Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage

Abstract Aneurysmal subarachnoid hemorrhage (aSAH) continues to be associated with significant morbidity and mortality despite advances in care and aneurysm treatment strategies. Cerebral vasospasm continues to be a major source of clinical worsening in patients. We intended to review the clinical and experimental aspects of aSAH and identify strategies that are being evaluated for the treatment of vasospasm. A literature review on aSAH and cerebral vasospasm was performed. Available treatments for aSAH continue to expand as research continues to identify new therapeutic targets. Oral nimodipine is the primary medication used in practice given its neuroprotective properties. Transluminal balloon angioplasty is widely utilized in patients with symptomatic vasospasm and ischemia. Prophylactic “triple‐H” therapy, clazosentan, and intraarterial papaverine have fallen out of practice. Trials have not shown strong evidence supporting magnesium or statins. Other calcium channel blockers, milrinone, tirilazad, fasudil, cilostazol, albumin, eicosapentaenoic acid, erythropoietin, corticosteroids, minocycline, deferoxamine, intrathecal thrombolytics, need to be further investigated. Many of the current experimental drugs may have significant roles in the treatment algorithm, and further clinical trials are needed. There is growing evidence supporting that early brain injury in aSAH may lead to significant morbidity and mortality, and this needs to be explored further.


| INTRODUC TI ON
Subarachnoid hemorrhage (SAH) has a reported incidence between 10 and 15 people per 100 000 in the United States. 1,2 Despite significant improvements in treatment modalities and critical care management, SAH is associated with significant morbidity, mortality, and socioeconomic impact. This is not only as a result of the hemorrhagic event, but further related to the sequelae of the irritating blood by-products that can lead to cerebral vasospasm and delayed cere-

| Presentation and diagnosis of SAH
Most SAHs are caused by a ruptured intracranial aneurysm and are referred to as aSAH. The prevalence of intracranial aneurysms is about 3%. 3 The primary symptom of aSAH is a sudden, severe headache classically described as the "worst headache of life," and may be accompanied by a brief loss of consciousness, nausea or vomiting, meningismus, and seizures. 4 At least 10%-15% of patients with aSAH die before reaching the hospital. Noncontrast head computed tomography (CT) scan is the mainstay of diagnosis of SAH. 5 Cerebral angiography is then pursued to identify the etiology of SAH. Both CT angiography (CTA) and magnetic resonance angiography (MRA) can identify aneurysms 3-5 mm or larger with a high degree of sensitivity, 6 but digital subtraction cerebral angiography remains the gold standard test to identify the etiology of SAH. Lumbar puncture can be considered if there is a strong suspicion of SAH despite a normal head CT. A patient presenting with aSAH is admitted to an intensive care unit for hemodynamic and neurological monitoring, and commonly ventriculostomy placement for drainage of CSF and recording of intracranial pressure. This is followed by definitive treatment of the ruptured aneurysm or pathology causing the SAH. 5

| Treatment of cerebral aneurysms
Treatment of cerebral aneurysms falls primarily under two treatment categories: surgical clipping and endovascular treatment. 7,8 Surgical management of cerebral aneurysms typically consists of clip placement across the neck of the aneurysm. It has been proven to be an effective and safe procedure and was long the most practiced technique for treatment of intracranial aneurysms. Endovascular therapy for cerebral aneurysms was introduced in the early 1990s with the advent of the Guglielmi platinum detachable coils. 9 Access is typically obtained through the femoral artery, and with the assistance of catheters and wires, the aneurysm is reached and coils are deployed.
A local thrombus then forms around the coils, obliterating the aneurysmal sac. More recent techniques have evolved to target complex aneurysms. These include stent-assisted coiling, 10 balloon-assisted coiling, 11 flow diverters, 12 and embolic agents. 13 Multiple factors affect the approach utilized to treat a cerebral aneurysm, most notably aneurysm location, size, and neck size. Endovascular treatment is often the preferred technique for posterior circulation aneurysms and ruptured aneurysms in elderly patients (>70 years of age) given higher surgical risks. 14 In contrast, aneurysms in the middle cerebral artery, ruptured aneurysms with large intraparenchymal hematomas, are most commonly approached surgically. 5 Combined endovascular and surgical techniques may be required with some very large or complex aneurysms.
The ISAT, a multicenter randomized trial comparing microsurgical and endovascular treatment, randomized 2143 patients with aSAH. 7 One-year outcomes demonstrated a reduction in death and disability from 31% in the microsurgery group to 24% in the endovascular arm (relative risk reduction of 24%). The risk of epilepsy and significant cognitive decline was also reduced in the endovascular group.
Rebleeding occurred more commonly in the endovascular treatment group (2.9% after endovascular repair vs 0.9% after open surgery).
The rate of complete aneurysm occlusion was lower with coiling (58% compared with 81% of clipped aneurysms). Due to lower morbidity, endovascular approaches are gaining more and more popularity. Both microsurgical and endovascular approaches are evaluated on a case-to-case basis.
A multitude of secondary events may arise after aneurysmal rupture, some even after securing the aneurysm, and may contribute to brain injury and affect clinical outcomes. (Table 1).

