Medical Care
Although there is a paucity of class A evidence regarding prevention and treatment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), a number of therapeutic strategies have been studied and found to have varying degrees of utility. [13]
Of the management options currently used, the hemodynamic augmentation strategy known as triple-H therapy, which includes hypertension, hemodilution, and hypervolemia, has been an important component. This approach was intended to improve cerebral perfusion by increasing mean arterial pressure (MAP) and reducing blood viscosity. [28]
One study found that approximately 70% of patients with vasospasm experienced improvement in their symptoms after initiation of triple-H therapy. [29] It must be kept in mind, however, that triple-H therapy can have significant complications, such as pulmonary edema and subsequent hypoxemia, which may be detrimental to an at-risk hypoperfused brain. A 2000 study by Lennihan et al found that hypervolemic therapy had no significant advantage over normovolemic therapy with respect to cerebral blood flow after subarachnoid hemorrhage and that the two therapies yielded similar incidences of symptomatic vasospasm. [30]
Increases in MAP alone have been shown to be beneficial to patients with vasospasm, and a number of medications have been investigated and utilized to achieve this goal. [31] Phenylephrine, norepinephrine, and dopamine are the primary pressors employed in this setting. [32, 33] Phenylephrine appears to have the most evidence to support its use; several trials have suggested that is effective in patients with preserved left ventricular function. [34, 35] Other medications, such as vasopressin, may play adjunctive roles to play in management. [36]
Calcium-channel antagonists have been widely investigated for prevention of vasospasm in aSAH. [37] In particular, nimodipine has been shown to improve neurologic outcomes after aSAH, but it does not decrease radiographic vasospasm and does not significantly reduce mortality. [38] Several studies have shown that nicardipine reduces vasospasm as determined by transcranial Doppler (TCD), but no clear improvements in outcome or mortality have been demonstrated. [39]
A myriad of other drugs, including magnesium oxide, antiplatelet agents, anti-inflammatory drugs, statins, and endothelin receptor antagonists, have been studied in attempts to exploit nuances of the many theories of vasospasm physiology, including inflammatory cascade, heme breakdown product–mediated oxidative injury, spreading depolarization, and potassium channel modulation, but there remains a need for data demonstrating clinical outcome benefit. [13, 40, 26, 41]
A review by Solar et al, which included six clinical articles and seven experimental articles using animal models of aSAH, found evidence to suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), especially coxibs, may be more effective than nimodipine in reducing post-aSAH vasospasm while yielding reducted mortality, improved functional outcome, and increased hypoaggregability. [42] The authors noted, however, that at the time of publication, there had been only one randomized, double-blind, placebo-controlled trial showing a tendency toward a better outcome with a lower incidence of vasospasm or mortality.
A retrospective analysis by Jentzsch et al compared milrinone with nimodipine in 30 patients with aneurysmal SAH, angiographically confirmed cerebral vasospasm, and at least one intra-arterial pharmacologic angioplasty. [43] The authors found intra-arterial nimodipine therapy to be superior to milrinone monotherapy. They suggested that nimodipine and milrinone may be used together in a complementary fashion within an escalation scheme (with nimodipine given first, complemented by milrinone in cases of severe vasospasm); they did not recommend milrinone monotherapy.
Shen et al carried out a systematic review and meta-analysis of 13 studies examining the efficacy of statins with respect to cerebral vasospasm, mortality, and DCI in patients with aSAH. [44] The analysis included 776 patients who received statins and 821 who received placebo. Statin administration significantly reduced the frequency of vasospasm, delayed ischemic neurological deficit (DIND), vasospasm-DCI, and mortality but had insignificant efficacy in the prevention of disability, a neurologic poor prognosis, and creatine kinase/alanine aminotransferase/aspartate aminotransferase elevation.
In contrast to nimodipine, the endothelin receptor antagonist clazosentan was found to reduce angiographic spasm but to have no effect on outcome, as noted in the CONSCIOUS trials. [45, 46]
Nimodipine has been recommended as first-line medical treatment for preventing post-aSAH cerebral vasospasm. It is usually given orally at a dosage of 60 mg every 4 hours for 21 days after the initial subarachnoid hemorrhage. [13] Maintenance of euvolemia and normal circulating blood volume is recommended to prevent vasospasm. [13] In symptomatic vasospasm, induction of hypertension is recommended to achieve increased cerebral blood flow. [13] Hypervolemia is no longer recommended as a measure to prevent vasospasm. [13] (See Guidelines.)
