Treatment of aneurysmal subarachnoid hemorrhage Authors Robert J Singer, MD Christopher S Ogilvy, MD Guy Rordorf, MD Section Editor Jose Biller, MD, FACP, FAAN, FAHA Deputy Editor John F Dashe, MD, PhD

Last literature review version 16.3: September 2008 | This topic last updated: October 14, 2008 (More)

INTRODUCTION — Subarachnoid hemorrhage (SAH) is often a devastating event. Approximately 10 percent of patients die prior to reaching the hospital while only one-third will have a "good result" after treatment [1] . Therapeutic advances have added to the armamentarium for treating this malignant process.

The treatment of SAH is reviewed here. Other aspects of this illness are discussed separately. (See "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage" and see "Unruptured intracranial aneurysms").

GRADING AND PROGNOSIS — The appropriate therapy for subarachnoid hemorrhage (SAH) depends in part upon the severity of hemorrhage. The most important prognostic factors for SAH include [2,3] : Level of consciousness and neurologic grade on admission Patient age (inverse correlation) Amount of blood on initial head computed tomography (CT) scan (inverse correlation)

Additional prognostic factors that contribute to unfavorable outcome after SAH include cerebral infarction, fever, and symptomatic vasospasm [3] . Mounting evidence suggests that anemia and/or red blood cell transfusions are also associated with worse outcome [4,5] .

A number of grading systems are used in practice to standardize the clinical classification of patients with SAH based upon the initial neurologic examination. The grading system proposed by Hunt and Hess (show table 1) and that of the World Federation of Neurological Surgeons (WFNS) (show table 2) are among the most widely used. The WFNS system incorporates the Glasgow Coma scale (show table 3) combined with the presence of motor deficit.

The Fisher grade is an index of vasospasm risk based upon a CT-defined hemorrhage pattern (show table 4), and the Claassen grading system is a similar index of the risk of delayed cerebral ischemia due to vasospasm (show table 5).

A system proposed by Ogilvy and Carter stratifies patients based upon age, Hunt and Hess grade, Fisher grade, and aneurysm size (show table 6). In addition to predicting outcome, this scale more accurately substratifies patients for therapy.

Grading scales for subarachnoid hemorrhage are discussed in greater detail separately. (See "Subarachnoid hemorrhage grading scales").

GENERAL MANAGEMENT — A patient presenting with aneurysmal subarachnoid hemorrhage (SAH) is admitted to an intensive care setting for constant hemodynamic monitoring. Patients are given stool softeners, kept at bedrest, and given analgesia to diminish hemodynamic fluctuations and lower the risk of rebleeding. Transcranial Doppler (TCD) ultrasonography measurements are taken and used as a baseline as the patient progresses through treatment; serial TCD is used to monitor for vasospasm. The institution of measures to prevent and treat vasospasm is of major importance. (See "Nimodipine" below, see "Prevention of vasospasm" below and see "Treatment of vasospasm" below).

Deep venous thrombosis (DVT) prophylaxis with pneumatic compression stockings is started prior to aneurysm treatment [6] . Subcutaneous unfractionated heparin 5000 IU three times daily can be added for DVT prophylaxis once the aneurysm is treated.

Antithrombotic discontinuation — Although there are few data, most experts favor reversal of all anticoagulation for acute SAH until the aneurysm is definitively repaired by surgery or coiling [7-9] .

Guidelines from the American Heart Association/American Stroke Association issued in 2006 recommend that all anticoagulants and antiplatelet agents should be discontinued after SAH [9] . In addition, the guidelines recommend that any anticoagulant effect should be reversed immediately with appropriate agents such as vitamin K, fresh frozen plasma, or unactivated prothrombin complex concentrate, which is also called factor IX complex (show table 7 and show table 8). The therapeutic approach to clinically significant bleeding in patients treated with warfarin is discussed in detail elsewhere. (See "Correcting excess anticoagulation after warfarin", section on Significant or life-threatening bleeding).

As noted above, subcutaneous unfractionated heparin can be added for DVT prophylaxis once the aneurysm is treated.

Intracranial pressure and blood pressure — Patients with SAH often develop increased intracranial pressure (ICP) that is usually due to acute hydrocephalus and reactive hyperemia after hemorrhage. (See "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage", section on Increased ICP).

With increased ICP, cerebral perfusion may be impaired. Cerebral perfusion pressure (CPP) equals the mean arterial pressure (MAP) minus the ICP. Thus, increases in MAP may be the only means to maintain CPP at a level necessary to maintain perfusion. On the other hand, elevated blood pressure can worsen a SAH since the mechanical force across the plugged bleeding site is related to the difference between the systemic blood pressure and the cerebrospinal fluid (CSF) pressure.

The optimal therapy of hypertension in SAH is not clear. While lowering blood pressure may decrease the risk of rebleeding, this benefit may be offset by an increased risk of infarction. The importance of these factors was illustrated in a report of 134 patients with subarachnoid hemorrhage, 80 of whom received antihypertensive therapy to lower the diastolic pressure below 100 mmHg [10] . The patients given antihypertensive therapy had a lower incidence of rebleeding (15 versus 33 percent) that was offset by a higher incidence of infarction (43 versus 22 percent).

