.
At the patient’s home. Instruct patients to clean the wound, wearing fresh disposable gloves each time, and to cover it with a new, dry dressing. Tell families to avoid sharing linens and clothing unless they have been washed in hot soap and water and dried in a heated dryer. MRSA can live for weeks or months on surfaces exposed to infected wounds11 ; these surfaces can be disinfected with a 10% solution of bleach.
In sports environments. Athletes who have a CA-MRSA infection should not compete unless the wound can be completely covered with a dry dressing. Recommend to those in charge of school and commercial facilities that, in a confirmed case of MRSA infection, they routinely clean locker rooms and sports equipment with either a 10% bleach solution or commercial disinfectant. There is no evidence, however, that more widespread or vigorous cleaning—such as dismantling a training room and all its cardio-fitness equipment for disinfecting—prevents the spread of MRSA.
Encourage athletes to wash their hands properly. Communal towels should be washed in hot water (>140°F) with bleach before reuse. Personal equipment should be cleaned according to the manufacturer’s instructions. Athletes should use a clean towel to provide a barrier between their skin and the surfaces of weight-room and cardio-fitness equipment. They should also clean equipment before and after use with an appropriate cleanser, such as a disinfectant hand wipe.
Screening household contacts for MRSA isn’t useful; attempts to eradicate colonization are generally ineffective. In a large study of military personnel, intranasal mupirocin failed to decrease nasal carriage of MRSA and the incidence of MRSA infections.11 The MRSA nasal colonization rate was 3.9%; 121 persons colonized with MRSA needed to be treated with nasal mupirocin to prevent one MRSA infection in the total study population.
More complex antibiotic regimens are sometimes used in an attempt to eradicate MRSA carriage, but they also have limited effectiveness and carry the general risks of antibiotic use (e.g., gastrointestinal disturbance, allergic reaction). If your office is considering an eradication attempt, consult first with an infectious disease clinician.
Suggested Reading
1. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. EMERGEncy ID Net Study Group Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666-674.
2. Cohen PR. The skin in the gym: a comprehensive review of the cutaneous manifestations of community-acquired methicillin-resistant Staphylococcus aureus infection in athletes. Clin Dermatol. 2008;26:16-26.
3. Cohen PR. Community-acquired methicillin-resistant Staphylococcus aureus skin infections: implications for patients and practitioners. Am J Clin Dermatol. 2007;8:259-270.
4. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S aureus infection: a prospective investigation. Clin Infect Dis. 2007;44:471-482.
5. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;23:123-127.
6. Eron LJ, Lipsky BA, Low DE, et al. Expert panel on managing skin and soft tissue infections Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother. 2003;52(Suppl 1):i3-i17.
7. Centers for Disease Control and Prevention American Medical Association Infectious Diseases Society of America. Outpatient management of skin and soft tissue infections in the era of community-associated MRSA. September 2007. Available at: http://www.amaassn.org/ama1/pub/upload/mm/36/ca_mrsa_desk_102007.pdf. Accessed November 11, 2008.
8. Rajendran PM, Young D, Maurer T, et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2007;51:4044-4048.
9. Stevens DL, Bisno AL, Chambers HF, et al. Infectious Diseases Society of America Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406.
10. Dellit TH, Duchin J. Guidelines for Evaluation and Management of Community-Associated Methicillin Resistant Staphylococcus aureus Skin and Soft Tissue Infections in Outpatient Settings. December 2007. Available at: http://www.kingcounty.gov/healthservices/health/communicable/providers/~/media/health/
publichealth/documents/communicable/MRSA_guide-lines.ashx. Accessed November 11, 2008.
11. Ellis MW, Griffith ME, Dooley DP, et al. Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother. 2007;51:3591-3598.
The author reports no financial disclosure relevant to this article.
- Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) abscesses are best managed surgically; postprocedure antibiotics do not substantially improve outcome. The cure rate with incision and drainage alone is at least 90%.