In a meta-analysis of five studies that included a total of 543 patients with aSAH, Saber et al found cilostazol, a selective inhibitor of phosphodiesterase 3, to be associated with decreased risks of symptomatic vasospasm, cerebral infarction, and poor outcome. [47] A large multicenter trial would be needed to confirm this association.
Surgical Care
More invasive means of treatment of vasospasm depend on the utilization of cerebral angiography. The most commonly employed methods have been the following:
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Intra-arterial vasodilator administration
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Balloon angioplasty
Papaverine was one of the drugs initially tried for intra-arterial injection, but it fell out of favor because of (1) the lack of evidence for its efficacy and (2) the possibility of serious side effects, including paradoxical vasospasm. Several studies suggested that intra-arterial verapamil may provide a benefit in terms of neurologic outcome but that the benefit may not be obtained via vasodilation. [41]
A retrospective study by Chen et al (N = 116) compared intra-arterial infusion of a single vasodilator (nicardipine or verapamil; n = 47) with intra-arterial infusion of a combination of nitroglycerin, verapamil, and nicardipine (n = 69) in patients with aSAH and cerebral vasospasm. [48] The multiple-agent regimen resulted in a 24.36% improvement in vessel diameter as compared with single-agent therapy and was associated with better functional outcome at discharge and at 90-day follow-up.
Angioplasty is an accepted modality for refractory vasospasm, [49] though there remains a need for more good-quality clinical data demonstrating its efficacy. Prophylactic angioplasty has not been demonstrated to yield any significant improvements in outcome. [50]
Guidelines have recommended intra-arterial vasodilator therapy and balloon angioplasty as reasonable treatment modalities in symptomatic patients who are not responding to hypertensive therapy. [13] (See Guidelines and Table 1 below.)
Table 1. Recommendations for Endovascular Treatment of Cerebral Vasospasm (Open Table in a new window)
| Degree of Radiographic Vasospasm | Clinical Findings |
|
|---|---|---|
| Asymptomatic | Symptomatic | |
| Mild | No intervention | Vasodilation (rare) |
| Moderate | Vasodilation | Vasodilation ± balloon angioplasty |
| Severe | Vasodilation ± balloon angioplasty (rare) | Vasodilation + balloon angioplasty |
A more recently developed approach to endovascular therapy for vasospasm involves mechanical dilation of vessels without obstruction of blood flow—for example, with the Comaneci device. [51, 52] In February 2022, this device received a US Food and Drug Administration breakthough designation for treatment of cerebral vasospasm after hemorrhagic stroke.
Prevention
Prevention of vasospasm after severe aSAH is challenging, in that vasospasm represents a natural progression of this disease process. Use of nimodipine continues to be recommended as a means to improve neurologic outcomes after aSAH, though it has not been shown to exert this effect by decreasing the incidence of vasospasm. [13]
Historically, strategies for preventing vasospasm emphasized triple-H therapy (hypervolemia, hemodilution, and hypertension). Systematic reviews of the literature have demonstrated that studies examining triple-H therapy have mostly been of poor design and quality. There is relatively little compelling evidence to supporting the use of triple-H therapy as an effective means of preventing vasospasm. [53, 54]
The American Heart Association (AHA) and the American Stroke Association (ASA) have stated that euvolemia should be the goal after aSAH and that induction of hypertension may be pursued once symptomatic vasospasm has been diagnosed. [13] (See Guidelines.)
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Diagnosis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
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Initial presenting head CT scan showing subarachnoid hemorrhage and blood filling basal cisterns.
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Initial cerebral angiogram from patient with subarachnoid hemorrhage.
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Three-dimensional reconstruction of cerebral angiogram showing anterior communicating artery aneurysm.
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Follow-up head CT scan showing subarachnoid blood.
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Cerebral angiogram obtained on posthemorrhage day 5 in patient symptomatic from vasospasm. Angiogram shows severe narrowing of right anterior cerebral artery.
Tables
| Degree of Radiographic Vasospasm | Clinical Findings |
|
|---|---|---|
| Asymptomatic | Symptomatic | |
| Mild | No intervention | Vasodilation (rare) |
| Moderate | Vasodilation | Vasodilation ± balloon angioplasty |
| Severe | Vasodilation ± balloon angioplasty (rare) | Vasodilation + balloon angioplasty |
