CASE: Lost needle tip
A 36-year-old woman (G3 P2012) with stress urinary incontinence (SUI) and abnormal uterine bleeding presented to a gynecologist. She had explored medical therapy for her SUI with no symptom improvement. She had a previous tubal ligation, and the gynecologist ordered urodynamic testing, the results of which led to a discussion of vaginal hysterectomy; anterior, posterior colporrhaphy; and mesh placement. It was felt that the patient had a number of risk factors for incontinence (including pregnancy with vaginal delivery, well-controlled diabetes mellitus, and obesity). She had a long-standing history of chronic pelvic pain, with an established diagnosis of diverticulosis with episodes of diverticulitis in the past.

The gynecologist had the patient keep a bladder diary for 1 week. When asked, the patient reported no problems with sexual dysfunction, stating that her quality of life was “fine” except for the vaginal bleeding and loss of urine refractory to medical therapy. The Urogenital Distress Inventory was administered, and it identified frequent urination, leakage, and incontinence related to activities. An Incontinence Impact Questionnaire also was administered. Physical examination included cotton-tipped swab urethral, or Q-tip, test and cough stress test as part of POP-Q (Pelvic Organ Prolapse Quantification system) evaluation. Urinary tract infection was ruled out. The gynecologist counseled the patient about possible medical therapies for urinary incontinence, and she requested definitive surgery.

The gynecologist obtained informed consent for surgery that included preoperative discussion of potential surgical complications, including bleeding, infection, trauma to surrounding structures, and the possibility of additional surgical procedures secondary to complications. The gynecologist also discussed transvaginal tape versus transobturator tape (TOT) placement, including potential complications and sequelae. The final planned procedure, which was performed by the gynecologist, included vaginal hysterectomy, anterior colporrhaphy, and TOT placement.

Intraoperatively, the patient was identified (upon entering the operating room [OR]); time-out occurred, and the gynecologist proceeded with surgery. During the procedure, the tip of a needle broke off. The gynecologist noted the broken tip as he removed the needle and handed it to the surgical technician. The gynecologist palpated the sidewall in the presumed area of the needle tip and felt it easily. He attempted to remove the tip, but his effort was fruitless. He made the intraoperative decision to leave the tip in situ. A needle and sponge count was performed, reported as correct, and it was felt there was no indication for imaging of the pelvis. The circulating nurse filled out an incident report immediately following the surgery, noting the missing needle tip. The occurrence was discussed by the surgical committee at the hospital.

Postoperatively, while the patient was in the hospital, she was informed of the intra-operative incident.

Three months later, the patient reported vaginal and pelvic pain on the sidewall in the area of the lost needle tip, with radiating pain down the involved extremity. A segment of the TOT was noted to be protruding into the vagina, and this was addressed in the OR with “trimming of such.”

Postoperatively, again the patient reported pain on the involved side. She sought the opinion of another gynecologist, who subsequently performed surgical intervention to remove the needle tip. Her symptoms improved.

The patient sued the original gynecologic surgeon, alleging pain and suffering from the surgery involving the lost needle tip.

What’s the verdict?
A defense verdict was awarded.

Medical teaching points
Medical evaluation seemed appropriate. Parity is associated with SUI (but not urge incontinence). In general, urinary incontinence is more commonly associated with a history of lower urinary tract infections. The patient in this case was asked about and evaluated for:

Was information on the broken needle handled appropriately? This case explores the question of what, if any, obligation the surgeon and hospital system have to the patient when informing her of a broken needle and the intraoperative decision-making process that led to its staying in place. When such a situation occurs, which is very uncommon, should an intraoperative x-ray be performed to assess the location of the needle tip? Should the patient automatically be brought back to the OR for removal?

The surgeon’s concern was a legitimate one—that additional attempts at removal could lead to complications far worse than having a small segment of a needle left in place. After all, shrapnel, bullets, etc, remain lodged in various locations throughout the body without subsequent ill effects. He did discuss with the patient the fact that a needle segment was left in the muscle wall. But how do you assess postoperative pelvic pain in a patient who had preoperative chronic pelvic pain? These are questions we as clinicians ask. Clearly, there are no black-and-white answers, and we will call upon our legal consultants for their expertise in addressing these queries.

From the gynecologic perspective, however, it is of paramount importance to address the patient’s postoperative vaginal pain and determine the best management approach. In this case the TOT, and its association with a 21.5% complication rate, including reported vaginal extrusion, introduces a whole new set of concerns.¹ The TOT use in itself raises the question of liability on the part of the surgeon. This mesh has more than 150 associated complications, including obturator nerve injuries, extensive blood loss, and ischiorectal fossa abscesses.² Once a device comes upon the radar screen of the US Food and Drug Administration for ­signi­ficant complications, where does that leave the clinician in regard to litigation? Let’s look to our legal colleagues for their insight and expertise.

Legal considerations
Given the facts in this case, it is not surprising that it resulted in a defense verdict. The majority of cases filed are ultimately disposed of in favor of the medical defendants, and the majority of medical malpractice cases that go to trial result in defense verdicts.

Medical malpractice, or “professional negligence,” consists of a claim that a medical professional had a duty of care to the patient, a breach of that duty, injury to the patient, and a causal connection (“causation”) between the breach of duty and the injury. It is the obligation of the plaintiff to prove the elements of negligence by a preponderance of the evidence.

Were the surgeon’s actions in line with other surgeons’ expected actions? The issue of the breach of the duty of care essentially is the question of whether the physician acted similarly to a reasonably careful practitioner of the same specialty under the same circumstances. Doctors are not held to a standard of perfection. That is, not every injury or bad outcome is negligence—only those injuries that result from actions, or inactions, that were not within the level of care acceptable in the profession.

Why would this patient file a lawsuit? The injury was not trivial (it had both pain and cost associated with it), but it was not catastrophic, and the negligence was going to be difficult to prove. Furthermore, lawsuits are expensive in terms of time, energy, and emotional commitment—few people file them for the fun of it. We can only speculate on the answer to the question but, frequently, such claims are a search for the answer to “What happened, and why?” or a reaction to feeling ignored or disrespected. There is little in the case facts that we have to work with to indicate what the communication was between the gynecologist and the patient and her family. The statement of facts, however, leaves the impression that communication deteriorated as the postoperative pain endured.

