Update of the Pharmacologic Management of Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke associated with significant morbidity and mortality. It is defined by bleeding into the subarachnoid space after the rupture of a cerebral artery aneurysm.1 Aneurysmal SAH accounts for roughly 3% of all strokes and has an incidence of 6 per 100000 persons per year worldwide.1 Despite advances in early diagnosis and improvements in neurocritical care, mortality remains high; the 90-day case-fatality rate is close to 30%.2 Long-term morbidity is significant, with roughly half of patients failing to return to baseline level of functioning and a quarter of patients requiring long-term assistance with activities of daily living.2 Treatment of aneurysmal SAH centers on limiting early rebleeding with subsequent monitoring and pharmacologic management of complications. After initial stabilization, the major complications of aneurysmal SAH include seizures, elevated intracranial pressure, and vasospasm leading to delayed cerebral ischemia.3 The purpose of this article is to describe contemporary pharmacologic strategies used to treat aneurysmal SAH.The hallmark clinical presentation of aneurysmal SAH is a severe, sudden "thunderclap" headache often characterized by patients as "the worst headache of my life." Other features include meningeal inflammation, neck stiffness, photophobia, nausea, and in some cases loss of consciousness.4 Computed tomography of the head is the standard diagnostic tool for patients with suspected aneurysmal SAH and has a sensitivity of nearly 100% in the early hours after aneurysmal rupture.5 For patients in whom a computed tomography scan shows no abnormality but suspicion for aneurysmal SAH is high, a lumbar puncture with cerebral spinal fluid analysis is recommended. Xanthochromia, a yellow discoloration of cerebrospinal fluid that indicates the presence of bilirubin formed from oxyhemoglobin released by red blood cells, is diagnostic for aneurysmal SAH. Once aneurysmal SAH is confirmed, subsequent evaluation to identify the specific location of the aneurysmal rupture is indicated.6 Digital subtraction angiography is the standard vascular imaging method used to identify the affected vessel because it can be used for both diagnosis and treatment to secure the aneurysm with endovascular coiling.2Initial management for aneurysmal SAH is focused on minimizing the risk of rebleeding, which can occur in up to 25% of patients if the aneurysm is left untreated.6 Rebleeding is most likely to occur within the first several hours after aneurysm rupture and is associated with a 20% to 60% mortality rate, so mitigation strategies are critical.7 The primary approach to limit rebleeding is to secure the aneurysm by a surgical (clipping) or endovascular (coiling) procedure. Coiling is generally the preferred method; a randomized trial demonstrated better long-term outcomes with coiling than with clipping.8 Blood pressure management and antifibrinolytic drug administration may also be used to reduce the impact of rebleeding before surgical coiling or clipping of the aneurysm.3Early after aneurysm rupture, acute hypertension is common due to excessive release of catecholamines. Elevations in blood pressure can be detrimental, particularly during the acute phase before the aneurysm is secured. Systolic blood pressures of greater than 160 mm Hg have been associated with higher rates of rebleeding.9 However, no randomized trials currently show a benefit of acute blood pressure lowering. Therefore, pharmacologic treatment of acute hypertension should be done with caution to avoid the risk of hypoperfusion and further complications.9Antifibrinolytics such as tranexamic acid and aminocaproic acid have been used to halt significant bleeding after trauma or surgery. These drugs inhibit the conversion of plasminogen to plasmin, thus reducing hemorrhagic potential. These drugs have been frequently used in patients with aneurysmal SAH before clipping or coiling of the aneurysm to reduce the risk of rebleeding.10 Unfortunately, there is little evidence that these drugs are beneficial in improving outcomes. A recent open-label, multicenter, randomized trial found that tranexamic acid (a 1-g intravenous bolus followed by continuous infusion of 1 g intravenously every 8 hours for a maximum of 24 hours before surgical clipping or coiling) failed to improve outcomes (according to modified Rankin Scale scores) when compared with