- If incision and drainage fail to promote healing within 7 days, oral antibiotics of choice are trimethoprim-sulfamethoxazole and tetracycline
- Eradication of nasal carriage of CA-MRSA generally does not help prevent spread of clinical MRSA infection in communities.
CASE: Tender suprapubic lesion
A previously healthy, 22-year-old law school student arrives at your office complaining of “abdominal pain.” She is previously healthy; temperature is normal.
You discover on examination that she has an erythematous, indurated, and tender 3-cm lesion on the suprapubic region. The lesion has no point, but its center is boggy.
Should you prescribe an antibiotic? And should you cover immediately for CA-MRSA? What other factors might influence your decision about treatment?
The incidence of MRSA is increasing in communities across the United States, challenging assumptions about the evaluation and management of skin and soft-tissue infections. In this article, I outline a rational approach to managing patients who have a lesion likely to be caused by CA-MRSA ( TABLE 1 ).
TABLE
Suspect CA-MRSA infection? Consider this treatment scheme
| When a patient meets these criteria… | Provide this management… | And select from these antibiotics |
|---|---|---|
| Lesion nonfluctuant; patient afebrile, healthy (Class 1 infection) | If no drainable abscess, give a common first-line antibiotic for skin and soft-tissue infection; reassess for response | —Semisynthetic penicillin —Oral first- or second-generation cephalosporin —Macrolide —Clindamycin |
| Lesion, fluctuant or pustular, <5 cm in diameter; fever or no fever (Class 2) | Drain abscess surgically if possible; use incision and drainage presumptively for MRSA and monitor closely for response; inpatient management may be indicated | —Trimethoprim sulfamethoxazole —Tetracycline —Clindamycin |
| Lesion, >5 cm in diameter, toxic appearance or at least one unstable comorbidity or a limb-threatening infection (Class 3) | Admit; consider infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Sepsis syndrome or life-threatening infection (necrotizing fasciitis)(Class 4) | Admit; institute aggressive surgical debridement; request infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Source: Eron et al6 and CDC7 . | ||
When to suspect MRSA skin infection
Patients who have a CA-MRSA skin infection often report a “spider bite” because the lesion appears suddenly and unexpectedly in an area where there is no history of trauma.1 Lesions often are pustular with central necrosis; there may be purulent drainage, redness, tenderness, and palpable fluctuance ( FIGURE ).
CA-MRSA skin lesions can occur anywhere on the body, though they appear most often in the axillae or the groin and buttocks. Patients may or may not have a fever.
Persons at increased risk of CA-MRSA disease include users of health clubs, participants in contact sports, men who have sex with men, children younger than 2 years, users of intravenous drugs, military personnel, and prisoners.2,3 Absence of these risk factors in a patient with a skin or soft-tissue infection does not, however, rule out MRSA.4
Regardless of the lesion’s appearance or the patient’s epidemiologic history, consider CA-MRSA if its prevalence in your community has reached 10% to 15%.
CA-MRSA can cause impetigo, but the often-benign nature of this clinical infection makes management decisions less crucial. However, do hospitalize any patient who has a MRSA infection who also exhibits fever or hypothermia, tachycardia >100 bpm, or hypotension with a systolic blood pressure <90 mm Hg or 20 mm Hg below baseline. A skin lesion >5 cm in diameter also likely requires hospitalization and a parenteral antibiotic.5
FIGURE Class-2 CA-MRSA lesion
This raised, red lesion contains a central eschar with dried pus. Such lesions are generally very tender and often fluctuant when palpated.
Incision and drainage are most important
Several management schemes have been proposed to guide the appropriate level of therapy based on presenting characteristics.6,7 If a lesion is clearly fluctuant, incise it and drain the fluid, or refer the patient for surgical consultation. If the lesion is not clearly fluctuant, needle aspiration may help to determine the need for more extensive incision and drainage or to collect a specimen for culture. Although culture of a skin lesion may not have been routine in the past, the advent of CA-MRSA has made it so—particularly given that MRSA lesions may not be clinically distinguishable from those caused by nonresistant S aureus.