Some additional areas of potential claims for liability in this case include:

What factors could have tipped the case toward the defense?
The defense verdict indicates that the jury determined there was no negligence, or that the patient could not prove any of these potential bases of liability. As noted above, what may have helped the defense is the fact that the surgeon documented the details of the informed consent conversation, including that “discussion was carried out regarding” the tape. The informed consent process is an important opportunity for communication with the patient, and a chance to make sure that expectations are reasonable. Liability for the failure of informed consent is not common. When something has gone wrong, however, it can matter whether the problem was something mentioned in the informed consent process. In addition, it was positive that postoperatively the patient was informed of the broken needle—although it is not clear who informed her about it.

A couple of other legal issues are worth noting. From our fact scenario we do not know what was documented in the incident report filed by the circulating nurse and reviewed by the surgical committee. We also do not know whether the plaintiff was privy to the incident report document. The surgical committee is likely a peer-review committee, and most states provide some privilege for such committees (to avoid disclosure of committee information for discovery or at trial). The deliberations and conclusions of the committee, therefore, were likely privileged. However, incident reports are frequently used for other purposes, such as administrative reports, that are not privileged—so the incident report often is determined to be discoverable depending on the interpretation of the state’s law.

No winner in this case
Despite the defense verdict, the physician was not really the “winner” after having spent a great deal of time, energy, money, and emotion defending this suit. Ultimately, the goal is not to win malpractice cases but to avoid them—in this case, among other things, by being frank with patients about expectations, keeping an open line of communication with patients when they are concerned with an outcome that is less than ideal, and referring a patient when it may be appropriate.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE: Lost needle tip
A 36-year-old woman (G3 P2012) with stress urinary incontinence (SUI) and abnormal uterine bleeding presented to a gynecologist. She had explored medical therapy for her SUI with no symptom improvement. She had a previous tubal ligation, and the gynecologist ordered urodynamic testing, the results of which led to a discussion of vaginal hysterectomy; anterior, posterior colporrhaphy; and mesh placement. It was felt that the patient had a number of risk factors for incontinence (including pregnancy with vaginal delivery, well-controlled diabetes mellitus, and obesity). She had a long-standing history of chronic pelvic pain, with an established diagnosis of diverticulosis with episodes of diverticulitis in the past.

The gynecologist had the patient keep a bladder diary for 1 week. When asked, the patient reported no problems with sexual dysfunction, stating that her quality of life was “fine” except for the vaginal bleeding and loss of urine refractory to medical therapy. The Urogenital Distress Inventory was administered, and it identified frequent urination, leakage, and incontinence related to activities. An Incontinence Impact Questionnaire also was administered. Physical examination included cotton-tipped swab urethral, or Q-tip, test and cough stress test as part of POP-Q (Pelvic Organ Prolapse Quantification system) evaluation. Urinary tract infection was ruled out. The gynecologist counseled the patient about possible medical therapies for urinary incontinence, and she requested definitive surgery.

The gynecologist obtained informed consent for surgery that included preoperative discussion of potential surgical complications, including bleeding, infection, trauma to surrounding structures, and the possibility of additional surgical procedures secondary to complications. The gynecologist also discussed transvaginal tape versus transobturator tape (TOT) placement, including potential complications and sequelae. The final planned procedure, which was performed by the gynecologist, included vaginal hysterectomy, anterior colporrhaphy, and TOT placement.

Intraoperatively, the patient was identified (upon entering the operating room [OR]); time-out occurred, and the gynecologist proceeded with surgery. During the procedure, the tip of a needle broke off. The gynecologist noted the broken tip as he removed the needle and handed it to the surgical technician. The gynecologist palpated the sidewall in the presumed area of the needle tip and felt it easily. He attempted to remove the tip, but his effort was fruitless. He made the intraoperative decision to leave the tip in situ. A needle and sponge count was performed, reported as correct, and it was felt there was no indication for imaging of the pelvis. The circulating nurse filled out an incident report immediately following the surgery, noting the missing needle tip. The occurrence was discussed by the surgical committee at the hospital.

Postoperatively, while the patient was in the hospital, she was informed of the intra-operative incident.

Three months later, the patient reported vaginal and pelvic pain on the sidewall in the area of the lost needle tip, with radiating pain down the involved extremity. A segment of the TOT was noted to be protruding into the vagina, and this was addressed in the OR with “trimming of such.”

Postoperatively, again the patient reported pain on the involved side. She sought the opinion of another gynecologist, who subsequently performed surgical intervention to remove the needle tip. Her symptoms improved.

The patient sued the original gynecologic surgeon, alleging pain and suffering from the surgery involving the lost needle tip.

What’s the verdict?
A defense verdict was awarded.

Medical teaching points
Medical evaluation seemed appropriate. Parity is associated with SUI (but not urge incontinence). In general, urinary incontinence is more commonly associated with a history of lower urinary tract infections. The patient in this case was asked about and evaluated for:

Was information on the broken needle handled appropriately? This case explores the question of what, if any, obligation the surgeon and hospital system have to the patient when informing her of a broken needle and the intraoperative decision-making process that led to its staying in place. When such a situation occurs, which is very uncommon, should an intraoperative x-ray be performed to assess the location of the needle tip? Should the patient automatically be brought back to the OR for removal?

The surgeon’s concern was a legitimate one—that additional attempts at removal could lead to complications far worse than having a small segment of a needle left in place. After all, shrapnel, bullets, etc, remain lodged in various locations throughout the body without subsequent ill effects. He did discuss with the patient the fact that a needle segment was left in the muscle wall. But how do you assess postoperative pelvic pain in a patient who had preoperative chronic pelvic pain? These are questions we as clinicians ask. Clearly, there are no black-and-white answers, and we will call upon our legal consultants for their expertise in addressing these queries.

From the gynecologic perspective, however, it is of paramount importance to address the patient’s postoperative vaginal pain and determine the best management approach. In this case the TOT, and its association with a 21.5% complication rate, including reported vaginal extrusion, introduces a whole new set of concerns.¹ The TOT use in itself raises the question of liability on the part of the surgeon. This mesh has more than 150 associated complications, including obturator nerve injuries, extensive blood loss, and ischiorectal fossa abscesses.² Once a device comes upon the radar screen of the US Food and Drug Administration for ­signi­ficant complications, where does that leave the clinician in regard to litigation? Let’s look to our legal colleagues for their insight and expertise.