standard care.11 Although the incidence of thromboembolic complications did not differ between groups in this trial, these drugs should be used with caution given the paucity of data showing any tangible improvement in outcomes after aneurysmal SAH.Early seizures are relatively common, occurring in up to 26% of patients within the first 24 hours after aneurysm rupture.6 Seizures are thought to be detrimental due to a potential increase in cerebral metabolic oxygen demand leading to cerebral hypoperfusion. Therefore, pharmacologic seizure prophylaxis has been advocated to mitigate the potential negative consequences of acute seizures. Phenytoin and levetiracetam are the agents most thoroughly studied for seizure prophylaxis. Phenytoin has been the traditional choice because of its efficacy for reducing seizure incidence in patients with traumatic brain injury.3 Levetiracetam has become a popular option because it tends to be well tolerated, has few drug interactions, and has a simple dosing schedule.12 Unfortunately, the data supporting the use of these agents for seizure prophylaxis following aneurysmal SAH are marginal at best. A meta-analysis of several prospective trials evaluated the effects of seizure prophylaxis on the incidence of in-hospital seizures and clinical outcomes.12 Pharmacologic seizure prophylaxis had a neutral effect on mitigating acute seizures and had a negative effect on clinical outcomes. There was a fair amount of heterogeneity among the trials. Duration of prophylaxis ranged widely, from 3 to 7 days or until the aneurysm was secure or the patient was discharged.12 Given the lack of definitive benefit for seizure prophylaxis, guidelines do not include recommendations for its routine use.3 If prophylaxis is used, a short course (<7 days) is preferable to longer courses of therapy.Other than rebleeding, delayed cerebral ischemia is the most impactful complication associated with aneurysmal SAH. Delayed cerebral ischemia is defined as a new occurrence of a decline in neurologic functioning that lasts more than 1 hour and is not attributable to another cause.13 Delayed cerebral ischemia tends to occur most frequently 3 to 14 days after aneurysmal SAH.13 It has historically been attributed to cerebral vasospasm, which is characterized by narrowing of the large cerebral arteries, leading to downstream reduction in blood flow and potential infarction. However, more recent evidence suggests that vasospasm is unlikely to be the sole contributor to delayed cerebral ischemia. Several different brain injury processes commonly occur during the early brain injury phase after aneurysmal SAH. Inflammation, blood-brain barrier breakdown, microthrombosis, and impaired cerebral autoregulation are all implicated in the development of delayed cerebral ischemia.13Several pharmacologic agents, including calcium channel antagonists, statins, magnesium, and other vasodilating agents, have been evaluated for the prevention of vasospasm after aneurysmal SAH. Of these, nimodipine is the only drug approved by the US Food and Drug Administration for the treatment of vasospasm and represents the mainstay of therapy in patients with aneurysmal SAH. Nimodipine is a cerebral-selective dihydropyridine calcium channel blocker that inhibits calcium influx, causing smooth muscle relaxation. The benefit of nimodipine for treating aneurysmal SAH appears to be distinct from its vasodilatory properties.14 The effect of nimodipine on angiographic vasospasm has been inconsistent in clinical trials. However, meta-analyses have found that patients treated with nimodipine are less likely than those who received placebo to die or experience dependence (relative risk, 0.67; 95% CI, 0.55–0.81).15 The mechanism of this benefit is unclear. However, the decrease in calcium influx may reduce calcium-mediated excitation associated with early brain injury. Nimodipine is available as a 30-mg capsule and as an oral solution. The dose is 60 mg given orally every 6 hours for 21 days; the therapy should be initiated within 96 hours of the aneurysmal SAH. Despite its relative cerebral selectivity, hypotension is the most important adverse event associated with nimodipine. Reducing the dose to 30 mg given every 2 hours has been advocated for patients with hypotension, albeit with little evidence to support the benefit of this strategy.16Beyond nimodipine, few pharmacologic options for reducing the impact of vasospasm exist. The results of small