Periodic postprocedure follow-up is indicated to ensure resolution of the infection. At the Boston University student health service, CA-MRSA patients return every few days for an appointment with nursing staff for wound irrigation and packing change until the lesion visibly improves. Systemic effects from the infection are monitored as well.
Incision and drainage technique reported. In one study, adult patients were treated with incision and drainage by a surgeon.8 The technique used a#11 blade applied in a “sawing motion” to create a wide opening. The wound cavity was explored for loculations and packed. The identical technique can be used in the office, with one caveat: This study included patients who had an abscess larger than 5 cm in diameter and some whose immune system was compromised—situations not managed routinely in the office.
Are antibiotics indicated after incision and drainage for MRSA?
In the same study,8 the cure rate with incision and drainage alone was just over 90%. The cure rate in the treatment arm of the study, in which patients also received an antibiotic, was 84% (the difference was statistically insignificant), and coverage was inadequate for MRSA. Treatment with cephalexin after incision and drainage resulted in one patient harmed for every 14 treated.
A pediatric study also showed that antibiotics do not affect the outcome of skin lesions following incision and drainage.5 When deciding whether to prescribe postprocedure antibiotics, keep in mind the need to avoid contributing further to bacterial resistance.
Generally, start the patient on trimethoprim (TMP)-sulfamethoxazole (SMX) or tetracycline if incision and drainage fail to promote healing of the MRSA lesion within 7 days. Clindamycin is an option, although resistance is increasingly common. Adjust the choice and dosage of antibiotic as needed once culture and susceptibility testing results are available.
TMP-SMX is generally well tolerated at the recommended dosage of one or two double-strength tablets (160 mg of TMP, 800 mg of SMX) twice daily for adults. If creatinine clearance is 15 to 30 mL/min, halve the dosage. The rate of sulfa allergy with TMP-SMX (3%) is similar to what is seen with other antibiotics.
Tetracycline’s dosing schedule—for adults, 250 or 500 mg, four times daily— makes it difficult to use. Gastrointestinal upset, phototoxicity, and hepatotoxicity can occur. The possibility of tooth discoloration precludes its use in children.
Clindamycin carries a high rate of gastrointestinal-related problems—Clostridium difficile infection in particular (10% incidence, regardless of route). Inducible resistance to clindamycin is 50% in MRSA infections.9 Recent use of antibiotics may increase the likelihood of clindamycin resistance, with erythromycin in particular inducing such resistance. The dosage typically is 150 to 300 mg, every 6 hours.
Doxycycline and minocycline are not recommended. Both carry a 21% failure rate.10
Linezolid is costly and has many drug interactions. In particular, linezolid has the potential to cause serotonin syndrome with agents that affect the serotonergic system. Linezolid may also interact with medications that affect the adrenergic system (pressor agents). Routine use in the community without infectious disease consultation is not advised.
For lesions that are neither fluctuant nor purulent
In such cases, appropriate first-line antibiotics are a semisynthetic penicillin (e.g., dicloxacillin), a first- or second-generation oral cephalosporin, a macrolide, and clindamycin.10 These antibiotics are preferable for group A streptococcal infections, erysipelas (which can be aggressive), and impetigo. Adjustments can be made as culture results become available or if the clinical response is inadequate. There is no particular utility in waiting to administer oral antibiotics in cases of erysipelas or impetigo, although topical antibiotics can often be used for limited cases of impetigo.
CASE RESOLVED
Your patient, who meets criteria for a Class 2 CA-MRSA infection, undergoes incision and drainage of the lesion. No antibiotic is administered.
Two weeks of daily packing of the wound follow—again, without an antibiotic. Subsequently, the wound heals without sign of infection.
Prevention: Simple precautions are the rule
Most CA-MRSA infections result from direct contact with a patient’s wound or from wound drainage on environmental surfaces.
In the medical office. In addition to using sterile technique during incision and drainage, all staff members must wash hands with soap and water or an alcohol-based sanitizer. For the most part, MRSA remains susceptible to triclosan, a topical antiseptic in commercial hand soaps.