Legal considerations
Given the facts in this case, it is not surprising that it resulted in a defense verdict. The majority of cases filed are ultimately disposed of in favor of the medical defendants, and the majority of medical malpractice cases that go to trial result in defense verdicts.

Medical malpractice, or “professional negligence,” consists of a claim that a medical professional had a duty of care to the patient, a breach of that duty, injury to the patient, and a causal connection (“causation”) between the breach of duty and the injury. It is the obligation of the plaintiff to prove the elements of negligence by a preponderance of the evidence.

Were the surgeon’s actions in line with other surgeons’ expected actions? The issue of the breach of the duty of care essentially is the question of whether the physician acted similarly to a reasonably careful practitioner of the same specialty under the same circumstances. Doctors are not held to a standard of perfection. That is, not every injury or bad outcome is negligence—only those injuries that result from actions, or inactions, that were not within the level of care acceptable in the profession.

Why would this patient file a lawsuit? The injury was not trivial (it had both pain and cost associated with it), but it was not catastrophic, and the negligence was going to be difficult to prove. Furthermore, lawsuits are expensive in terms of time, energy, and emotional commitment—few people file them for the fun of it. We can only speculate on the answer to the question but, frequently, such claims are a search for the answer to “What happened, and why?” or a reaction to feeling ignored or disrespected. There is little in the case facts that we have to work with to indicate what the communication was between the gynecologist and the patient and her family. The statement of facts, however, leaves the impression that communication deteriorated as the postoperative pain endured.

Some additional areas of potential claims for liability in this case include:

What factors could have tipped the case toward the defense?
The defense verdict indicates that the jury determined there was no negligence, or that the patient could not prove any of these potential bases of liability. As noted above, what may have helped the defense is the fact that the surgeon documented the details of the informed consent conversation, including that “discussion was carried out regarding” the tape. The informed consent process is an important opportunity for communication with the patient, and a chance to make sure that expectations are reasonable. Liability for the failure of informed consent is not common. When something has gone wrong, however, it can matter whether the problem was something mentioned in the informed consent process. In addition, it was positive that postoperatively the patient was informed of the broken needle—although it is not clear who informed her about it.

A couple of other legal issues are worth noting. From our fact scenario we do not know what was documented in the incident report filed by the circulating nurse and reviewed by the surgical committee. We also do not know whether the plaintiff was privy to the incident report document. The surgical committee is likely a peer-review committee, and most states provide some privilege for such committees (to avoid disclosure of committee information for discovery or at trial). The deliberations and conclusions of the committee, therefore, were likely privileged. However, incident reports are frequently used for other purposes, such as administrative reports, that are not privileged—so the incident report often is determined to be discoverable depending on the interpretation of the state’s law.

No winner in this case
Despite the defense verdict, the physician was not really the “winner” after having spent a great deal of time, energy, money, and emotion defending this suit. Ultimately, the goal is not to win malpractice cases but to avoid them—in this case, among other things, by being frank with patients about expectations, keeping an open line of communication with patients when they are concerned with an outcome that is less than ideal, and referring a patient when it may be appropriate.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE: Lost needle tip
A 36-year-old woman (G3 P2012) with stress urinary incontinence (SUI) and abnormal uterine bleeding presented to a gynecologist. She had explored medical therapy for her SUI with no symptom improvement. She had a previous tubal ligation, and the gynecologist ordered urodynamic testing, the results of which led to a discussion of vaginal hysterectomy; anterior, posterior colporrhaphy; and mesh placement. It was felt that the patient had a number of risk factors for incontinence (including pregnancy with vaginal delivery, well-controlled diabetes mellitus, and obesity). She had a long-standing history of chronic pelvic pain, with an established diagnosis of diverticulosis with episodes of diverticulitis in the past.

The gynecologist had the patient keep a bladder diary for 1 week. When asked, the patient reported no problems with sexual dysfunction, stating that her quality of life was “fine” except for the vaginal bleeding and loss of urine refractory to medical therapy. The Urogenital Distress Inventory was administered, and it identified frequent urination, leakage, and incontinence related to activities. An Incontinence Impact Questionnaire also was administered. Physical examination included cotton-tipped swab urethral, or Q-tip, test and cough stress test as part of POP-Q (Pelvic Organ Prolapse Quantification system) evaluation. Urinary tract infection was ruled out. The gynecologist counseled the patient about possible medical therapies for urinary incontinence, and she requested definitive surgery.

The gynecologist obtained informed consent for surgery that included preoperative discussion of potential surgical complications, including bleeding, infection, trauma to surrounding structures, and the possibility of additional surgical procedures secondary to complications. The gynecologist also discussed transvaginal tape versus transobturator tape (TOT) placement, including potential complications and sequelae. The final planned procedure, which was performed by the gynecologist, included vaginal hysterectomy, anterior colporrhaphy, and TOT placement.

Intraoperatively, the patient was identified (upon entering the operating room [OR]); time-out occurred, and the gynecologist proceeded with surgery. During the procedure, the tip of a needle broke off. The gynecologist noted the broken tip as he removed the needle and handed it to the surgical technician. The gynecologist palpated the sidewall in the presumed area of the needle tip and felt it easily. He attempted to remove the tip, but his effort was fruitless. He made the intraoperative decision to leave the tip in situ. A needle and sponge count was performed, reported as correct, and it was felt there was no indication for imaging of the pelvis. The circulating nurse filled out an incident report immediately following the surgery, noting the missing needle tip. The occurrence was discussed by the surgical committee at the hospital.

Postoperatively, while the patient was in the hospital, she was informed of the intra-operative incident.

Three months later, the patient reported vaginal and pelvic pain on the sidewall in the area of the lost needle tip, with radiating pain down the involved extremity. A segment of the TOT was noted to be protruding into the vagina, and this was addressed in the OR with “trimming of such.”

Postoperatively, again the patient reported pain on the involved side. She sought the opinion of another gynecologist, who subsequently performed surgical intervention to remove the needle tip. Her symptoms improved.

