Pharmacologic Options for Prevention and Management of Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage

Abstract

Background

Cerebral vasospasm and delayed cerebral ischemia continue to be major contributors to morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH).

Purpose

The purpose of this review was to evaluate the pharmacotherapy interventions for the prevention and management of cerebral vasospasm in patients with SAH.

Methods

A search of MEDLINE (January 1966-April 2012) and EMBASE (January 1974-April 2012) was conducted to retrieve relevant studies of pharmacotherapy options for prevention or treatment of cerebral vasospasm in SAH.

Results

Triple-H therapy (hypervolemia, hemodilution, hypertension) has been a widely accepted option by many clinicians for the management of cerebral vasospasm and delayed cerebral ischemia. However, implementation of Triple-H therapy varies considerably at individual institutions. Nimodipine and nicardipine have demonstrated the most dependable improvements in patient outcomes to date. High doses of intravenous magnesium have failed to show consistent benefits. Magnesium supplementation to prevent hypomagnesaemia should be employed. Statin therapy should be continued in patients who are taking statins prior to hospital admission. Use of statins in naive patients may be recommended when the results of an ongoing prospective study are available. Of the available locally administered pharmacologic therapies, nicardipine and thrombolytics appear to provide the most intriguing benefit-to-risk ratio. However, the data supporting the use of locally administered therapy are modest at best and require careful consideration prior to application.

Conclusions

Clinical studies have tested a variety of pharmacotherapy interventions for the prevention and treatment of cerebral vasospasm. Of available therapies, nimodipine has demonstrated consistent benefits and should be employed routinely. Demonstration of reduced cerebral vasospasm and improved neurological outcomes in larger prospective studies are needed for most pharmacologic therapy options prior to recommending their routine use.

Aneurysmal subarachnoid hemorrhage (SAH) is an acute cerebrovascular event that affects approximately 30,000 Americans each year and carries an attributable mortality rate of 40% to 60%.^1–3 Early intervention utilizing coil embolization or microsurgical clip ligation reduces rebleeding risk; however, patients who survive the initial stroke still have continued risk of secondary complications. ⁴ Cerebral vasospasm and delayed cerebral ischemia are 2 of the most common and detrimental problems that can occur in patients who survive beyond 24 hours after SAH. The pathophysiology of cerebral vasospasm is not well understood, and a variety of factors including inflammatory and immunologic mechanisms, free radical production, and alterations in ion channels have been proposed to cause the deregulations in vessel constriction and relaxation. Oxyhemoglobin, a breakdown product of erythrocytes, may be the primary culprit catalyzing many of these pro-vasospasm mechanisms. ⁵ This hypothesis is consistent with the finding that patients with visual amounts of thick blood (Fisher grading scale of 4) in the ventricles or basal cisterns appear to be at the highest risk for cerebral vasospasm. ⁶

Cerebral vasospasm is defined as a decrease in the diameter of the cerebral arteries and may be caused by arterial vasoconstriction, vascular endothelium enlargement, or subendothelial fibrosis. ⁷ The peak incidence of cerebral vasospasm is approximately 5 to 7 days after SAH, with the majority of events occurring between days 3 and 14 following SAH. The occurrence of cerebral vasospasm is a significant event, because it results in decreased cerebral blood flow and oxygen delivery, ultimately causing delayed cerebral ischemia or infarction. If the vasospasm persists and cannot be controlled, further neurological damage and reduced functional outcomes are likely to be observed.^8–10

Due to the significant morbidity and mortality associated with cerebral vasospasm, repeated neurologic assessments with a goal of identifying early clinical symptoms of cerebral vasospasm are obligatory. Further diagnostic escalation should occur in all SAH patients with alterations in their mental status, because identification of new neurological deficits can be a hallmark finding in vasospasm and delayed cerebral ischemia. Angiography is the preferred method for diagnosis of cerebral vasospasm due to its ability to directly visualize the blood vessels. However, noninvasive procedures, such as transcranial Doppler (TCD) ultrasonography, provide a mechanism for bedside surveillance of cerebral blood flow velocity and remain an important tool for evaluating cerebral vasospasm. ¹¹ Confirmation of cerebral vasospasm and/or delayed cerebral ischemia by one of these diagnostic techniques should prompt clinicians to initiate treatment with pharmacologic and/or nonpharmacologic mechanisms. ¹² The purpose of this article is to discuss the pharmacologic options frequently utilized for the prevention and management of cerebral vasospasm in patients with SAH.