We generally place a ventriculostomy in appropriate patients; this allows direct measurement of intracranial pressure and often drops systemic blood pressure into the normal range. In the absence of ICP measurement, antihypertensive therapy is often withheld unless there is a severe elevation in blood pressure because of concern about cerebral ischemia and the frequent compensatory nature of acute hypertension [11] . The patients cognitive status may be a useful guide; if the patient is alert, then CPP is adequate, and lowering the blood pressure may decrease the risk of rerupture; we typically keep the systolic blood pressure in such patients below 140 mmHg. In contrast, antihypertensive therapy is generally withheld in those with a severely impaired level of consciousness since the impairment may be due to a reduced CPP.

When blood pressure control is necessary, the use of vasodilators such as nitroprusside or nitroglycerin should be avoided because of their propensity to increase cerebral blood volume and therefore intracranial pressure. Labetalol is preferred.

Nimodipine — The calcium channel blocker nimodipine was initially used in patients with SAH to prevent vasospasm. (See "Prevention of vasospasm" below). However, despite the vasodilatory effects of nimodipine on cerebral vessels, there is no convincing evidence that nimodipine affects the incidence of either angiographic or symptomatic vasospasm [12-17] . Nevertheless, nimodipine has been demonstrated to improve outcomes in SAH and is the standard of care in these patients [12-15,18-20] .

A meta-analysis of seven randomized trials of prophylactic nimodipine administered for SAH noted the following benefits [16] : Nimodipine treatment compared with placebo improved the odds of a good outcome after SAH by 1.86 (99% CI 1.07-3.25). Nimodipine reduced the odds of deficit, mortality, or both attributed to vasospasm by 0.46, and it reduced the infarction rate on CT by 0.58 (99% CI 0.38-0.90). Overall mortality was slightly reduced in the nimodipine group, but the trend was not statistically significant. The treatment effect of nimodipine in individual trials was positively correlated with the severity of SAH.

A 1998 systematic review found that nimodipine treatment compared with placebo was associated with a 24 percent relative risk reduction of poor outcome (95% CI 12-38) [17] . The number needed to treat (NNT) with nimodipine to prevent one poor outcome was 13 (95% CI 8-30). A similar conclusion was reached by a 2007 meta-analysis of calcium antagonists for aneurysmal SAH [21] , where the benefits of calcium antagonists depended largely on one large trial of nimodipine [15] .

Nimodipine is marketed as a cerebral selective drug. Nevertheless, blood pressure fluctuations are common after administration. Thus, blood pressure monitoring is essential to avoid hypotension and decreased cerebral perfusion pressure. Nimodipine can also temporarily reduce brain tissue pO2 in patients with poor grade SAH [22] , although the clinical importance of this property is unknown.

The mechanism of benefit of nimodipine in SAH is unknown. Putative mechanisms include neuroprotection via reduction of calcium-dependent excitotoxicity, diminished platelet aggregation, dilation of small arteries not visible on angiograms, inhibition of ischemia triggered by red blood cell products, or some combination of these actions.

Nimodipine is ideally administered within four days of SAH. The typical dose is 60 mg every four hours by mouth or nasogastric tube. Nimodipine must be given orally; inadvertent intravenous administration has been associated with serious adverse events, including death.

Physiologic derangements — Physiologic derangements occur frequently in the acute phase of SAH and might worsen the diffuse brain injury. A cohort study of 413 patients identified four variables that were independently associated with increased risk of death or disability three months after SAH [23] : Hypoxemia (arterio-alveolar gradient >125 mmHg) Metabolic acidosis (serum bicarbonate <20 mmol/L) Hyperglycemia (serum glucose >180 mg/dL [10 mmol/L]) Cardiovascular instability (MAP of <70 or >130 mmHg)

Other studies have also found that hyperglycemia is associated with poor outcome after SAH [24-26] . In addition, SAH appears to be a risk factor for infectious and noninfectious fever, which in turn is associated with poor outcome [27,28] .

Correction of these physiologic derangements in patients with SAH is suggested [6] , although no studies have confirmed the benefit of such treatments.

Seizure prophylaxis — The use of antiepileptic drugs (AEDs) to prevent seizures in patients with SAH has been a widely debated topic [29] . Many experts believe that seizure prophylaxis in the setting of an unsecured aneurysm is reasonable, given the relatively low risk associated with AED administration versus the potential deleterious effects of seizures on an already dysautoregulated brain [2,30] . However, evidence from a large case series suggests that AED exposure may be associated with worse neurologic and cognitive outcome after SAH [31] . Therefore, the use of AEDs for seizure prophylaxis after SAH should probably be minimized whenever possible.

The decision to treat with antiepileptic agents can be based upon the distribution of blood on axial imaging studies. A lower impetus to start antiepileptic agents is warranted in the setting of perimesencephalic blood without cortical layering, since this pattern of hemorrhage is associated with a particularly good prognosis. (See "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage").

Continuation of AED therapy may not be necessary in most patients after undergoing aneurysmal clipping following a SAH, especially those without acute seizures who present with a good grade (see "Antiepileptic drug therapy" below).

Antifibrinolytic therapy — Antifibrinolytic agents have been investigated in aneurysmal SAH. A meta-analysis of nine trials concluded that although antifibrinolytic treatment reduces the risk of rebleeding (odds ratio [OR] 0.55, 95% CI 0.42-0.71), it does not show any evidence of reducing poor outcome defined as death, vegetative state, or severe disability (OR 1.12, 95% CI 0.88-1.43) [32] . In earlier trials this lack of overall benefit appeared to be due to an increased risk of cerebral ischemia in patients treated with antifibrinolytic agents.