The patient sued the original gynecologic surgeon, alleging pain and suffering from the surgery involving the lost needle tip.

What’s the verdict?
A defense verdict was awarded.

Medical teaching points
Medical evaluation seemed appropriate. Parity is associated with SUI (but not urge incontinence). In general, urinary incontinence is more commonly associated with a history of lower urinary tract infections. The patient in this case was asked about and evaluated for:

Was information on the broken needle handled appropriately? This case explores the question of what, if any, obligation the surgeon and hospital system have to the patient when informing her of a broken needle and the intraoperative decision-making process that led to its staying in place. When such a situation occurs, which is very uncommon, should an intraoperative x-ray be performed to assess the location of the needle tip? Should the patient automatically be brought back to the OR for removal?

The surgeon’s concern was a legitimate one—that additional attempts at removal could lead to complications far worse than having a small segment of a needle left in place. After all, shrapnel, bullets, etc, remain lodged in various locations throughout the body without subsequent ill effects. He did discuss with the patient the fact that a needle segment was left in the muscle wall. But how do you assess postoperative pelvic pain in a patient who had preoperative chronic pelvic pain? These are questions we as clinicians ask. Clearly, there are no black-and-white answers, and we will call upon our legal consultants for their expertise in addressing these queries.

From the gynecologic perspective, however, it is of paramount importance to address the patient’s postoperative vaginal pain and determine the best management approach. In this case the TOT, and its association with a 21.5% complication rate, including reported vaginal extrusion, introduces a whole new set of concerns.¹ The TOT use in itself raises the question of liability on the part of the surgeon. This mesh has more than 150 associated complications, including obturator nerve injuries, extensive blood loss, and ischiorectal fossa abscesses.² Once a device comes upon the radar screen of the US Food and Drug Administration for ­signi­ficant complications, where does that leave the clinician in regard to litigation? Let’s look to our legal colleagues for their insight and expertise.

Legal considerations
Given the facts in this case, it is not surprising that it resulted in a defense verdict. The majority of cases filed are ultimately disposed of in favor of the medical defendants, and the majority of medical malpractice cases that go to trial result in defense verdicts.

Medical malpractice, or “professional negligence,” consists of a claim that a medical professional had a duty of care to the patient, a breach of that duty, injury to the patient, and a causal connection (“causation”) between the breach of duty and the injury. It is the obligation of the plaintiff to prove the elements of negligence by a preponderance of the evidence.

Were the surgeon’s actions in line with other surgeons’ expected actions? The issue of the breach of the duty of care essentially is the question of whether the physician acted similarly to a reasonably careful practitioner of the same specialty under the same circumstances. Doctors are not held to a standard of perfection. That is, not every injury or bad outcome is negligence—only those injuries that result from actions, or inactions, that were not within the level of care acceptable in the profession.

Why would this patient file a lawsuit? The injury was not trivial (it had both pain and cost associated with it), but it was not catastrophic, and the negligence was going to be difficult to prove. Furthermore, lawsuits are expensive in terms of time, energy, and emotional commitment—few people file them for the fun of it. We can only speculate on the answer to the question but, frequently, such claims are a search for the answer to “What happened, and why?” or a reaction to feeling ignored or disrespected. There is little in the case facts that we have to work with to indicate what the communication was between the gynecologist and the patient and her family. The statement of facts, however, leaves the impression that communication deteriorated as the postoperative pain endured.

Some additional areas of potential claims for liability in this case include:

What factors could have tipped the case toward the defense?
The defense verdict indicates that the jury determined there was no negligence, or that the patient could not prove any of these potential bases of liability. As noted above, what may have helped the defense is the fact that the surgeon documented the details of the informed consent conversation, including that “discussion was carried out regarding” the tape. The informed consent process is an important opportunity for communication with the patient, and a chance to make sure that expectations are reasonable. Liability for the failure of informed consent is not common. When something has gone wrong, however, it can matter whether the problem was something mentioned in the informed consent process. In addition, it was positive that postoperatively the patient was informed of the broken needle—although it is not clear who informed her about it.

A couple of other legal issues are worth noting. From our fact scenario we do not know what was documented in the incident report filed by the circulating nurse and reviewed by the surgical committee. We also do not know whether the plaintiff was privy to the incident report document. The surgical committee is likely a peer-review committee, and most states provide some privilege for such committees (to avoid disclosure of committee information for discovery or at trial). The deliberations and conclusions of the committee, therefore, were likely privileged. However, incident reports are frequently used for other purposes, such as administrative reports, that are not privileged—so the incident report often is determined to be discoverable depending on the interpretation of the state’s law.

No winner in this case
Despite the defense verdict, the physician was not really the “winner” after having spent a great deal of time, energy, money, and emotion defending this suit. Ultimately, the goal is not to win malpractice cases but to avoid them—in this case, among other things, by being frank with patients about expectations, keeping an open line of communication with patients when they are concerned with an outcome that is less than ideal, and referring a patient when it may be appropriate.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Transvaginal mesh not properly placed
In January 2007, polypropylene mesh (Gynecare Prolift Transvaginal Mesh; Ethicon) was inserted in a 57-year-old woman to treat bladder and rectal prolapse. The patient developed small-intestine obstruction, bladder contraction, and a large pelvic abscess. Surgical treatment of the complications included creation of a colostomy. She required daily self-catheterization. The patient died of unrelated causes after the suit was filed.

Estate’S CLAIM The gynecologist did not properly insert the mesh and did not fully inform the patient of possible complications.

PHYSICIAN’S DEFENSE The mesh was properly inserted. The patient developed an unpreventable adverse reaction to the mesh. Proper consent was obtained.

VERDICT A New York defense verdict was returned.

Polypropylene mesh removed due to pain
Polypropylene mesh (Obtryx Transobturator Midurethal Sling system, Boston Scientific Corporation [BSC]) was used to treat a woman’s stress urinary incontinence (SUI) in 2008. Following surgery, the patient reported pain. The mesh was partially removed in 2011. The patient has continuing pain and complications caused by remaining pieces of the mesh that the surgeon believes cannot be removed safely.

PATIENT’S CLAIM Although BSC warned that the material could oxidize and become brittle, the surgeon used it anyway. The mesh eroded through the urethra, causing permanent damage. BSC was negligent in the design, marketing, and instructions for Obtryx.