Clean equipment as needed with 10% sodium hypochlorite solution or another agent effective against MRSA. Surgical instruments should be disposable or sterilized after each use.
At the patient’s home. Instruct patients to clean the wound, wearing fresh disposable gloves each time, and to cover it with a new, dry dressing. Tell families to avoid sharing linens and clothing unless they have been washed in hot soap and water and dried in a heated dryer. MRSA can live for weeks or months on surfaces exposed to infected wounds11 ; these surfaces can be disinfected with a 10% solution of bleach.
In sports environments. Athletes who have a CA-MRSA infection should not compete unless the wound can be completely covered with a dry dressing. Recommend to those in charge of school and commercial facilities that, in a confirmed case of MRSA infection, they routinely clean locker rooms and sports equipment with either a 10% bleach solution or commercial disinfectant. There is no evidence, however, that more widespread or vigorous cleaning—such as dismantling a training room and all its cardio-fitness equipment for disinfecting—prevents the spread of MRSA.
Encourage athletes to wash their hands properly. Communal towels should be washed in hot water (>140°F) with bleach before reuse. Personal equipment should be cleaned according to the manufacturer’s instructions. Athletes should use a clean towel to provide a barrier between their skin and the surfaces of weight-room and cardio-fitness equipment. They should also clean equipment before and after use with an appropriate cleanser, such as a disinfectant hand wipe.
Screening household contacts for MRSA isn’t useful; attempts to eradicate colonization are generally ineffective. In a large study of military personnel, intranasal mupirocin failed to decrease nasal carriage of MRSA and the incidence of MRSA infections.11 The MRSA nasal colonization rate was 3.9%; 121 persons colonized with MRSA needed to be treated with nasal mupirocin to prevent one MRSA infection in the total study population.
More complex antibiotic regimens are sometimes used in an attempt to eradicate MRSA carriage, but they also have limited effectiveness and carry the general risks of antibiotic use (e.g., gastrointestinal disturbance, allergic reaction). If your office is considering an eradication attempt, consult first with an infectious disease clinician.
Suggested Reading
The author reports no financial disclosure relevant to this article.
- Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) abscesses are best managed surgically; postprocedure antibiotics do not substantially improve outcome. The cure rate with incision and drainage alone is at least 90%.
- If incision and drainage fail to promote healing within 7 days, oral antibiotics of choice are trimethoprim-sulfamethoxazole and tetracycline
- Eradication of nasal carriage of CA-MRSA generally does not help prevent spread of clinical MRSA infection in communities.
CASE: Tender suprapubic lesion
A previously healthy, 22-year-old law school student arrives at your office complaining of “abdominal pain.” She is previously healthy; temperature is normal.
You discover on examination that she has an erythematous, indurated, and tender 3-cm lesion on the suprapubic region. The lesion has no point, but its center is boggy.
Should you prescribe an antibiotic? And should you cover immediately for CA-MRSA? What other factors might influence your decision about treatment?
The incidence of MRSA is increasing in communities across the United States, challenging assumptions about the evaluation and management of skin and soft-tissue infections. In this article, I outline a rational approach to managing patients who have a lesion likely to be caused by CA-MRSA ( TABLE 1 ).
TABLE
Suspect CA-MRSA infection? Consider this treatment scheme
| When a patient meets these criteria… | Provide this management… | And select from these antibiotics |
|---|---|---|
| Lesion nonfluctuant; patient afebrile, healthy (Class 1 infection) | If no drainable abscess, give a common first-line antibiotic for skin and soft-tissue infection; reassess for response | —Semisynthetic penicillin —Oral first- or second-generation cephalosporin —Macrolide —Clindamycin |
| Lesion, fluctuant or pustular, <5 cm in diameter; fever or no fever (Class 2) | Drain abscess surgically if possible; use incision and drainage presumptively for MRSA and monitor closely for response; inpatient management may be indicated | —Trimethoprim sulfamethoxazole —Tetracycline —Clindamycin |
| Lesion, >5 cm in diameter, toxic appearance or at least one unstable comorbidity or a limb-threatening infection (Class 3) | Admit; consider infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Sepsis syndrome or life-threatening infection (necrotizing fasciitis)(Class 4) | Admit; institute aggressive surgical debridement; request infectious disease consult | Broad-spectrum agent, including vancomycin, for MRSA coverage |
| Source: Eron et al6 and CDC7 . | ||
When to suspect MRSA skin infection
Patients who have a CA-MRSA skin infection often report a “spider bite” because the lesion appears suddenly and unexpectedly in an area where there is no history of trauma.1 Lesions often are pustular with central necrosis; there may be purulent drainage, redness, tenderness, and palpable fluctuance ( FIGURE ).