pilot studies were initially promising for both magnesium and statins, but in larger prospective trials both agents were found to be ineffective for improving clinical outcomes.17 In recent years cilostazol has emerged as a possible option. Cilostazol has antiplatelet and vasodilatory effects because of its ability to inhibit phosphodiesterase 3.18 A growing body of evidence suggests that cilostazol reduces the impact of cerebral vasospasm and improves outcomes. A meta-analysis of 5 studies involving 537 patients found a nearly 70% reduction in the incidence of symptomatic vasospasm in patients treated with cilostazol.18 This finding was coupled with a 60% lower rate of poor outcomes, as compared with standard care. These results were supported by those of a more recent publication examining the impact on clinical outcomes of various drug therapies used postoperatively in patients with aneurysmal SAH.19 This large meta-analysis included 44 trials and more than 10000 patients treated with at least 1 of a dozen possible drugs. Of all of the available drugs, only nimodipine and cilostazol significantly improved clinical outcomes.19The classic approach to treating vasospasm has been to use hyperdynamic therapy along with fluids, vasopressors, and inotropic agents. "Triple-H" therapy has been used to theoretically increase cerebral perfusion by raising blood pressure (hypertension and hypervolemia) and to enhance cerebral blood flow by reducing blood viscosity (hemodilution) by administering high volumes of intravenous fluids.14 The evidence for the benefit of this practice is limited. Excessive fluid administration in particular has been associated with pulmonary edema in several studies, so aiming for euvolemia with isotonic solutions is preferred.20 Guidelines do not include strong recommendations for or against blood pressure augmentation using vasopressors or inotropes but state that conducting a trial of induced hypertension (systolic blood pressure goal of 140–240 mm Hg) is reasonable in selected patients who have a reliable clinical examination to assess potential reversal of symptoms of delayed cerebral ischemia.20,21Milrinone is a phosphodiesterase 3 antagonist that has been traditionally reserved for the augmentation of cardiac output in patients with acute heart failure. Since milrinone has both inotropic effects and cerebral vasodilatory properties, its pharmacologic profile is theoretically favorable for the treatment of vasospasm.14 Milrinone has been used in patients with aneurysmal SAH to treat vasospasm or delayed cerebral ischemia via intra-arterial and intravenous routes of administration. However, intravenous administration has produced the most compelling clinical data.3 A recent observational, single-center French trial evaluated the effects of intravenous milrinone plus induced hypertension versus induced hypertension alone (standard care) in 94 patients being treated for vasospasm.22 The study end points included the incidence of functional disability (score of ≥2 on the modified Rankin Scale), vasospasm-related infarction, and the incidence of rescue interventions for vasospasm. Milrinone was infused at rates ranging from 0.5 to 1.5 μg/kg/min for a median of 5 days per patient. The researchers found that after adjusting for covariates, treatment with milrinone was associated with a lower risk of functional disability at 6 months (odds ratio, 0.28; 95% CI, 0.10–0.77) and with a lower chance of vasospasm-related brain infarction (odds ratio, 0.19; 95% CI, 0.04–0.94) when compared with the control group. Furthermore, patients in the milrinone group received significantly fewer angioplasty procedures than those in the control group (15% vs 53%; P=.0001). For 29% of patients in the milrinone group, therapy was discontinued because of poor tolerance to the blood pressure–lowering effects of the drug.22 Nonetheless, milrinone appears to be a promising agent for combatting the negative effects of cerebral vasospasm after aneurysmal SAH.Aneurysmal SAH is a complex and devastating disease associated with significant morbidity. Treatment is focused on preventing early rebleeding and mitigating delayed cerebral ischemia. Nimodipine remains the mainstay of pharmacotherapy to improve outcomes after aneurysmal SAH. A growing body of evidence for medications such as cilostazol and milrinone may help expand the available options to treat patients with cerebral vasospasm and associated ischemic complications.