A subsequent randomized trial (included in the above meta-analysis) treated all patients with nimodipine and hypervolemia to try to prevent ischemia and found that although treatment with the antifibrinolytic agent tranexamic acid in this setting did not increase cerebral ischemia, there was still no reduction in poor outcome compared with placebo [33] . This suggests that recovery from cerebral ischemia may have been impaired by antifibrinolytic therapy [32] . There has been some discussion at meetings about acute, ultra-short use of antifibrinolytics, but there is not any substantial supportive data at this time.

Glucocorticoid therapy — Glucocorticoid therapy for cerebral injury remains controversial. There is some justification for using glucocorticoids in the setting of SAH because of their putative effects on cerebral edema, prevention of vasospasm, and delayed hydrocephalus [30] . However, limited evidence from available clinical trials supports neither a beneficial nor adverse effect of glucocorticoids for the treatment of aneurysmal SAH [34] .

PREVENTION OF VASOSPASM — Clinically significant vasospasm occurs in approximately 20 to 30 percent of patients with aneurysmal SAH, and it is thought to be related to spasmogenic substances generated during the lysis of subarachnoid blood clots [35] . It typically begins no earlier than day three after hemorrhage, reaching a peak at days seven to eight. (See "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage", section on Vasospasm).

Vasospasm is manifested clinically by a decline in neurologic status including the onset of focal neurologic abnormalities. It is the leading cause of death and disability after aneurysm rupture [35] . Treatment of vasospasm can be difficult (see "Treatment of vasospasm" below). Thus, prevention is important.

Hyperdynamic therapy — Following aneurysmal occlusion, hyperdynamic therapy, including modest hemodilution, induced hypertension (with pressor agents such as phenylephrine or dopamine), and hypervolemia (so-called "triple-H" therapy), has been used to try to prevent vasospasm. A systematic review of triple-H therapy for prophylaxis of vasospasm found that there were few well-designed prospective studies [36] ; the reviewers concluded that despite wide confidence intervals, the results from two studies did suggest some benefit of triple-H therapy on symptomatic vasospasm and mortality.

A subsequent analysis identified only one truly randomized trial and one quasi-randomized trial of volume expansion therapy in patients with aneurysmal SAH [37] . Both trials were small, and no beneficial effect of volume expansion was found.

Surgical approaches — Other methods to prevent vasospasm may be used at the time of surgery in patients with SAH. In one study, 28 patients who underwent surgery within 72 hours of the onset of severe SAH received a cisternal infusion of urokinase after aneurysm clipping in an effort to diminish clot size [38] . No symptomatic vasospasm occurred in any patients, and the treatment was safe. A randomized trial of intrathecal urokinase infusion into the cisterna magna in patients with SAH who had been treated with coil embolization also showed a significant decrease in symptomatic vasospasm and a lower rate of permanent neurologic deficits but had no impact on mortality [39] . Early cisternal cerebrospinal fluid (CSF) washout during the operative repair may reduce the incidence of vasospasm and hydrocephalus [40] . CSF irrigation cannot be performed with endovascular therapy. However, the incidence of symptomatic vasospasm appears to be similar after treatment with surgery or coiling, despite the inability to perform CSF irrigation with coiling [41] .

Statins — The pleiotropic effects of statin therapy appear promising for vasospasm prevention, based upon the potential to improve cerebral vasomotor reactivity by upregulating endothelial nitric oxide synthase, increase cerebral blood flow, and attenuate vasculopathy [42-45] .

Findings from at least three small randomized placebo-controlled trials suggest that statin treatment is beneficial for preventing vasospasm and improving outcome after SAH [46-48] . These trials randomly assigned patients to either statin (pravastatin 40 mg daily or simvastatin 80 mg daily) or placebo within 48 to 96 hours after aneurysmal SAH; treatment was continued for 14 to 21 days. A meta-analysis of these trials included a total of 158 patients; only three were receiving statins prior to SAH. Most patients received concurrent nimodipine. The following statistically significant observations were reported [49] : Compared with placebo, statin treatment reduced the incidence of radiologically confirmed clinical vasospasm (relative risk [RR] 0.73, 95% CI 0.54-0.99) Statin treatment reduced the incidence of delayed ischemic deficits (RR 0.38, 95% CI 0.17-0.83) Statin treatment reduced mortality (RR 0.22, 95% CI 0.06-0.82)

The strength of the meta-analysis is limited by small numbers of patients and events. In addition, the included studies used different definitions of vasospasm, and the statistical test of heterogeneity for the primary outcome (incidence of vasospasm) was significant, suggesting that it may not be appropriate to combine the included studies for this outcome.

Thus, larger placebo-controlled trials are still needed to confirm that statin treatment is effective therapy for SAH. Nevertheless, given the available data suggesting benefit and the relative safety of statins, we suggest initiating statin treatment within 48 hours of aneurysmal SAH and continuing until discharge from intensive care. In addition, we suggest continuing statin therapy after SAH for patients who were taking statins prior to SAH.

Investigational approaches — A number of agents are under investigation for the prevention of vasospasm after SAH, including endothelin receptor antagonists, magnesium sulfate, nicardipine prolonged-release implants, and statins. Endothelin (ET) receptor antagonists - Endothelin 1 (ET1) is a 21 amino acid peptide that acts as a direct and potent vasoconstrictor [50,51] . The action of ET1 is mediated mainly through two major endothelin receptors, ET-A and ET-B. ET-A receptors are located on vascular smooth muscle cells where they mediate both vasoconstriction and smooth muscle cell proliferation. In comparison, ET-B receptors are found primarily on vascular endothelial cells and mediate vasodilation via the release of endothelium-derived nitric oxide. ET-B receptors are also located on vascular smooth muscle cells where they mediate vasoconstriction.