DEFENDANTS’ DEFENSE The surgeon  read the instructions and felt the product was safe. BSC claimed the mesh is safe for SUI use. Directions for use clearly warn of possible erosion. A BSC engineer admitted that the tissue that surrounds the mesh can shrink, encapsulating nerves and causing chronic pain.

VERDICT A Massachusetts defense verdict was returned.

Abscesses, nerve damage: $73M
A 42-year-old woman reported SUI to her gynecologist. In January 2011, the gynecologist placed polypropylene pelvic mesh (Obtryx Trans-obturator Midurethal Sling system, BSC). Following surgery, the patient reported pain and fever; pelvic abscesses were found.

Multiple procedures partially removed the mesh and treated the infection. During one procedure, her femoral and obturator nerves were damaged; she walks with a limp. Dyspareunia and pain continue. Additional operations will be needed to remove more mesh and treat continuing infection.

PATIENT’S CLAIM BSC was negligent in the product’s design and marketing. Warnings for use were inadequate concerning the nature and extent of possible permanent injuries: groin and pelvic pain, dyspareunia, nerve damage, and chronic urinary tract infections. BSC withheld or concealed clinical trial information and did not perform and report proper post-market surveillance.

When pivotal study results were published in 2009, indicating that further research was needed to confirm that Obtryx was appropriate for treating SUI, the BSC sales department received an email telling them to not share this information with physicians.

At trial, BSC corporate executives knew little about system design and warnings regarding its use. Data that BSC provided to document the safety of Obtryx were not about that product.  

MANUFACTURER’S DEFENSE Both sides agreed not to introduce discussion of the FDA and 510(k) process. BSC blamed a call-center for not passing along complaints from customers in a timely manner.

VERDICT A $73,465,000 Texas verdict was returned against BSC. The jury determined that the manufacturer displayed gross negligence; the design of the Obtryx system is faulty. The award included $50 million for exemplary damages, which the judge reduced to $11.2 million due to state caps, for a total award of $34.6 million.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Transvaginal mesh not properly placed
In January 2007, polypropylene mesh (Gynecare Prolift Transvaginal Mesh; Ethicon) was inserted in a 57-year-old woman to treat bladder and rectal prolapse. The patient developed small-intestine obstruction, bladder contraction, and a large pelvic abscess. Surgical treatment of the complications included creation of a colostomy. She required daily self-catheterization. The patient died of unrelated causes after the suit was filed.

Estate’S CLAIM The gynecologist did not properly insert the mesh and did not fully inform the patient of possible complications.

PHYSICIAN’S DEFENSE The mesh was properly inserted. The patient developed an unpreventable adverse reaction to the mesh. Proper consent was obtained.

VERDICT A New York defense verdict was returned.

Polypropylene mesh removed due to pain
Polypropylene mesh (Obtryx Transobturator Midurethal Sling system, Boston Scientific Corporation [BSC]) was used to treat a woman’s stress urinary incontinence (SUI) in 2008. Following surgery, the patient reported pain. The mesh was partially removed in 2011. The patient has continuing pain and complications caused by remaining pieces of the mesh that the surgeon believes cannot be removed safely.

PATIENT’S CLAIM Although BSC warned that the material could oxidize and become brittle, the surgeon used it anyway. The mesh eroded through the urethra, causing permanent damage. BSC was negligent in the design, marketing, and instructions for Obtryx.

DEFENDANTS’ DEFENSE The surgeon  read the instructions and felt the product was safe. BSC claimed the mesh is safe for SUI use. Directions for use clearly warn of possible erosion. A BSC engineer admitted that the tissue that surrounds the mesh can shrink, encapsulating nerves and causing chronic pain.

VERDICT A Massachusetts defense verdict was returned.

Abscesses, nerve damage: $73M
A 42-year-old woman reported SUI to her gynecologist. In January 2011, the gynecologist placed polypropylene pelvic mesh (Obtryx Trans-obturator Midurethal Sling system, BSC). Following surgery, the patient reported pain and fever; pelvic abscesses were found.

Multiple procedures partially removed the mesh and treated the infection. During one procedure, her femoral and obturator nerves were damaged; she walks with a limp. Dyspareunia and pain continue. Additional operations will be needed to remove more mesh and treat continuing infection.

PATIENT’S CLAIM BSC was negligent in the product’s design and marketing. Warnings for use were inadequate concerning the nature and extent of possible permanent injuries: groin and pelvic pain, dyspareunia, nerve damage, and chronic urinary tract infections. BSC withheld or concealed clinical trial information and did not perform and report proper post-market surveillance.

When pivotal study results were published in 2009, indicating that further research was needed to confirm that Obtryx was appropriate for treating SUI, the BSC sales department received an email telling them to not share this information with physicians.

At trial, BSC corporate executives knew little about system design and warnings regarding its use. Data that BSC provided to document the safety of Obtryx were not about that product.  

MANUFACTURER’S DEFENSE Both sides agreed not to introduce discussion of the FDA and 510(k) process. BSC blamed a call-center for not passing along complaints from customers in a timely manner.

VERDICT A $73,465,000 Texas verdict was returned against BSC. The jury determined that the manufacturer displayed gross negligence; the design of the Obtryx system is faulty. The award included $50 million for exemplary damages, which the judge reduced to $11.2 million due to state caps, for a total award of $34.6 million.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Transvaginal mesh not properly placed
In January 2007, polypropylene mesh (Gynecare Prolift Transvaginal Mesh; Ethicon) was inserted in a 57-year-old woman to treat bladder and rectal prolapse. The patient developed small-intestine obstruction, bladder contraction, and a large pelvic abscess. Surgical treatment of the complications included creation of a colostomy. She required daily self-catheterization. The patient died of unrelated causes after the suit was filed.

Estate’S CLAIM The gynecologist did not properly insert the mesh and did not fully inform the patient of possible complications.

PHYSICIAN’S DEFENSE The mesh was properly inserted. The patient developed an unpreventable adverse reaction to the mesh. Proper consent was obtained.

VERDICT A New York defense verdict was returned.