CA-MRSA skin lesions can occur anywhere on the body, though they appear most often in the axillae or the groin and buttocks. Patients may or may not have a fever.
Persons at increased risk of CA-MRSA disease include users of health clubs, participants in contact sports, men who have sex with men, children younger than 2 years, users of intravenous drugs, military personnel, and prisoners.2,3 Absence of these risk factors in a patient with a skin or soft-tissue infection does not, however, rule out MRSA.4
Regardless of the lesion’s appearance or the patient’s epidemiologic history, consider CA-MRSA if its prevalence in your community has reached 10% to 15%.
CA-MRSA can cause impetigo, but the often-benign nature of this clinical infection makes management decisions less crucial. However, do hospitalize any patient who has a MRSA infection who also exhibits fever or hypothermia, tachycardia >100 bpm, or hypotension with a systolic blood pressure <90 mm Hg or 20 mm Hg below baseline. A skin lesion >5 cm in diameter also likely requires hospitalization and a parenteral antibiotic.5
FIGURE Class-2 CA-MRSA lesion
This raised, red lesion contains a central eschar with dried pus. Such lesions are generally very tender and often fluctuant when palpated.
Incision and drainage are most important
Several management schemes have been proposed to guide the appropriate level of therapy based on presenting characteristics.6,7 If a lesion is clearly fluctuant, incise it and drain the fluid, or refer the patient for surgical consultation. If the lesion is not clearly fluctuant, needle aspiration may help to determine the need for more extensive incision and drainage or to collect a specimen for culture. Although culture of a skin lesion may not have been routine in the past, the advent of CA-MRSA has made it so—particularly given that MRSA lesions may not be clinically distinguishable from those caused by nonresistant S aureus.
Periodic postprocedure follow-up is indicated to ensure resolution of the infection. At the Boston University student health service, CA-MRSA patients return every few days for an appointment with nursing staff for wound irrigation and packing change until the lesion visibly improves. Systemic effects from the infection are monitored as well.
Incision and drainage technique reported. In one study, adult patients were treated with incision and drainage by a surgeon.8 The technique used a#11 blade applied in a “sawing motion” to create a wide opening. The wound cavity was explored for loculations and packed. The identical technique can be used in the office, with one caveat: This study included patients who had an abscess larger than 5 cm in diameter and some whose immune system was compromised—situations not managed routinely in the office.
Are antibiotics indicated after incision and drainage for MRSA?
In the same study,8 the cure rate with incision and drainage alone was just over 90%. The cure rate in the treatment arm of the study, in which patients also received an antibiotic, was 84% (the difference was statistically insignificant), and coverage was inadequate for MRSA. Treatment with cephalexin after incision and drainage resulted in one patient harmed for every 14 treated.
A pediatric study also showed that antibiotics do not affect the outcome of skin lesions following incision and drainage.5 When deciding whether to prescribe postprocedure antibiotics, keep in mind the need to avoid contributing further to bacterial resistance.
Generally, start the patient on trimethoprim (TMP)-sulfamethoxazole (SMX) or tetracycline if incision and drainage fail to promote healing of the MRSA lesion within 7 days. Clindamycin is an option, although resistance is increasingly common. Adjust the choice and dosage of antibiotic as needed once culture and susceptibility testing results are available.