The investigational drug clazosentan is a specific ET receptor antagonist that has a much higher affinity for the ET-A than the ET-B receptors [52,53] . Clazosentan therefore potently inhibits the ET-A receptor-mediated vasoconstriction effect of ET1 and minimally inhibits the ET-B receptor-mediated vasodilation.

Clazosentan appears promising for the prevention of vasospasm associated with SAH. In a small phase II randomized controlled trial of patients with severe aneurysmal SAH, clazosentan treatment was associated with a significantly reduced incidence of angiographically evident vasospasm compared with placebo (6 of 15 versus 15 of 17 patients [40 versus 88 percent]) [54] . Larger trials are needed to confirm the effectiveness of clazosentan for vasospasm prevention and to determine whether it is effective for improving clinical outcome. Magnesium sulfate therapy has been proposed as a means to prevent vasospasm based upon its efficacy in preventing neurologic complications in pregnant women with eclampsia. A small study of 40 patients with SAH found a trend toward improved outcomes in patients treated with magnesium compared with controls [55] , and a subsequent randomized controlled trial involving 283 patients with SAH found a reduced risk of delayed cerebral ischemia in those assigned to magnesium [56] , but these differences were not statistically significant and require further evaluation. Nicardipine prolonged-release implants (NPRIs) are polymers that are loaded with nicardipine and implanted into the basal cisterns, in contact with the large arteries of the circle of Willis, thus permitting local delivery of constant high doses of nicardipine to the intracranial vessels. In a preliminary randomized controlled trial, implantation of NPRIs was associated with a significant reduction in angiographic vasospasm, and improved clinical outcome [57] .

TREATMENT OF ANEURYSMS — Surgery has been the mainstay of therapy of intracranial aneurysms, although endovascular techniques are becoming more widely used. In the future, gene therapy combined with endovascular techniques may offer improved results for aneurysm treatment [58] .

Surgery — Surgical management of cerebral aneurysms is an effective and safe procedure with the evolution of microsurgical techniques in the hands of an experienced surgeon. Placement of a clip across the neck of the aneurysm remains the treatment of choice for most aneurysms (show radiograph 1).

Temporary vessel occlusion using cerebroprotective techniques such as hypothermia, induced hypertension, and mannitol, has greatly facilitated safe dissection near the aneurysm [59] . Temporary clip occlusion may be achieved via traditional extraluminal clip placement or with an intravascular balloon. Intraoperative angiography is a useful diagnostic adjunct to micro Doppler sonography in confirming parent vessel patency after clip occlusion.

A protocol employing immediate ventriculostomy placement, aneurysm clipping (if intracranial pressure was less than or equal to 30 mmHg without an intracranial clot or less than or equal to 50 mmHg in the presence of a clot), and aggressive postoperative hypertensive, hypervolemic, and hemodilutional therapy was evaluated in 35 patients with poor-grade aneurysmal SAH [60] . The outcome was reported as good in 19 patients (54 percent), fair in 4 (11 percent), and poor in 4 (11 percent); eight patients (23 percent) died. In contrast, 19 poor-grade patients who received no surgical treatment survived a mean of 32 hours with 100 percent mortality. This aggressive approach to therapy in patients with poor grade aneurysmal SAH was supported in another report [61] . It should be emphasized, however, that the data available reflects the experience of large cerebrovascular centers with abundant experience and support for the management of this exceedingly tenuous patient population.

Operative risks associated with aneurysm treatment include new or worsened neurologic deficits caused by brain retraction, temporary arterial occlusion, and intraoperative hemorrhage [62-64] . Procedure-related surgical complications occurred in 29 (20 percent) of 143 patients in a retrospective series [65] , although functional outcome was good in 22 (76 percent) of those patients. Treatment at specialized neurosurgical centers performing high volumes of cerebral aneurysm procedures is associated with better outcome compared with treatment at lower volume centers [66] .

Hypothermia — Despite laboratory evidence of benefit [59] and widespread use in clinical practice, intraoperative hypothermia does not appear to improve neurologic outcome after surgery for intracranial aneurysm clipping. A randomized clinical trial of 1001 patients with "good grade" SAH found no benefit on any outcome measure for patients randomly assigned to intraoperative hypothermia compared with those assigned to normothermia [67] .

Endovascular therapy — Advances in biopolymers and image chain devices have allowed the intraluminal approach to cerebral aneurysms to emerge as a safe and often effective alternative to surgical clipping. The Guglielmi electrolytically detachable coil system was introduced in the early 1990s for the treatment of these lesions [68] . The platinum coil is inserted into the lumen of the aneurysm (show radiograph 2). A local thrombus then forms around the coils, obliterating the aneurysmal sac [69] . Aneurysms with broad necks, a low neck-to-fundus ratio, distal segment lesions, and a number of giant aneurysms are not amenable to endovascular therapy [70] ; surgical therapy is preferred in these circumstances.

Endovascular therapy compares favorably to surgery in selected patients [71,72] . As an example, a prospective, randomized study of 109 patients with acute (less than 72 hours)

subarachnoid hemorrhage due to a ruptured aneurysm found that significantly better primary angiographic results occurred after surgery in patients with anterior cerebral artery aneurysm, but after endovascular therapy in patients with posterior circulation aneurysm [73] . Technique related mortality was lower in the endovascular therapy group (2 versus 4 percent). There was no difference in clinical outcome at three months between the two groups.