Polypropylene mesh removed due to pain
Polypropylene mesh (Obtryx Transobturator Midurethal Sling system, Boston Scientific Corporation [BSC]) was used to treat a woman’s stress urinary incontinence (SUI) in 2008. Following surgery, the patient reported pain. The mesh was partially removed in 2011. The patient has continuing pain and complications caused by remaining pieces of the mesh that the surgeon believes cannot be removed safely.

PATIENT’S CLAIM Although BSC warned that the material could oxidize and become brittle, the surgeon used it anyway. The mesh eroded through the urethra, causing permanent damage. BSC was negligent in the design, marketing, and instructions for Obtryx.

DEFENDANTS’ DEFENSE The surgeon  read the instructions and felt the product was safe. BSC claimed the mesh is safe for SUI use. Directions for use clearly warn of possible erosion. A BSC engineer admitted that the tissue that surrounds the mesh can shrink, encapsulating nerves and causing chronic pain.

VERDICT A Massachusetts defense verdict was returned.

Abscesses, nerve damage: $73M
A 42-year-old woman reported SUI to her gynecologist. In January 2011, the gynecologist placed polypropylene pelvic mesh (Obtryx Trans-obturator Midurethal Sling system, BSC). Following surgery, the patient reported pain and fever; pelvic abscesses were found.

Multiple procedures partially removed the mesh and treated the infection. During one procedure, her femoral and obturator nerves were damaged; she walks with a limp. Dyspareunia and pain continue. Additional operations will be needed to remove more mesh and treat continuing infection.

PATIENT’S CLAIM BSC was negligent in the product’s design and marketing. Warnings for use were inadequate concerning the nature and extent of possible permanent injuries: groin and pelvic pain, dyspareunia, nerve damage, and chronic urinary tract infections. BSC withheld or concealed clinical trial information and did not perform and report proper post-market surveillance.

When pivotal study results were published in 2009, indicating that further research was needed to confirm that Obtryx was appropriate for treating SUI, the BSC sales department received an email telling them to not share this information with physicians.

At trial, BSC corporate executives knew little about system design and warnings regarding its use. Data that BSC provided to document the safety of Obtryx were not about that product.  

MANUFACTURER’S DEFENSE Both sides agreed not to introduce discussion of the FDA and 510(k) process. BSC blamed a call-center for not passing along complaints from customers in a timely manner.

VERDICT A $73,465,000 Texas verdict was returned against BSC. The jury determined that the manufacturer displayed gross negligence; the design of the Obtryx system is faulty. The award included $50 million for exemplary damages, which the judge reduced to $11.2 million due to state caps, for a total award of $34.6 million.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

Stroke is one of the most feared medical conditions, with the specter of suddenly finding oneself unable to talk, eat, walk, or live independently, according to study results.

In mid-February, results from three trials reported at the International Stroke Conference in Nashville, Tenn., changed the face of ischemic stroke treatment by proving that emergency endovascular catheterization to remove the embolus blocking cerebral blood flow produced better long-term outcomes than standard treatment with intravenous thrombolysis.

Courtesy American Heart Association

It wasn’t just that patients did better with endovascular embolectomy; it was how much they did better. In the two trials run in the United States and abroad, SWIFT PRIME and ESCAPE, the percentage of patients rated as not disabled (a modified Rankin Scale score of 0-1) when assessed after 90 days was 36% and 42% for patients treated with endovascular therapy in the two studies, compared with 17% and 19% in the two control arms. Embolectomy boosted the fraction of patients having the best stroke outcomes more than twofold, a breathtaking leap in efficacy.

Dr. Jeffrey L. Saver from UCLA, lead investigator for SWIFT PRIME, called it a “once-in-a-field” result, meaning that never again will stroke clinicians see this degree of incremental improvement by adding a new intervention.

The frustrating irony is how challenging delivery of this disease-altering treatment will be on a national scale. One problem is that it didn’t result from a single change in treatment, but from a careful mix of new diagnostic techniques with sophisticated CT imaging, new systems for expediting diagnosis, triage, transport, and treatment, in combination with new technology in the form of emboli-retrieving stents.

Stroke management specialists see a daunting series of issues to tackle as they attempt to roll out emergency endovascular interventions on a routine scale throughout much of the United States. Many more centers must open, modeled on the ones that succeeded in the trials. The centers need to be rationally positioned so they are close to patients but also give each center enough case volume to foster high interventional-skill levels. Staffing must be found for fast-moving stroke response teams that can make the diagnostics and interventions available around the clock and interpret the images to select appropriate patients. Ambulance systems have to be set up that take likely stroke patients to the centers that will best meet their treatment needs.

The stroke and public health communities will need to invest a lot of time, money, and leadership to make this happen, but it’s a clear mandate, given the promise endovascular treatment now holds to blunt the impact of one of medicine’s most feared maladies.

[email protected]


On Twitter @mitchelzoler

To the Editor: Recently, Drs. Zimmerman and Pantalone¹ cited the Diabetes Control and Complications Trial (DCCT)² and the United Kingdom Prospective Diabetes Study (UKPDS)³ as evidence that glycemic control lowers cardiac risk in type 2 diabetes. And in a related counterpoint article, Drs. Menon and Aggarwal⁴ also discussed the UKPDS.

These studies should not be cited in this context, since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available. The UKPDS was launched in 1977 and completed in 1997, and statins were not available until 1987. Indeed, the UKPDS showed that the strongest risk factor for myocardial infarction was an elevated level of low-density lipoprotein cholesterol, followed by a low level of high-density lipoprotein cholesterol.⁵ It is therefore not surprising that in the initial UKPDS report the incidence of myocardial infarction was not increased in the group with a 0.9% higher hemoglobin A_1c, but that in the 10-year follow-up, when statins were probably used by most patients, myocardial infarction was reduced by a significant 15% (P = .01).^3,6 As would be expected in the more modern studies, ie, the Action to Control Cardiovascular Risk (ACCORD),⁷ the Action in Diabetes and Vascular Disease (ADVANCE),⁸ and the Veteran Affairs Diabetes Trial (VADT),⁹ cardiovascular events were not reduced with improved glycemic control.