Pharmacologic Interventions

Triple-H Therapy (Hypervolemia, Hemodilution, Hypertension)

Hypervolemia

Decreased circulating blood volume has been frequently associated with increased risk of cerebral vasospasm and worse clinical outcomes in patients with SAH. ¹³ Therefore, administration of fluid therapy should help counter this provoking mechanism by increasing intravascular volume and cerebral blood flow. Prophylactic administration of isotonic fluids (eg, 0.9% sodium chloride at ∼80 mL/h) to maintain euvolemia in patients after SAH is recommended. If patients demonstrate signs of cerebral vasospasm despite euvolemia, hypervolemia created by further volume expansion (eg, delivery of 0.9% sodium chloride at 15 mL/kg over 1 hour) may prevent cerebral ischemia by increasing cardiac output and blood pressure. ¹⁴ The addition of 5% or 25% albumin to 0.9% sodium chloride therapy is a frequently employed strategy and will increase serum oncotic pressure and potentially improve microcirculatory blood flow. ¹⁵ Albumin is generally considered safe; however, certain critically ill subpopulations have demonstrated worsening mortality when administered albumin, and further studies are needed in patients with SAH prior to recommending its routine addition to crystalloid therapy. ¹⁶ In patients with poor clinical grade SAH and increased intracranial pressure (ICP), the use of hypertonic saline may provide additional clinical benefits. A single administration of a 0.5 to 2 mL/kg infusion of hypertonic saline 23.4% over 10 to 30 minutes has demonstrated the ability to improve cerebral blood flow and oxygenation for approximately 2 to 4 hours. ¹⁷ When inducing hypervolemia, volume status should be routinely monitored. The use of central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) monitoring may provide additional tools for assessing a patient's volume status. A target CVP of 8 to 12 mm Hg or PAOP of 12 to 18 mm Hg has been utilized in many clinical studies and appears to be reasonable for most patients.^18,19 However, studies evaluating hypervolemic therapy have yet to fully elucidate an optimal fluid administration and monitoring strategy, and variations in practice amongst institutions is common.

Hemodilution

The intentional dilution of blood, via phlebotomy or administration of fluids, theoretically reduces blood viscosity and improves the characteristics of blood flow through the cerebral vasculature. ²⁰ Unfortunately, these effects may be countered by the reduced oxygen-carrying capacity of the hemodiluted blood. Therefore, intentional hemodilution to lower the hemoglobin or hematocrit concentration cannot be routinely recommended for prophylaxis of cerebral vasospasm.

Conversely, administration of packed red blood cells (PRBCs) has been a strategy to improve oxygen delivery to areas of brain ischemia. ²¹ Although little evidence exists to support the use of PRBCs, it has been recommended to maintain a hemoglobin concentration of at least 8 to 10 g/dL in patients with SAH. Some neurointensivists advocate for a hemoglobin ≥10 g/dL in patients with SAH, although the higher transfusion goals are recommended predominately for patients with active cerebral ischemia.^12,22 Unfortunately, transfusion of PRBCs has been associated with significant adverse events, ²³ so more evidence is needed before definitive conclusions on the benefits and risks of therapy can be made.

Hypertension

The use of pharmacologic therapy to increase arterial pressure results in improved cerebral perfusion pressure and cerebral blood flow. Increasing the systolic blood pressure (SBP) by 20 to 60 mm Hg to a typical range of approximately 140 to 190 mm Hg or increasing the mean arterial pressure to >100 to 110 mm Hg has been effective for treating cerebral vasospasm in clinical studies; however, the exact goal target rise in blood pressure has yet to be established. A maximum SBP of 160 mm Hg has been suggested in patients with unsecured aneurysms.^12,24 Dopamine, phenylephrine, and norepinephrine are all effective at increasing blood pressure and are the most commonly utilized vasopressors in clinical practice.^24–26 The addition of arginine vasopressin (at a dose of 0.01-0.04 units/min) to one of these primary vasopressors may allow the use of lower vasopressor dosages, but it is unclear if there are any other additional clinical benefits that would promote its clinical use. ²⁷ Augmentation of cardiac output with dobutamine or milrinone may be useful in patients with reduced cardiac output and hypervolemia. ²⁸