Another prospective study found that clinical and neuropsychological outcomes were similar at one year in patients treated within 72 hours of an acute subarachnoid hemorrhage with either surgery or endovascular therapy; most aneurysms in both groups were in the anterior and middle cerebral artery circulations [74] .

The use of coils will undoubtedly rise as the number of experienced interventionalists increases. Some have argued that coiling will gradually replace surgical clipping for nearly all aneurysmal treatment as the endovascular technology advances and that this transition has already occurred to a large extent in the United Kingdom [75] . Questions remain, however, regarding the long-term efficacy of intraluminal occlusions. Most follow-up studies to this point are in the range of a few years; complete aneurysm obliteration rates are generally cited to be 80 percent or greater.

Intraprocedural aneurysm rupture — Aneurysm rupture during surgical clipping or endovascular coil embolization is associated with an increased risk of poor outcome. The largest reported experience comes from the CARAT study cohort of 1010 patients with aneurysmal SAH who were treated with surgical clipping (n = 711) or coil embolization (n = 299) at high-volume centers in the United States [76] . The following observations were reported: Overall, intraprocedural rupture occurred in 148 patients (15 percent). There was a significantly higher risk of periprocedural death or disability in those with intraprocedural rupture compared with those without this complication (34 versus 17 percent). The risk of periprocedural death or disability associated with intraprocedural rupture was nonsignificantly higher for surgical clipping compared with endovascular coiling (5.8 versus 3.3 percent), even though intraprocedural rupture was significantly more frequent in those treated with clipping than in those treated with coiling (19 versus 5 percent). However, this was tempered by a lesser impact of this complication in patients who had clipping. The risk of periprocedural death or disability with clipping, comparing patients who had intraprocedural rupture to those without, was 31 versus 18 percent. The corresponding risk with coiling was 63 versus 15 percent.

Timing and choice of therapy — The timing of surgery following intracranial aneurysm rupture is an area of controversy. The potential benefits of early surgery (within 48 to 72 hours of the hemorrhage) include prevention of rebleeding and management of vasospasm. The usual methods of treating vasospasm (hypervolemia, induced hypertension, intraarterial papaverine, and balloon angioplasty) are dangerous in the presence of an untreated aneurysm. (See "Early rebleeding" below and see "Treatment of vasospasm" below).

On the other hand, early surgery may be more technically challenging than delaying the procedure for 10 to 14 days due to the presence of edema (which may prevent brain

retraction and relaxation) and clot around the aneurysm. In addition, early surgery may be associated with an increased risk of ischemic complications [77] .

Early aneurysm repair in patients with good grade aneurysms (Hunt and Hess grades 1 to 3) (show table 1) is a generally accepted treatment with a satisfying outcome in the large majority of patients. Approximately 70 to 90 percent of patients have a good neurologic recovery, with a mortality rate of 1.7 percent to 8 percent [78] . Limited clinical trial evidence suggests that early aneurysm surgery may be associated with a lower risk of rebleeding and better outcome than later surgery, but the results did not achieve statistical significance [79] .

A subset of patients with good grade aneurysms may do well, or even better, with endovascular coiling. In the International Subarachnoid Aneurysm Trial (ISAT), 2143 patients with ruptured intracranial aneurysms were randomly assigned to neurosurgical clipping or endovascular coiling [80,81] . Significantly fewer patients undergoing coiling were dependent or dead at one year compared with patients undergoing surgical clipping (23.5 versus 30.9 percent), with an absolute risk reduction of 7.4 percent (95% CI 3.6-11.2) favoring coiling. The main difference between the two treatment groups was in the category of "significant restriction in lifestyle," not in mortality [82] . Mortality rates at one year among patients assigned to endovascular and neurosurgical treatment were 8.0 percent (95% CI 6.4-9.8) and 9.9 percent (95% CI 8.2-11.9), respectively [81] .

The risk of post-treatment seizures was significantly lower in the endovascular group compared with the neurosurgery group (relative risk 0.52, 95% CI 0.37-0.74) [81] . Post-treatment rebleeding from the target aneurysm was more common in the endovascular therapy group than the surgical group during the first year (2.6 versus 1.0 percent). Few rebleeding events occurred in either treatment group after one year. (See "Late rebleeding" below).

The patients randomized in ISAT represented a selected subgroup in which 88 percent were of good clinical status, 90 percent of the target aneurysms were smaller than 10 mm in diameter, and 95 percent of aneurysms were in the anterior circulation [81] ; the results can only be applied to patients that fit these general characteristics, which is a small percentage of patients presenting with SAH [80] . Nevertheless, for such patients, endovascular coiling should be considered if expertise to perform the procedure is available on an emergency basis.

Early surgery in patients with Hunt and Hess grades IV and V aneurysms is difficult due to excessive cerebral edema, and the outlook for these patients has traditionally been dismal. Endovascular techniques also may offer a less invasive and often definitive mode of therapy for this group; the concerns regarding the increased difficulty of early surgery do not apply to intraluminal therapy. Although not substantiated by any large series, the use of intravascular embolization of aneurysms in the acute setting may facilitate aggressive medical management algorithms for proactive treatment of cerebral vasospasm (see "Treatment of vasospasm" below). Definitive surgical clipping can be performed later if the aneurysm is not completely obliterated.