| Hydrocephalus
Hydrocephalus after aSAH is thought to be caused by obstruction of CSF flow by blood products or adhesions, or by a reduction of CSF absorption at the arachnoid granulations, or by an increase in CSF secretion. 15 The reported rate of hydrocephalus after aSAH ranges from 15% to 87% on CT imaging. 5 Acute hydrocephalus associated with aSAH is usually managed by external ventricular drainage or lumbar drainage. Acute CSF diversion for patients who develop hydrocephalus is shown to improve neurological outcomes. [16][17][18] Chronic hydrocephalus associated with aSAH is usually treated with a shunt placement for continuous CSF drainage, typically a ventriculoperitoneal shunt. 19

| Rebleeding
Treatment of the ruptured aneurysm should be performed as early as possible to reduce the rate of rebleeding after aSAH. Rebleeding occurs in 7%-23% of patients and is a major predictor of poor outcome in patients with aSAH. [20][21][22] Most studies have found that the risk of rebleeding is highest in the first 24 hours after aSAH.
Patients are at substantial risk of rebleeding early after presentation if the aneurysm is unsecured, with reported rates of rebleeding ranging from 4% to 13.6% within the first 24 hours. The risk is at its highest within six hours of the initial hemorrhage. The risk of rebleeding drops later to 1%-2% each day in the first month following the hemorrhage. 5,21,23,24 The mortality associated with rebleeding is reported to be as high as 70%. 25 The main factors that increase the risk of rebleeding are longer time to aneurysm treatment, worse neurological condition on presentation, larger aneurysm size, and persistently elevated systolic blood pressure. 21,24 Hypertension should be controlled after aSAH and until aneurysm treatment. A decrease in systolic blood pressure to <160 mm Hg is reasonable. 5 Antifibrinolytic therapy has been shown to reduce the incidence of aneurysm rebleeding when there is a delay in aneurysm obliteration. This may increase the risk of deep venous thrombosis. 26 For patients with an unavoidable delay in obliteration of aneurysm, and no contraindications, short-term (<72 hours) therapy with tranexamic acid or aminocaproic acid could be attempted to decrease the risk of early aneurysm rebleeding. 5

| Vasospasm
Cerebral vasospasm after aSAH is defined as narrowing of the large and medium-sized intracranial arteries. It represents one of the major causes of morbidity and mortality in patients with aSAH who reach the hospital and are undergoing medical care.
The risk of vasospasm typically begins around day 3 and peaks around days 7-10. The risk typically resolves 21 days after the bleed. 5 Angiographic vasospasm is seen in 30%-70% of patients with aSAH, and clinical or symptomatic vasospasm is seen in 20%-30% of patients. 27,28 Cerebral vasospasm is a clinical diagnosis, and radiographic studies are utilized to support the diagnosis.
The gold standard for detecting cerebral vasospasm remains digital subtraction angiography, and it has the advantage of being both a diagnostic and therapeutic tool. CTA is often employed as well for the detection of cerebral vasospasm, as it can provide a quick tool for diagnosis and monitoring of vasospasm. CT perfusion is another tool that can be useful to assess for cerebral ischemia and infarction as a result of vasospasm. 29 Transcranial Doppler sonography (TCD) is widely used for detecting and monitoring vasospasm in aSAH in the clinical setting. It is often used daily in the first 2 weeks after aSAH and can follow the temporal course of vasospasm. TCD is highly operator-dependent, and data obtained from TCD should always be correlated with how the patient is doing clinically. 30 Cerebral vasospasm can lead to regional cerebral hypoperfusion and DCI, which constitutes a major cause of death and disability in patients with aSAH. DCI typically causes neurological deterioration or new focal neurological deficits.
Vasospasm leads to DCI in approximately 20%-30% of patients with aSAH. [31][32][33] Though the exact mechanism of how vasospasm occurs is still not completely elucidated, there are many proposed mechanisms, with cerebral vasospasm likely being a multifactorial pathology.
The major proposed pathways contributing to vasospasm include the following: endothelial damage and formation of microthrombi, smooth muscle contraction from lysis of subarachnoid blood clots and blood degradation products and hemoglobin released into the subarachnoid space, decreased nitric oxide production leading to prolonged vasoconstriction, increased production and release of the potent vasoconstrictor endothelin-1, cortical spreading depolarization, inflammation-mediated oxidative stress and free radical damage to smooth muscle cells, and upregulation of apoptosis pathways following aSAH (Table 2). [34][35][36][37][38][39] As a consequence of the significant neurological morbidity or mortality of cerebral vasospasm and DCI, research has heavily focused on understanding the physiological mechanisms behind these events and developing effective preventive and therapeutic measures ( Table 3). The cornerstone of vasospasm treatment continues to be focused on prevention given risk for worse clinical outcomes in patients who develop this condition.