TMP-SMX is generally well tolerated at the recommended dosage of one or two double-strength tablets (160 mg of TMP, 800 mg of SMX) twice daily for adults. If creatinine clearance is 15 to 30 mL/min, halve the dosage. The rate of sulfa allergy with TMP-SMX (3%) is similar to what is seen with other antibiotics.
Tetracycline’s dosing schedule—for adults, 250 or 500 mg, four times daily— makes it difficult to use. Gastrointestinal upset, phototoxicity, and hepatotoxicity can occur. The possibility of tooth discoloration precludes its use in children.
Clindamycin carries a high rate of gastrointestinal-related problems—Clostridium difficile infection in particular (10% incidence, regardless of route). Inducible resistance to clindamycin is 50% in MRSA infections.9 Recent use of antibiotics may increase the likelihood of clindamycin resistance, with erythromycin in particular inducing such resistance. The dosage typically is 150 to 300 mg, every 6 hours.
Doxycycline and minocycline are not recommended. Both carry a 21% failure rate.10
Linezolid is costly and has many drug interactions. In particular, linezolid has the potential to cause serotonin syndrome with agents that affect the serotonergic system. Linezolid may also interact with medications that affect the adrenergic system (pressor agents). Routine use in the community without infectious disease consultation is not advised.
For lesions that are neither fluctuant nor purulent
In such cases, appropriate first-line antibiotics are a semisynthetic penicillin (e.g., dicloxacillin), a first- or second-generation oral cephalosporin, a macrolide, and clindamycin.10 These antibiotics are preferable for group A streptococcal infections, erysipelas (which can be aggressive), and impetigo. Adjustments can be made as culture results become available or if the clinical response is inadequate. There is no particular utility in waiting to administer oral antibiotics in cases of erysipelas or impetigo, although topical antibiotics can often be used for limited cases of impetigo.
CASE RESOLVED
Your patient, who meets criteria for a Class 2 CA-MRSA infection, undergoes incision and drainage of the lesion. No antibiotic is administered.
Two weeks of daily packing of the wound follow—again, without an antibiotic. Subsequently, the wound heals without sign of infection.
Prevention: Simple precautions are the rule
Most CA-MRSA infections result from direct contact with a patient’s wound or from wound drainage on environmental surfaces.
In the medical office. In addition to using sterile technique during incision and drainage, all staff members must wash hands with soap and water or an alcohol-based sanitizer. For the most part, MRSA remains susceptible to triclosan, a topical antiseptic in commercial hand soaps.
Clean equipment as needed with 10% sodium hypochlorite solution or another agent effective against MRSA. Surgical instruments should be disposable or sterilized after each use.
At the patient’s home. Instruct patients to clean the wound, wearing fresh disposable gloves each time, and to cover it with a new, dry dressing. Tell families to avoid sharing linens and clothing unless they have been washed in hot soap and water and dried in a heated dryer. MRSA can live for weeks or months on surfaces exposed to infected wounds11 ; these surfaces can be disinfected with a 10% solution of bleach.
In sports environments. Athletes who have a CA-MRSA infection should not compete unless the wound can be completely covered with a dry dressing. Recommend to those in charge of school and commercial facilities that, in a confirmed case of MRSA infection, they routinely clean locker rooms and sports equipment with either a 10% bleach solution or commercial disinfectant. There is no evidence, however, that more widespread or vigorous cleaning—such as dismantling a training room and all its cardio-fitness equipment for disinfecting—prevents the spread of MRSA.
Encourage athletes to wash their hands properly. Communal towels should be washed in hot water (>140°F) with bleach before reuse. Personal equipment should be cleaned according to the manufacturer’s instructions. Athletes should use a clean towel to provide a barrier between their skin and the surfaces of weight-room and cardio-fitness equipment. They should also clean equipment before and after use with an appropriate cleanser, such as a disinfectant hand wipe.
Screening household contacts for MRSA isn’t useful; attempts to eradicate colonization are generally ineffective. In a large study of military personnel, intranasal mupirocin failed to decrease nasal carriage of MRSA and the incidence of MRSA infections.11 The MRSA nasal colonization rate was 3.9%; 121 persons colonized with MRSA needed to be treated with nasal mupirocin to prevent one MRSA infection in the total study population.