Posttreatment management — Patients are managed in the intensive care unit after aneurysm therapy. Continuous cardiodynamic and neurologic monitoring is critical. Postoperative angiography is used at the surgeons discretion. Aggressive physical, occupational, and, when necessary, speech therapy evaluations should be obtained as soon as possible in order to assess long-term physical and cognitive requirements.

MANAGEMENT OF COMPLICATIONS — Prevention of complications is an important aspect of SAH management [6] . However, complications still occur and must be treated.

Treatment of vasospasm — Nimodipine treatment reduces poor outcome associated with vasospasm in a significant number of patients (see "Prevention of vasospasm" above). However, aggressive therapy is often necessary when symptomatic vasospasm occurs.

An important prognostic distinction must be made between angiographic vasospasm, which is seen in 30 to 70 percent of angiograms performed at day seven after SAH, and clinical or symptomatic vasospasm, which is seen in 20 to 30 percent of patients [35] : Symptomatic vasospasm portends a poorer prognosis and may not be identifiable on cerebral angiography; microperforator spasm defies the resolution of even state-of-the-art angiography. Isolated angiographic vasospasm traditionally has not been treated. However, it is increasingly being used to identify patients who might benefit from therapies such as intraluminal papaverine, a smooth muscle relaxant, or angioplasty.

Aggressive therapy of vasospasm can only be pursued after the aneurysm has been treated with surgery or intraluminal therapy. Following aneurysmal occlusion, hyperdynamic therapy, including modest hemodilution, induced hypertension (with pressor agents such as phenylephrine or dopamine), and hypervolemia (so-called "triple-H" therapy), is instituted in an effort to raise the mean arterial pressure and thereby increase cerebral perfusion. Volume expansion is achieved via crystalloid or colloid solution dependent upon physician preference.

Refractory vasospasm — Vasospasm that persists despite triple-H therapy has been treated successfully in some cases by percutaneous intraarterial angioplasty [83] or by the administration of vasodilators including intraarterial (IA) papaverine [84,85] , IA nicardipine [86] , IA nimodipine [87] , and intrathecal nitroprusside [88] . Intraarterial papaverine and angioplasty also may be used in combination [85] . In one series of 15 patients, intraarterial papaverine reversed arterial narrowing in 78 percent of cases, although major clinical improvement only occurred in 26 percent [84] . A study of angioplasty found dramatic, moderate, and minimal or nonexistent clinical improvement after 12, 11, and 9 procedures, respectively [83] . Intrathecal nitroprusside administered by intraventricular or subdural catheter or by direct intraoperative suffusion was effective in five of six patients who had cerebral vasospasm that was refractory to conventional treatment in one report [88] .

Despite a lack of clinical trial evidence, balloon angioplasty has become the mainstay of treatment at many centers for symptomatic vasospasm that is refractory to aggressive medical therapy, particularly for focal vasospasm of larger vessels [89] . Diffuse vasospasm

involving smaller arterial branches may be more amenable to IA infusion of vasodilators, such as papaverine, verapamil, nicardipine, or nimodipine.

Cervical sympathetic block at the level of the superior cervical ganglion was studied in nine patients, six of whom were conscious prior to the procedure [90] . The six conscious patients all had complete resolution of symptoms; two of the three comatose patients had transient improvements, but all three eventually died.

Hydrocephalus — Hydrocephalus after SAH is thought to be caused by obstruction of cerebrospinal fluid (CSF) flow by blood products or adhesions, or by a reduction of CSF absorption at the arachnoid granulations. (See "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage", section on Hydrocephalus). Although data are scant, surgical and endovascular treatments appear to be associated with comparable risks of developing shunt-dependent hydrocephalus [91] .

Ventricular drain placement can improve the clinical grade of patients presenting with SAH. Drainage should be considered for patients who have a deteriorating level of consciousness and for those in whom no improvement in hydrocephalus occurs within 24 hours [92] . External drainage of CSF is often complicated by ventriculitis, particularly when drainage is continued for more than three days [93] . Although earlier reports suggested that the frequency of rebleeding was increased with external ventricular drainage for acute hydrocephalus after aneurysmal SAH [93,94] , these studies had methodologic limitations [95] , and later reports have found no association of external drainage with the risk of rebleeding [96] .

The need for long term CSF diversion can be assessed on a subacute basis after appropriate treatment of the aneurysm. (See "Evaluation and management of elevated intracranial pressure in adults").

Hyponatremia — Hyponatremia following SAH may be due to inappropriate secretion of antidiuretic hormone (SIADH) or to cerebral salt-wasting. (See "Cerebral salt-wasting").

SIADH and cerebral salt-wasting are physiologically different and require divergent treatment algorithms. Both disorders are associated with water retention due to the presence of ADH. The distinction between the two is usually made by an assessment of intravascular volume status. Cerebral salt-wasting is characterized by volume depletion, which leads to the release of ADH. It is usually treated with infusions of isotonic saline since the restoration of euvolemia will suppress the release of ADH and allow the excess water to be excreted. (See "Cerebral salt-wasting"). In comparison, patients with SIADH are euvolemic; therapy of asymptomatic hyponatremia in this disorder usually consists of water restriction. However, fluid restriction is not desirable in patients with SAH. Thus, the hyponatremia is treated with isotonic saline, which may lower the plasma sodium concentration in some patients, or, if necessary, hypertonic saline. (See "Hyperdynamic therapy" above and see "Treatment of hyponatremia: SIADH and reset osmostat", section on Salt administration).