| Hyperdynamic therapy
used as a method to prevent and treat cerebral vasospasm. [40][41][42] The goal of this technique is to raise the mean arterial pressure and increase cerebral perfusion. It was one of the mainstays of vasospasm management and prevention. However, studies failed to show benefit of prophylactic triple-H therapy and highlighted some notable risks. [41][42][43] This strategy has fallen out of favor and is not recommended any longer.
Studies have shown that hypervolemic therapy did not prevent DCI when compared to euvolemia; in fact, hypervolemia may increase the risk pulmonary edema, myocardial ischemia, and cerebral edema. 44 In a randomized trial, prophylactic hypervolemia caused an overall fourfold increase in the risk of adverse events. 45 The current guidelines have shifted toward a more euvolemic approach with main goal of avoiding hypovolemia without volume overload; prophylactic hypervolemia before the development of angiographic vasospasm is not recommended. 5 Hemodilution is thought to increase global CBF by decreasing blood viscosity. However, it results in reduced oxygen delivery capacity and may not increase the overall cerebral oxygen delivery. 46 It has mostly fallen out of favor as a current treatment modality for vasospasm. In spite of widespread early adoption, primarily based on retrospective studies, systematic reviews of "triple-H" therapy for prophylaxis of vasospasm concluded that it does not appear to be beneficial for the prevention of vasospasm. 42,47 Some components of this regimen are still currently in practice for treatment of symptomatic vasospasm, but not typically employed as a prophylactic measure for all patients. The induced hypertension component of "triple-H" therapy is more effective in increasing CBF than hypervolemia and hemodilution. The loss of innate autoregulation during vasospasm makes cerebral perfusion pressure even more dependent on systemic blood pressure. 48 This strategy is not used a preventive tool, but aims to reduce the risk of ischemia in patients developing vasospasm. Induced hypertension increases cerebral blood flow and brain tissue oxygenation, and may help in reversing neurological deficits. Induced hypertension relies on use of pressors, notably norepinephrine, dopamine, and phenylephrine, all of which have been shown to be successful in improving CBF and neurological outcome. 49