Calcium Channel Blockers

Calcium channel blockers cause moderate cerebral vasodilation and thereby modulate the incidence and severity of cerebral vasospasm and delayed cerebral ischemia. In the largest controlled study to date, ni-modipine 60 mg orally every 4 hours for 21 days significantly reduced cerebral infarction and poor outcomes. ²⁹ The most common major adverse effect seen with nimodipine is reduced blood pressure. If hypotension occurs, adjusting the nimodipine dose to 30 mg every 2 hours is preferred to withholding therapy. ¹² Intravenous nicardipine provides an alternative to nimodipine therapy in patients who cannot tolerate oral therapy or in patients in whom adequate absorption is questionable. Lower dose intravenous nicardipine (0.075 mg/kg/h) provides equal efficacy to high-dose nicardipine and should be utilized to avoid increased adverse events.^30,31 A recent meta-analysis evaluating more than 3,000 patients who received either nimodipine or nicardipine prophylaxis demonstrated that calcium antagonists not only reduced the incidence of cerebral vasospasm, but also reduced the risk of poor outcomes (death or dependence). ³² Therefore, the routine use of prophylactic calcium channel blockers (preferentially oral nimodipine) is recommended for the prevention of cerebral vasospasm in all patients with SAH.

Magnesium

Magnesium is believed to inhibit cerebral vasospasm by causing smooth muscle relaxation and vasodilation by mechanisms similar to the calcium channel antagonists. ³³ High-dose magnesium therapy (an intravenous bolus dose of 5-6 g over 30 minutes followed by an infusion of 0.5-2 g/h for up to 14 days) titrated to achieve a doubling of the patient's baseline magnesium concentration or a plasma concentration of 2.5 mmol/L has demonstrated mostly favorable results for the prevention of cerebral vasospasm in several small studies. Unfortunately, a recent large phase III study was unable to demonstrate any significant benefits in cerebral vasospasm prevention or in improved favorable outcomes. ³⁴ Similarly, a meta-analysis of almost 900 patients was only able to find a modest decrease in delayed cerebral ischemia and only a slight increase in favorable outcomes, both of which were statistically nonsignificant. ³⁵ These recent findings have dampened enthusiasm for routine administration of high-dose magnesium therapy; therefore, the current recommendation is to provide routine magnesium supplementation only as necessary to avoid hypomagnesemia in patients with SAH. ¹²

Statins

Statins can produce a variety of positive effects in addition to their ability to lower cholesterol levels. Statins have the potential to upregulate endothelial nitric oxide synthase, modulate the inflammatory response, and reduce free radical production. These effects are postulated to be the beneficial mechanisms for prevention of cerebral vasospasm in patients with SAH. ³⁶ Simvastatin (80 mg daily), pravastatin (40 mg daily), or atorvastatin (40 mg daily), administered for up to 21 days after SAH, have been evaluated for prevention of cerebral vasospasm and delayed cerebral ischemia with mixed results.^37–39 Therefore, the routine administration of statin therapy is only recommended in patients who were receiving these agents prior to hospital admission. This recommendation is primarily due to the concern for possible worsened outcomes that have been seen after discontinuation of statin therapy in patients with ischemic stroke or myocardial infarction. ¹² Due to the high statin doses utilized in most studies, it is prudent to monitor liver function and creatinine phosphokinase periodically during treatment for early identification of hepatotoxicity or rhabdomyolysis. A large controlled trial (Simvastatin in Aneurysmal Subarachnoid Hemorrhage [STASH] trial) is currently being conducted and should provide more definitive results regarding the routine use of statin therapy.

Locally Administered Pharmacotherapy

Direct administration (intra-arterial, intrathecal, or intraventricular) of medications provides a targeted approach to the treatment of cerebral vasospasm. Small clinical studies or uncontrolled case series have demonstrated positive results with a variety of medications, including papaverine, nicardipine, verapamil, nitroprusside, milrinone, and thrombolytics.

Papaverine

Papaverine inhibits phosphodiesterase activity causing preferential vasodilation of the vascular smooth muscle. Intra-arterial administration of papaverine (total doses of 150-600 mg) has demonstrated moderate success in the treatment of cerebral vasospasm in reported clinical experiences.^40,41 When administering papaverine, appropriate dilution with 0.9% sodium chloride is necessary to avoid the risk of potential vessel infarction due to drug precipitation. Most studies have diluted papaverine to concentrations of 0.1% to 0.8% and infused doses over 30 to 60 minutes. Repeated administration can be performed as necessary in patients who are unresponsive. Other significant adverse effects reported with papaverine therapy include hemiplegia, seizures, increased ICP, systemic hypotension, and neurotoxicity due to altered mitochondrial cellular respiration. ⁴² Safer alternatives to papaverine are now available, so papaverine therapy is not routinely recommended for the treatment of vasospasm.