Early rebleeding — Rebleeding is associated with a poor prognosis. In a prospective study involving 574 hospitalized patients admitted within 14 days of SAH, rebleeding was associated with a 12-fold reduction in the probability of survival with functional independence at three months (odds ratio 0.08, 95% CI 0.02-0.34) after correction for admission Hunt-Hess grade and aneurysm size [97] .

Various strategies short of surgery have been attempted to decrease the risk of rebleeding following SAH, including induced hypotension and antifibrinolytic therapy. Both of these strategies have proven unsuccessful [32,98] . Only aneurysm treatment is effective in this regard.

The CARAT study followed over 1000 patients treated with coil embolization or surgical clipping at high-volume centers in the United States for a mean of four years and reported the following observations [99] : Postprocedural aneurysm rerupture occurred in 19 patients at a median time of three days; rerupture led to death in 11 (58 percent) The risk of rerupture was associated with the degree of aneurysm occlusion after treatment in both univariate and multivariate analysis:

      -  In 760 patients with complete aneurysm occlusion, rerupture occurred in 1.1 percent

      -  In 173 patients with 91 to 99 percent aneurysm occlusion, rerupture occurred in 2.9 percent

      -  In 51 patients with 70 to 90 percent occlusion, rerupture occurred in 5.9 percent

      -  In 17 patients with <70 percent occlusion, rerupture occurred in 17.6 percent The risk of rerupture was greater after treatment with coil embolization than with surgical clipping (3.4 versus 1.3 percent), but the difference was not statistically significant after adjustment for confounders (hazard ratio 1.09; 95% CI 0.32-3.69)

These data suggest that complete aneurysm occlusion is the best way to prevent rerupture [99] .

Antiepileptic drug therapy — Antiepileptic drugs are usually continued for approximately six months in patients who have experienced an acute seizure (within seven days) following SAH, although there are no strict guidelines. Agents such as phenytoin, carbamazepine, and phenobarbital are typically used.

The incidence of late epilepsy (more than two weeks after surgery) after surgical management of SAH is unclear. In a retrospective report of 472 patients with aneurysmal SAH who had undergone surgical clipping of the aneurysm between 1994 and 2000 and were followed for at least 12 months, late epilepsy occurred in only 23 (4.9 percent) [100] . Patients presenting with a poor grade had a higher incidence of epilepsy (9.6 and 12.5 percent of those grades 3 and 4, respectively). (See "Grading and prognosis" above).

These findings suggest that antiepileptic drug therapy may not be necessary after aneurysmal clipping following SAH in most patients, particularly in those who present with a good grade and who have not had early seizures. This study excluded patients who had been treated endovascularly and those who had surgery occurring more than 21 days after the bleed.

OUTCOME AFTER TREATMENT — Outcome after treatment of aneurysmal subarachnoid hemorrhage (SAH) is affected by potential brain injury from the SAH and subsequent complications, as well as by risks related to neurosurgery (see "Surgery" above).

Several studies suggest that SAH survivors have high rates of memory, mood, and neurocognitive impairment [1,101-103] . The largest prospective evaluation of neuropsychological function evaluated 873 survivors of SAH [103] . At three months after aneurysmal clipping, global impairment was present in approximately 20 percent of all patients and in 16 percent of those with the best preoperative condition. Detailed neuropsychological testing of patients following surgically treated SAH has commonly shown cognitive deficits, even among patients making an otherwise good neurologic recovery [104] . The importance of these deficits to long-term morbidity is controversial, but they are often permanent [105] . The location of the aneurysm responsible for SAH does not appear to influence cognitive outcome [1] .

Neurocognitive assessments must be utilized in order to compare outcomes of surgical versus intraluminal approaches to therapy. The question arises whether the long-term neurocognitive deficits are the result of the hemorrhage itself, the intervention, or both.

Late rebleeding — Both surgical clipping and endovascular coiling are effective for the prevention of rebleeding, although surgical treatment may have a slightly lower risk of late rebleeding than endovascular coiling. As note above, rebleeding from the target aneurysm in ISAT was uncommon in either treatment group after one year, and the overall difference was not significant [81] .

A later retrospective study of 1010 patients who had surgery (n = 711) or coiling (n = 299) for ruptured saccular aneurysms found no cases of rebleeding in the surgical treatment group after the first year (mean follow-up 4.4 years) and only one case in the coil embolization group (mean follow-up 3.7 years), giving an annual rerupture rate of 0.11 percent for coiling [106] .

Screening for aneurysm recurrence — Patients who have SAH and successful surgical treatment remain at increased risk of recurrence. This observation comes from a retrospective study that followed 752 patients who had aneurysmal SAH, successful clipping of all detected aneurysms, and recovery to an independent state [107] . Over a mean follow-up of eight years, 18 patients had a recurrent SAH, and a total of 19 recurrent aneurysms were found; 14 were at a new location, four were at the surgical clip site, and one was unclassified. The cumulative incidence of recurrent SAH in the first 10 years after the initial SAH was 3.2 percent (95% CI 1.5-4.9). The relative risk of an SAH recurrence in

the first 10 years compared with a healthy cohort matched for age and sex was 22 (95% CI 12-38).

Independent risk factors for recurrent SAH were current smoking (hazard ratio [HR] 6.5, 95% CI 1.7-24.0), young age (HR 0.5 per 10 years, 95% CI 0.3-0.8), and multiple aneurysms at the time of the initial SAH (HR 5.5, 95% CI 2.2-14.1) [107] . Hypertension was an additional important risk factor for aneurysm regrowth or de novo aneurysm formation in another retrospective study [108] .