| Nimodipine
Nimodipine is a calcium channel blocker originally used for blood pressure management. It crosses the blood-brain barrier and causes vasodilation of vascular smooth muscle cells and thus is a main tool used in aSAH.
Nimodipine was initially studied in patients with aSAH as a means to prevent vasospasm. However, there is no convincing evidence that nimodipine affects the incidence of either angiographic or symptomatic vasospasm. 50 But, nimodipine has been shown to improve neurological outcomes and to decrease mortality in patients with aSAH and is part of the standard of care due to its neuroprotective role. 51,52 Per the AHA/ASA recommendations, oral nimodipine should be initiated as soon as possible, typically at a dose of 60 mg every 4 hours, and maintained for about 21 days following SAH. 5 The underlying mechanism for these effects is unclear, but it is known to be separated from its vasodilatory effects and could be related to resistance to calcium-mediated excitotoxicity and a reduction in the formation of microthromboses, which play a role in development of vasospasm and DCI. 36 Nimodipine is the only FDA-approved drug to improve outcomes in aSAH. It has been reported to reduce the incidence of poor neurological outcome by 40%. 53 In a trial by Allen et al 51 that included 125 SAH patients, 1 of 56 patients who received nimodipine suffered from neurological deficit or death, which was statistically significant when compared to patients given a placebo (8 of 60 patients, P = .03). Several additional trials have confirmed the benefit of nimodipine in reducing the incidence of DCI and improving outcomes in SAH. A meta-analysis that analyzed the results of 16 trials evaluating the role of calcium channel blockers in aSAH, encompassing 3361 patients, concluded that calcium channel blockers reduce the risk of poor outcome and secondary ischemia after aneurysmal SAH with oral nimodipine producing the most significant benefit and only with modest risks, systemic hypotension being the most common side effect of nimodipine. 52 Other calcium channel blockers have been studied for treatment of vasospasm and DCI, most notably nicardipine, nitroprusside, and verapamil. There may be a role for the other calcium channel blockers, but the benefit does not surpass that of nimodipine. 52 In a trial on nicardipine that treated 449 patients with IV nicardipine vs 457 patients with placebo, nicardipine-treated patients had significantly reduced vasospasm compared to placebo (32% vs 46%, P < .001), but clinical outcomes were similar between the groups at 3 months. 54

| Magnesium
Magnesium leads to vasodilatation of cerebral arteries by blocking the voltage-dependent calcium channels. Magnesium may TA B L E 2 Proposed mechanisms underlying cerebral vasospasm and DCI Prolonged smooth muscle contraction from lysis of subarachnoid blood clots and blood degradation products

Endothelial damage and formation of microthrombosis
Decreased nitric oxide production leading to prolonged vasoconstriction Increased production and release of the potent vasoconstrictor endothelin-1 Cortical spreading depolarization increasing metabolic demand and decreasing blood supply Inflammation-mediated oxidative stress and free radical damage to smooth muscle cells Upregulation of apoptosis pathways following aSAH Abbreviations: aSAH, aneurysmal subarachnoid haemorrhage; DCI, delayed cerebral ischemia.

Mechanism of action in vasospasm Use in clinical practice Comment
Hyperdynamic and "triple-H" therapy Increase the mean arterial pressure and increase cerebral perfusion Hypervolemia and hemodilution have fallen out of practice. Induced hypertension is utilized to reduce the risk of ischemia in patients who develop vasospasm but is not used as a prophylactic measure for all patients.
Systematic reviews concluded that "triple-H" therapy does not appear to be beneficial for the prevention of vasospasm. Hypervolemia may increase the risk pulmonary edema, myocardial ischemia, and cerebral edema; maintaining euvolemia is recommended.

Nimodipine
Calcium channel blocker causing vasodilatation of vascular smooth muscle cells. Neuroprotective effect could be related to resistance to calciummediated excitotoxicity and a reduction in the formation of microthromboses Oral nimodipine should be initiated as soon as possible after aSAH at a dose of 60 mg every 4 h and maintained for about 21 d following SAH No convincing evidence that nimodipine affects the incidence of either angiographic or symptomatic vasospasm But, nimodipine has been shown to improve neurological outcomes and to decrease mortality in patients with aSAH and is part of the standard of care due to its neuroprotective role.
Nicardipine, nitroprusside, and verapamil Other calcium channel blockers causing vasodilation of vascular smooth muscle cells.
Frequently utilized for blood pressure management in aSAH, especially nicardipine, but not routinely tailored for vasospasm prophylaxis and treatment (Continues)

Mechanism of action in vasospasm Use in clinical practice Comment
Cilostazol Platelet aggregation inhibitor may have a role in preventing microthrombi formation and has a vasodilatory effect by inhibiting phosphodiesterase 3 and increasing intracellular cAMP Not used routinely Cilostazol seems to be a safe and promising agent. One meta-analysis showed a decreased risk of symptomatic vasospasm, cerebral infarction, and poor outcome. Further large multicenter trials are needed.

Albumin
Neuroprotective properties likely related to its antioxidant and antiinflammatory properties. It increases oncotic pressure and reduces cerebral edema, increases neuronal survival, and maintains blood-brain barrier integrity.
Used occasionally for volume resuscitation in SAH. Not routinely used for vasospasm prophylaxis or treatment.
ALISAH study identified that 1.25 g/kg/d of albumin is safe in patients with aSAH and may be associated with improved outcomes with no major complications. Further studies are currently underway.

Eicosapentaenoic acid
Inhibits Rho-kinase activation and smooth muscle contraction.