More complex antibiotic regimens are sometimes used in an attempt to eradicate MRSA carriage, but they also have limited effectiveness and carry the general risks of antibiotic use (e.g., gastrointestinal disturbance, allergic reaction). If your office is considering an eradication attempt, consult first with an infectious disease clinician.
Suggested Reading
1. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. EMERGEncy ID Net Study Group Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666-674.
2. Cohen PR. The skin in the gym: a comprehensive review of the cutaneous manifestations of community-acquired methicillin-resistant Staphylococcus aureus infection in athletes. Clin Dermatol. 2008;26:16-26.
3. Cohen PR. Community-acquired methicillin-resistant Staphylococcus aureus skin infections: implications for patients and practitioners. Am J Clin Dermatol. 2007;8:259-270.
4. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S aureus infection: a prospective investigation. Clin Infect Dis. 2007;44:471-482.
5. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;23:123-127.
6. Eron LJ, Lipsky BA, Low DE, et al. Expert panel on managing skin and soft tissue infections Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother. 2003;52(Suppl 1):i3-i17.
7. Centers for Disease Control and Prevention American Medical Association Infectious Diseases Society of America. Outpatient management of skin and soft tissue infections in the era of community-associated MRSA. September 2007. Available at: http://www.amaassn.org/ama1/pub/upload/mm/36/ca_mrsa_desk_102007.pdf. Accessed November 11, 2008.
8. Rajendran PM, Young D, Maurer T, et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2007;51:4044-4048.
9. Stevens DL, Bisno AL, Chambers HF, et al. Infectious Diseases Society of America Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406.
10. Dellit TH, Duchin J. Guidelines for Evaluation and Management of Community-Associated Methicillin Resistant Staphylococcus aureus Skin and Soft Tissue Infections in Outpatient Settings. December 2007. Available at: http://www.kingcounty.gov/healthservices/health/communicable/providers/~/media/health/
publichealth/documents/communicable/MRSA_guide-lines.ashx. Accessed November 11, 2008.
11. Ellis MW, Griffith ME, Dooley DP, et al. Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother. 2007;51:3591-3598.
1. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. EMERGEncy ID Net Study Group Methicillin-resistant S aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666-674.
2. Cohen PR. The skin in the gym: a comprehensive review of the cutaneous manifestations of community-acquired methicillin-resistant Staphylococcus aureus infection in athletes. Clin Dermatol. 2008;26:16-26.
3. Cohen PR. Community-acquired methicillin-resistant Staphylococcus aureus skin infections: implications for patients and practitioners. Am J Clin Dermatol. 2007;8:259-270.
4. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S aureus infection: a prospective investigation. Clin Infect Dis. 2007;44:471-482.
5. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;23:123-127.
6. Eron LJ, Lipsky BA, Low DE, et al. Expert panel on managing skin and soft tissue infections Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother. 2003;52(Suppl 1):i3-i17.
7. Centers for Disease Control and Prevention American Medical Association Infectious Diseases Society of America. Outpatient management of skin and soft tissue infections in the era of community-associated MRSA. September 2007. Available at: http://www.amaassn.org/ama1/pub/upload/mm/36/ca_mrsa_desk_102007.pdf. Accessed November 11, 2008.
8. Rajendran PM, Young D, Maurer T, et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2007;51:4044-4048.
9. Stevens DL, Bisno AL, Chambers HF, et al. Infectious Diseases Society of America Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406.
10. Dellit TH, Duchin J. Guidelines for Evaluation and Management of Community-Associated Methicillin Resistant Staphylococcus aureus Skin and Soft Tissue Infections in Outpatient Settings. December 2007. Available at: http://www.kingcounty.gov/healthservices/health/communicable/providers/~/media/health/
publichealth/documents/communicable/MRSA_guide-lines.ashx. Accessed November 11, 2008.
11. Ellis MW, Griffith ME, Dooley DP, et al. Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother. 2007;51:3591-3598.