The long-term outcome of patients after aneurysm clipping was also investigated in a study of 112 patients (140 clipped aneurysms) who had agreed to undergo cerebral angiography a mean of nine years after clipping [109] . Four aneurysm regrowths (3 percent) were detected, and de novo aneurysms were found in nine patients (8 percent). The authors concluded that follow-up angiography may be warranted 9 to 10 years after surgical clipping.

The true incidence of de novo aneurysms after surgical clipping is unclear, partly because data are scarce, and partly because aneurysms may be missed at the time of initial hemorrhage. As an example, a study that used CT angiography (CTA) to screen 495 patients with prior surgical clipping of a ruptured aneurysm found at least one aneurysm at a different location than the clip site in 87 patients (17.6 percent) [110] . Of these 87 patients, the original digital subtraction angiography (DSA) or CTA was available for 51 patients with 62 aneurysms detected on the follow-up screening study, with a mean time to follow-up of 8.1 years (range 4 to 14 years). Comparison of the original and screening studies revealed that 19 of 62 aneurysms (31 percent) were de novo, and 43 (69 percent) were visible in retrospect. Almost a quarter of the aneurysms visible in retrospect had increased in size.

Aneurysm recurrence appears to be more common in patients who undergo endovascular treatment. A study that reanalyzed 2108 patients originally treated in ISAT used late aneurysm retreatment (>3 months after the first endovascular coiling or >1 month after the first neurosurgical clipping) as a surrogate for aneurysm recurrence [111] . Late retreatment after endovascular coiling was significantly more frequent than after clipping (8.6 percent versus 0.9 percent, HR 6.9 [95% CI 3.4-14.1]). The mean time to late retreatment after endovascular coiling was 21 months; risk factors for late retreatment after coiling were younger age, larger lumen size, and incomplete initial occlusion. In a retrospective analysis of 501 aneurysms treated with endovascular coiling in 466 patients, 34 percent of aneurysms had recurrences at a mean of 12 months after treatment, and 21 percent had major recurrences at a mean of 17 months after treatment [112] . Predictors of recurrence included aneurysm size ≥ 10 mm, treatment during the acute phase of rupture, and incomplete initial occlusion. The authors of this study felt that long-term follow-up of aneurysms treated endovascularly was mandatory.

Decision models — Decision models have been used to evaluate the utility of screening for new or recurrent aneurysms after SAH. Two studies from the Netherlands illustrate the potential of this approach: In the first study, it was assumed that patients had obliteration of all aneurysms by surgical clipping or endovascular coiling [113] . The expected quality-

adjusted life years was virtually the same (about 8.3 years) for no screening, screening once at five years, and screening every two years, regardless of the initial type of treatment. Screening prevented new episodes of SAH, but the benefit was offset by the cost of increased morbidity from diagnostic tests and preventive treatment. As an example, with screening every two years after coiling, the expected rate of SAH decreased from 1.9 to 0.5 percent and mortality decreased from 0.9 to 0.6 percent, but the disability rate increased from 0.5 to 1.9 percent. In the second study, 610 patients with SAH were screened with CTA two to 18 years after aneurysm clipping, and the results of screening were used as input for a decision analysis [114] . Screening every five years (compared with no screening) prevented nearly half of the SAH recurrences, but life expectancy increased only marginally, and these benefits were offset by a negative impact on quality of life and by increased costs. Screening became cost-effective but did not increase quality of life in patients when the risks of aneurysm formation and rupture were doubled, and screening was cost-effective and improved quality of life in patients with a 4.5-fold increase in both risks. In addition, screening increased quality of life at acceptable costs in patients with fear for a recurrence.

The investigators concluded that screening all patients with previous SAH is not cost-effective [114] . However, screening can be cost-effective and increase quality of life in patients with a substantially increased risk of both aneurysm formation and rupture. Screening may also be justified in patients with fear for a recurrence.

Recommendations — In the face of limited and conflicting data, it is our opinion that patients who have either surgical or endovascular treatment require comprehensive follow-up for SAH. Extra vigilance is warranted for patients with risk factors for regrowth, such as large aneurysm size, multiple aneurysms, older age, hypertension, and cigarette smoking.

For patients treated with endovascular coiling, we obtain immediate evaluation of the coil mass by angiography during the procedure. Plain skull films typically provide excellent coil visualization and are obtained immediately post procedure. Plain skull film screening is also obtained at two weeks, three months, and six months post procedure. If the plain skull films reveal evidence of aneurysmal recanalization such as coil compaction, loosening, or reorientation, digital subtraction angiography (DSA) is obtained. In addition, we recommend DSA at three months for all patients who have undergone coiling, as angiography remains the gold standard.

For patients treated with surgical clipping of aneurysms, we obtain screening with magnetic resonance angiography (MRA) or CTA at three and six months. Additional angiography is performed only if there are worrisome features on the noninvasive studies.

It should be noted that coil artifacts may interfere with interpretation of CTA in patients treated with coiling, whereas MRA interpretation may be impaired by large artifacts around clipped aneurysms [115,116] . Therefore, CTA is preferred for assessment of patients with clipped aneurysms, and MRA is preferred for patients with coiled aneurysms.

Screening of family members — First-degree relatives of patients with SAH have a three to five-fold increased risk of SAH compared with the general population [117] . It may be

reasonable to screen some family members for the presence of cerebral aneurysm. This issue is discussed in detail separately. (See "Screening for intracranial aneurysm").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Stroke symptoms and diagnosis" and see "Patient information: Hemorrhagic stroke treatment"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.