Not currently used in the clinical setting
Early reports showed positive results, and further studies are needed.
Heparin and low molecular weight heparin Attenuates inflammatory response, this is different than its function in anticoagulation.
High-dose heparin/low molecular weight heparin infusions are not currently recommended routinely given concern for hemorrhage. Low doses are used for prophylaxis against venous thromboembolism Inconsistent results with concern for hemorrhage.
Erythropoietin neuroprotective properties through an indeterminate mechanism that seems to be unrelated to its function in erythropoiesis Not commonly used in practice The overall mechanisms and role in vasospasm are still unclear as well as the effect on clinical outcomes.

Corticosteroids
Antiinflammatory properties Not commonly used in practice A randomized trial that administered high-dose methylprednisolone (16 mg/kg) reported better functional outcome at one year. Further studies are needed.

Minocycline
Antiinflammatory effects as well as serving as an iron chelator. Likely neuroprotective role.
Not commonly used in practice Multiple trials have evaluated minocycline in acute ischemic stroke and intracranial hemorrhage patients with promising results and with a good safety profile. Role currently being evaluated in SAH.

Deferoxamine
Iron chelator. May target iron and hemoglobin-induced early brain injury Not commonly used in practice Could be a promising agent; currently being evaluated in ICH and SAH and has reached clinical trials in ICH.

Intrathecal thrombolytics
Clearance of blood from the basal cisterns and ventricular system.
Not commonly used in practice A meta-analysis showed an absolute risk reduction in DCI, poor clinical outcome, and mortality. Intrathecal thrombolytics are still being investigated and not currently recommended.
Transluminal balloon angioplasty Hypomagnesemia occurs in a large proportion of patients with SAH and could lead to worse outcomes. 60 While maintaining magnesium within normal limits in patients with aSAH is reasonable, the current evidence does not support routine prophylactic and aggressive therapy in patients with aSAH. Furthermore, side effects associated with intravenous magnesium may offset any potential benefit (eg, hypocalcemia, hypotension).

| Milrinone
Milrinone is a phosphodiesterase 3 inhibitor. It leads to an increased level of intracellular cAMP causing vasodilation. In addition, milrinone also has potential antiinflammatory effects at the cerebral vessel wall. Milrinone's antiinflammatory effects may inhibit the ab-

| Statins
Statins are HMG-CoA reductase inhibitors thought to have the potential to improve cerebral vasomotor reactivity by upregulating endothelial nitric oxide synthase and increasing nitric oxide biosynthesis. 67 This can increase cerebral blood flow and could play a role in prevention and treatment of vasospasm and DCI. Additionally, statins may play a role in decreasing glutamate-mediated excitotoxicity and help control the inflammatory response in vasospasm. 68 There have been some positive trials evaluating the role of statin treatment in aSAH. [69][70][71][72] A phase II placebo-controlled trial randomized 80 patients with aSAH to either 40 mg of daily oral pravastatin or placebo for up to 14 days. In patients treated with pravastatin, vasospasm and severe vasospasm were decreased by 32% (P = .006) and 42% (P = .044), respectively, in pravastatin-treated patients. Pravastatin also decreased the incidence of vasospasm-DCI by 83% (P < .001) and mortality by 75% (P = .037). 72 However, more recent trials have not replicated those results. 68 Given the relative safety of statins, they are still used in clinical practice (pravastatin 40 mg daily or simvastatin 80 mg daily). The latest AHA/ASA recommendation published in 2012 states that it is reasonable to administer statin therapy to patients after aSAH to prevent vasospasm despite the lack of strong evidence of benefit. 5 If statins were to be initiated, therapy should be started early (within 48 hours) and continued for 14-21 days. Hepatotoxicity and rhabdomyolysis are rare complications of statins but have not been prominent in most trials despite the high-dose regimens used. More definitive trials may still be needed to confirm the effect of statins on outcomes, vasospasm, and DCI in aSAH given current mixed findings in the literature.

| Endothelin receptor antagonists
Endothelin receptor antagonists inhibit the binding of endothelin 1, a vasoconstrictive peptide that affects vascular smooth muscle contraction. Endothelin is overproduced in SAH and is linked to development of vasospasm. 75 Clazosentan is the most commonly studied endothelin receptor antagonist in SAH.