While the UKPDS clearly demonstrated a decrease in microvascular disease due to improved glycemic control, it should not be used as evidence that improved glycemic control in type 2 diabetes decreases cardiac events.^3,6

To the Editor: Recently, Drs. Zimmerman and Pantalone¹ cited the Diabetes Control and Complications Trial (DCCT)² and the United Kingdom Prospective Diabetes Study (UKPDS)³ as evidence that glycemic control lowers cardiac risk in type 2 diabetes. And in a related counterpoint article, Drs. Menon and Aggarwal⁴ also discussed the UKPDS.

These studies should not be cited in this context, since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available. The UKPDS was launched in 1977 and completed in 1997, and statins were not available until 1987. Indeed, the UKPDS showed that the strongest risk factor for myocardial infarction was an elevated level of low-density lipoprotein cholesterol, followed by a low level of high-density lipoprotein cholesterol.⁵ It is therefore not surprising that in the initial UKPDS report the incidence of myocardial infarction was not increased in the group with a 0.9% higher hemoglobin A_1c, but that in the 10-year follow-up, when statins were probably used by most patients, myocardial infarction was reduced by a significant 15% (P = .01).^3,6 As would be expected in the more modern studies, ie, the Action to Control Cardiovascular Risk (ACCORD),⁷ the Action in Diabetes and Vascular Disease (ADVANCE),⁸ and the Veteran Affairs Diabetes Trial (VADT),⁹ cardiovascular events were not reduced with improved glycemic control.

While the UKPDS clearly demonstrated a decrease in microvascular disease due to improved glycemic control, it should not be used as evidence that improved glycemic control in type 2 diabetes decreases cardiac events.^3,6

To the Editor: Recently, Drs. Zimmerman and Pantalone¹ cited the Diabetes Control and Complications Trial (DCCT)² and the United Kingdom Prospective Diabetes Study (UKPDS)³ as evidence that glycemic control lowers cardiac risk in type 2 diabetes. And in a related counterpoint article, Drs. Menon and Aggarwal⁴ also discussed the UKPDS.

These studies should not be cited in this context, since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available. The UKPDS was launched in 1977 and completed in 1997, and statins were not available until 1987. Indeed, the UKPDS showed that the strongest risk factor for myocardial infarction was an elevated level of low-density lipoprotein cholesterol, followed by a low level of high-density lipoprotein cholesterol.⁵ It is therefore not surprising that in the initial UKPDS report the incidence of myocardial infarction was not increased in the group with a 0.9% higher hemoglobin A_1c, but that in the 10-year follow-up, when statins were probably used by most patients, myocardial infarction was reduced by a significant 15% (P = .01).^3,6 As would be expected in the more modern studies, ie, the Action to Control Cardiovascular Risk (ACCORD),⁷ the Action in Diabetes and Vascular Disease (ADVANCE),⁸ and the Veteran Affairs Diabetes Trial (VADT),⁹ cardiovascular events were not reduced with improved glycemic control.

While the UKPDS clearly demonstrated a decrease in microvascular disease due to improved glycemic control, it should not be used as evidence that improved glycemic control in type 2 diabetes decreases cardiac events.^3,6

In Reply: We appreciate Dr. Bell’s interest in and comments regarding our recent article. Dr. Bell contends that the DCCT¹ and UKPDS² studies should not be cited since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available.

While we can appreciate his point of view, we disagree with his interpretation of the available data. These studies, and their respective observational follow-up reports,^3,4 provide evidence that early intervention may reduce cardiovascular risk, and that our approach to examining cardiovascular risk reduction in high-risk cardiovascular patients, as in ACCORD,⁵ ADVANCE,⁶ and VADT,⁷ may be short-sighted. There is an important difference between reducing long-term cardiovascular risk by treating younger and healthier patients with diabetes (type 1 or type 2) early in the disease course, before the development of complications (including cardiovascular disease), as was the case in DCCT and UKPDS, vs treating older patients with diabetes who have established cardiovascular disease or who have numerous risk factors substantially increasing their cardiovascular risk, as in ACCORD, ADVANCE, and VADT.

To his second point, that the UKPDS did not demonstrate cardiovascular risk reduction until after the 10-year follow-up when statins were probably utilized by the vast majority of patients, there would not have been a difference in cardiac events between treatment and control groups during this observational period if the statins were the cause of the reduced rate of cardiac events. The control and treatment groups would have had the same reduction in events. That was not the case. The finding of a lower risk of myocardial infarction at the completion of the follow-up period, despite ubiquitous statin use by both the treatment and control groups during this 10-year period, suggests another variable—ie, that the early differences in glycemic control achieved between the treatment and control groups during the UKPDS was responsible for the observed reduction in the risk of myocardial infarction.

In Reply: We appreciate Dr. Bell’s interest in and comments regarding our recent article. Dr. Bell contends that the DCCT¹ and UKPDS² studies should not be cited since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available.

While we can appreciate his point of view, we disagree with his interpretation of the available data. These studies, and their respective observational follow-up reports,^3,4 provide evidence that early intervention may reduce cardiovascular risk, and that our approach to examining cardiovascular risk reduction in high-risk cardiovascular patients, as in ACCORD,⁵ ADVANCE,⁶ and VADT,⁷ may be short-sighted. There is an important difference between reducing long-term cardiovascular risk by treating younger and healthier patients with diabetes (type 1 or type 2) early in the disease course, before the development of complications (including cardiovascular disease), as was the case in DCCT and UKPDS, vs treating older patients with diabetes who have established cardiovascular disease or who have numerous risk factors substantially increasing their cardiovascular risk, as in ACCORD, ADVANCE, and VADT.

To his second point, that the UKPDS did not demonstrate cardiovascular risk reduction until after the 10-year follow-up when statins were probably utilized by the vast majority of patients, there would not have been a difference in cardiac events between treatment and control groups during this observational period if the statins were the cause of the reduced rate of cardiac events. The control and treatment groups would have had the same reduction in events. That was not the case. The finding of a lower risk of myocardial infarction at the completion of the follow-up period, despite ubiquitous statin use by both the treatment and control groups during this 10-year period, suggests another variable—ie, that the early differences in glycemic control achieved between the treatment and control groups during the UKPDS was responsible for the observed reduction in the risk of myocardial infarction.

In Reply: We appreciate Dr. Bell’s interest in and comments regarding our recent article. Dr. Bell contends that the DCCT¹ and UKPDS² studies should not be cited since the DCCT is a study of type 1 and not type 2 diabetic patients, and the UKPDS was performed in an era when statins were not available.