Nicardipine

Intravenous formulations of nicardipine can be administered by intra-arterial, intrathecal, or intraventricular routes for the treatment of cerebral vasospasm.^43–45 The use of locally administered nicardipine is highly effective at inducing vessel vasodilation and can improve peak cerebral vessel flow velocities for up to 4 days after infusion. Nicardipine has been administered safely for up to 17 days after SAH. ⁴⁴ Monitoring for increased ICP and hypotension can help manage common side effects of therapy. Intra-arterial nicardipine (intravenous nicardipine diluted with 0.9% sodium chloride to 0.1 mg/mL) can be administered in 1 mL aliquots through a microcatheter to a maximum dose of 5 mg per vessel. ⁴³ Intrathecal or intraventricular nicardipine is commonly given as 4 mg every 12 hours with a recommendation to clamp drains for 30 minutes following each administration.^44-45 Only a small amount of literature currently exists evaluating locally administered nicardipine therapy; however, it appears to provide effective and durable effects on the cerebral vasculature with minimal adverse effects.

Verapamil

Verapamil is a calcium channel blocker that is effective for treating coronary vasospasm. Due to success for this indication, the use of intra-arterial verapamil has been extrapolated to the management of cerebral vasospasm. Observational studies evaluating moderate dose verapamil (mean ± SD total dose of 41 ± 29 mg [mean infusion of 0.24 ± 0.09 mg/min]) and ultra-high-dose verapamil (dosage between 25 and 360 mg [total dose per treatment of 70-720 mg administered over 1.0-20.5 hours]) have demonstrated that it is effective for reversing cerebral vasospasm.^46,47 ICP, heart rate, blood pressure, and potential for cytochrome P450 drug interactions should be monitored during administration to limit adverse effects. Verapamil does not appear to offer any significant benefits over nicardipine for this indication, so its future use in clinical practice may be limited to centers that have traditionally utilized this option.

Nitroprusside

Sodium nitroprusside causes vasodilation of the vascular smooth muscle via release of nitric oxide. A small single-center study of intraventricular nitroprusside (4 mg/mL) administered in escalating dosages and frequency depending on the patient's change in mean cerebral flow velocity effectively treated 7 of 10 patients with severe vasospasm refractory to conventional therapy. The mean nitroprusside dose administered was 18.4 mg (range, 8-30 mg). Adverse effects related to nitroprusside were hypotension and vomiting. ⁴⁸ Even though clinicians frequently give nitroprusside intravenously, the use of local administration in clinical practice has been limited.

Milrinone

Milrinone provides inotropic and vasodilator effects by inhibiting the phosphodiesterase III isozyme found in cardiac and vascular muscle. Both intra-arterial and cisternal irrigation administration of milrinone have been evaluated for the management of cerebral vasospasm.^49,50 In patients with angiographically proven cerebral vasospasm, intravenous milrinone 0.5 to 1.5 mcg/kg/min combined with intra-arterial milrinone (8 mg over 30 minutes, repeated up to a maximum of 24 mg as needed) resulted in a mean cerebral artery diameter increase of 53% and was effective in reversing cerebral vasospasm. The most common adverse effect related to milrinone was increased heart rate. ⁴⁹ In a study of 11 patients, prevention of cerebral vasospasm with a continuously infused cisternal irrigation of milrinone (lactated Ringer solution containing urokinase [120 IU/mL], ascorbic acid [3.5 mg/mL], and milrinone [3.6 mcg/mL]) at 30 mL/h for up to 14 days was effective at preventing symptomatic cerebral vasospasm in 82% of the patients. ⁵⁰ The potential benefits of milrinone for both the prevention and treatment of cerebral vasospasm are intriguing; however, additional studies are warranted to confirm these findings prior to implementation.