While we can appreciate his point of view, we disagree with his interpretation of the available data. These studies, and their respective observational follow-up reports,^3,4 provide evidence that early intervention may reduce cardiovascular risk, and that our approach to examining cardiovascular risk reduction in high-risk cardiovascular patients, as in ACCORD,⁵ ADVANCE,⁶ and VADT,⁷ may be short-sighted. There is an important difference between reducing long-term cardiovascular risk by treating younger and healthier patients with diabetes (type 1 or type 2) early in the disease course, before the development of complications (including cardiovascular disease), as was the case in DCCT and UKPDS, vs treating older patients with diabetes who have established cardiovascular disease or who have numerous risk factors substantially increasing their cardiovascular risk, as in ACCORD, ADVANCE, and VADT.

To his second point, that the UKPDS did not demonstrate cardiovascular risk reduction until after the 10-year follow-up when statins were probably utilized by the vast majority of patients, there would not have been a difference in cardiac events between treatment and control groups during this observational period if the statins were the cause of the reduced rate of cardiac events. The control and treatment groups would have had the same reduction in events. That was not the case. The finding of a lower risk of myocardial infarction at the completion of the follow-up period, despite ubiquitous statin use by both the treatment and control groups during this 10-year period, suggests another variable—ie, that the early differences in glycemic control achieved between the treatment and control groups during the UKPDS was responsible for the observed reduction in the risk of myocardial infarction.

Edited by: Arthur T. Skarin, MD, FACP, FCCP

Ovarian cancer is the second most common gynecologic cancer among women in the United States. It is also the fifth leading cause of cancer mortality in women and the leading cause of death among women with gynecologic malignancies. The American Cancer Society statistics released in 2015 estimate that 21,290 new cases of ovarian cancer will occur during the year, with approximately 14,180 deaths. Globally, there were 238,719 new cases of ovarian cancer diagnosed in 2012, representing 3.6% of all cancers in women, and nearly 151,905 deaths. The highest incidence of ovarian cancer occurs in northern, central, and eastern Europe, followed by western Europe and North America, with the lowest incidence in parts of Africa and Asia. The majority of women presenting with ovarian cancer will present at an advanced stage, and the 5-year survival in this group is less than 30%.

To read the full article in PDF:

Click here

Edited by: Arthur T. Skarin, MD, FACP, FCCP

Ovarian cancer is the second most common gynecologic cancer among women in the United States. It is also the fifth leading cause of cancer mortality in women and the leading cause of death among women with gynecologic malignancies. The American Cancer Society statistics released in 2015 estimate that 21,290 new cases of ovarian cancer will occur during the year, with approximately 14,180 deaths. Globally, there were 238,719 new cases of ovarian cancer diagnosed in 2012, representing 3.6% of all cancers in women, and nearly 151,905 deaths. The highest incidence of ovarian cancer occurs in northern, central, and eastern Europe, followed by western Europe and North America, with the lowest incidence in parts of Africa and Asia. The majority of women presenting with ovarian cancer will present at an advanced stage, and the 5-year survival in this group is less than 30%.

To read the full article in PDF:

Click here

Edited by: Arthur T. Skarin, MD, FACP, FCCP

Ovarian cancer is the second most common gynecologic cancer among women in the United States. It is also the fifth leading cause of cancer mortality in women and the leading cause of death among women with gynecologic malignancies. The American Cancer Society statistics released in 2015 estimate that 21,290 new cases of ovarian cancer will occur during the year, with approximately 14,180 deaths. Globally, there were 238,719 new cases of ovarian cancer diagnosed in 2012, representing 3.6% of all cancers in women, and nearly 151,905 deaths. The highest incidence of ovarian cancer occurs in northern, central, and eastern Europe, followed by western Europe and North America, with the lowest incidence in parts of Africa and Asia. The majority of women presenting with ovarian cancer will present at an advanced stage, and the 5-year survival in this group is less than 30%.

To read the full article in PDF:

Click here

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons

Source: American Gastroenterological Association

Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.

To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).

Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.

Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.

Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.

Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.

The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.

High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons

Source: American Gastroenterological Association

Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.

To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).

Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.

Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.

Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.

Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.

The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.

High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.

The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons

Source: American Gastroenterological Association

Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.

To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).

Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.

Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.

Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.

Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.

The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.

Anemia occurs in more than half of patients with cancer and is associated with worse performance status, quality of life, and survival. Anemia is often attributed to the effects of chemotherapy; however, a 2004 European Cancer Anemia Survey reported that 39% of patients with cancer were anemic prior to starting chemotherapy and the incidence of anemia may be as high as 90% in patients on chemotherapy. The pathogenesis of cancer-related anemia is multifactorial; it can be a direct result of cancer invading the bone marrow, or result from the effects of radiation, chemotherapy-induced anemia, chronic renal disease, and cancer-related inflammation leading to functional iron deficiency anemia.

To read the full article in PDF:

Click here

Anemia occurs in more than half of patients with cancer and is associated with worse performance status, quality of life, and survival. Anemia is often attributed to the effects of chemotherapy; however, a 2004 European Cancer Anemia Survey reported that 39% of patients with cancer were anemic prior to starting chemotherapy and the incidence of anemia may be as high as 90% in patients on chemotherapy. The pathogenesis of cancer-related anemia is multifactorial; it can be a direct result of cancer invading the bone marrow, or result from the effects of radiation, chemotherapy-induced anemia, chronic renal disease, and cancer-related inflammation leading to functional iron deficiency anemia.

To read the full article in PDF:

Click here

Anemia occurs in more than half of patients with cancer and is associated with worse performance status, quality of life, and survival. Anemia is often attributed to the effects of chemotherapy; however, a 2004 European Cancer Anemia Survey reported that 39% of patients with cancer were anemic prior to starting chemotherapy and the incidence of anemia may be as high as 90% in patients on chemotherapy. The pathogenesis of cancer-related anemia is multifactorial; it can be a direct result of cancer invading the bone marrow, or result from the effects of radiation, chemotherapy-induced anemia, chronic renal disease, and cancer-related inflammation leading to functional iron deficiency anemia.

To read the full article in PDF:

Click here

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.