Thrombolytics

Patients with visual amounts of thick blood (Fisher grading scale of 4) in the ventricles or basal cisterns appear to be at the highest risk for cerebral vasospasm. ⁶ Locally administered intrathecal thrombolytics cause fibrinolysis, speeding blood clearance from the basal cisterns and ventricles, potentially reducing the incidence of cerebral vasospasm. Urokinase and alteplase are the best studied thrombolytics in patients with SAH.^51–54 A recent meta-analysis of 5 randomized controlled trials, with a total of 465 patients, concluded that intrathecal thrombolytics significantly reduced angiographic vasospasm, delayed neurologic deficits, and reduced poor outcomes.” Administration of intrathecal thrombolytics does have risks, and exacerbations of perihematomal edema and other significant adverse effects have been reported. ⁵⁴

The most appropriate dosing strategy for thrombolytic therapy remains an unanswered question. Urokinase dosages of 6,000 to 120,000 IU daily and durations of 1 to 12 days have been utilized.^51–53 Administration of alteplase at dosages of 1 to 3 mg (clamp external ventricular drain for 1 hour after administration) twice daily until clearance of blood from the ventricles is recommended over previously used higher dosage strategies. ⁵⁴ Notwithstanding the potential improvement in cerebral vasospasm and poor outcomes rates, administration of intrathecal thrombolytic administration should be reserved to the select SAH subpopulations that are most likely to benefit from therapy.^12,36

Conclusions

Considerable knowledge gained over the past couple decades has further elucidated the pathophysiology, identification, risk factors, and management strategies for cerebral vasospasm. Nevertheless, cerebral vasospasm and delayed cerebral ischemia continue to be major contributors to morbidity and mortality after SAH. A plethora of pharmacologic interventions for the prevention and treatment of cerebral vasospasm have been evaluated in clinical studies, with a predominance of therapies targeted at smooth muscle relaxation, cerebral vessel vasodilation, or increased cerebral blood flow. However, very few large controlled trials have been completed to date, making the preferred pharmacologic approach heavily dependent on clinician experience and institutional bias.

Utilization of Triple-H therapy has been a widely accepted tactic by many clinicians for both prophylaxis and management of cerebral vasospasm and delayed cerebral ischemia. However, implementation of Triple-H therapy varies considerably at individual institutions. Prophylactic avoidance of hypovolemia via administration of isotonic crystalloids is recommended for prevention. Utilization of 0.9% sodium chloride, with or without albumin, to induce hypervolemia may be a reasonable first approach to treatment in patients who experience cerebral vasospasm. Prophylactic intentional hemodilution in an attempt to reduce the hematocrit is generally not recommended. Some institutions will transfuse PRBCs to maintain hematocrit values of 30% to 35% with a goal of improving cerebral oxygenation, but data supporting this approach are deficient. Induction of hypertension with vasopressor therapy is beneficial in symptomatic patients. The selection of appropriate blood pressure targets and vasopressor therapy should be based upon patient-specific factors and desired pharmacologic effects. Signs of cardiac failure, pulmonary edema, and electrolyte abnormalities should be routinely monitored to prevent adverse effects related to Triple-H therapy.

The calcium channel blockers nimodipine and nicardipine have demonstrated the most consistent improvements in patient outcomes to date. Routine administration of oral nimodipine for 21 days post SAH should be considered in all patients. Due to elevated cost and lack of superiority when compared to nimodipine, intravenous nicardipine should be reserved for patients who cannot receive oral nimodipine therapy. Administration of high doses of intravenous magnesium has failed to show considerable benefits in clinical studies and cannot be routinely recommended at this time. Instead, magnesium supplementation administered as needed to prevent hypomagnesaemia should be employed. Statin therapy should be continued in patients who are taking these medications prior to hospital admission. A recommendation for routine use of statins in naïve patients must be reserved until the results of uncompleted large prospective studies are available. Locally administered pharmacologic therapy may be an appropriate intervention for the treatment of cerebral vasospasm. Of the currently available vasodilators that can be administered by intra-arterial, intrathecal, or intraventricular routes, nicardipine appears to provide the most simplified option with potentially the best benefit-to-risk ratio. Intrathecal thrombolytics may be beneficial in patients with visible thick blood in the ventricles or basal cisterns. However, the data supporting the use of locally administered therapy are modest at best and require careful consideration prior to application.

In summary, the optimal strategy for prevention and treatment of cerebral vasospasm after SAH has yet to be defined. A variety of pharmacologic approaches have been tested, with very few options demonstrating marked benefits. This lack of clarity has led to substantial reliance on clinician predilection for developing pharmacologic management plans and inserts considerable divergence in institutional practices. Larger multi-center, prospective, randomized, pharmacologic studies evaluating the prevention and treatment of cerebral vasospasm, and the overall effect on neurological function, are essential to better guide clinicians.