CONSCIOUS-1, a phase II trial that randomized 413 patients
to clazosentan or placebo, reported dose-dependent reductions in angiographic vasospasm. 76  A total of 728 patients received IV clazosentan (5 mg/h) and 389 patients received placebo. The group receiving clazosentan did not have statistically significant improvement in clinical outcomes.
All-cause mortality, vasospasm-related infarcts, DCI, and rescue therapy for vasospasm occurred less frequently in the clazosentan group (21%) compared to the placebo group (25%); however, this difference was not significant (P = .1).
Furthermore, this trial highlighted many side effects that included pulmonary edema, hypotension, pleural effusion, and cerebral infarction that required stopping the drug. Based on these findings, the CONSCIOUS-3 trial that was recruiting patients was stopped early, enrolling 577 patients. 78 Results were comparable for the 5 mg/h clazosentan dose. Clazosentan at 15 mg/h decreased the occurrence of vasospasm-related morbidity, but did not improve functional outcomes (P = .266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan. This is also further demonstrated in meta-analyses. 79

| Tirilazad
Tirilazad functions as a free radical scavenger. This antioxidant effect is believed to confer a neuroprotective benefit in aSAH. 82,83 A trial that enrolled 1015 patients randomized to receive tirilazad at 6 mg/ kg/day demonstrated significantly reduced overall mortality (P < .01) and improved clinical outcomes at 3 months compared to patients who received placebo (P < .01). 84 The benefits of treatment with tirilazad were predominantly shown in men rather than in women.
The North American multicenter cooperative tirilazad trial studied 897 patients who received 6 mg/kg per day tirilazad or placebo. 85 At 3 months post-SAH, there were no significant differences in mortality, clinical outcome, or employment status. During the first 14 days after the SAH, there were no significant differences in the incidence or severity of clinical or angiographic cerebral vasospasm.
A meta-analysis that included five double-blind, placebo-con-

| Fasudil
Fasudil is a Rho-kinase inhibitor that acts as a vasodilator. Rho-kinase is thought to play a role in the mechanisms dictating vasoconstriction, endothelial injury, inflammation, and production of reactive oxygen species. 86 In a trial by Shibuya et al 87 that randomized 131 patients to receive IV fasudil for 14 days and 136 patients to placebo, fasudil reduced angiographic vasospasm by 38% from 61% in the placebo group (P = .0023) and symptomatic vasospasm by 30% (P = .0247) and significantly improved clinical outcomes according to the onemonth GOS scores (P = .0152). In a randomized clinical trial, the use of fasudil 30 mg as a daily IV bolus was compared with IV nimodipine. 86 Neither the incidence of clinical vasospasm nor the occurrence of CT hypodensities differed significantly between the two groups.
However, the clinical outcomes were more favorable in the fasudil group than in the nimodipine group (74.5% vs 61.7%, P = .040).
There were no serious adverse events reported with fasudil. In this study, however, the nimodipine group received approximately half of the recommended treatment dose. Fasudil has been primarily studied in Japan and is currently utilized in Japan for vasospasm prophylaxis. 89 Because of the limited number of trials, it is not as popular elsewhere. Large randomized, controlled clinical trials are needed to further establish the benefit of fasudil in aSAH.

| Cilostazol
Cilostazol is a platelet aggregation inhibitor. It may have a role in preventing microthrombus formation that is cytotoxic and may contribute to cerebral vasospasm. Cilostazol has a vasodilatory effect on the cerebral arteries as well through its inhibitory effect on phos- Cilostazol seems to be a safe and promising agent, and further large multicenter trials are needed before it gets widely adopted in clinical practice.

| Albumin
Human albumin is thought to have neuroprotective properties likely related to its antioxidant and antiinflammatory properties. 93,94 It has been shown to increase serum oncotic pressure and reduce cerebral edema, increase neuronal survival, and maintain blood-brain barrier integrity. 95,96 The Albumin in Subarachnoid Hemorrhage (ALISAH) pilot study included 47 patients and identified that 1.25 g/kg/d of albumin is safe in patients with aSAH and may be associated with positive outcomes. 93 There were no major complications. A secondary analysis showed that higher dosages of albumin were associated with a lower incidence of vasospasm, DCI, and cerebral infarction at 90 days, in a dose-dependent fashion. 97 Further studies are currently underway to further evaluate the role of albumin in the management of aSAH and cerebral vasospasm.

| Eicosapentaenoic acid
The sphingosylphosphorylcholine-Rho-kinase pathway plays an important role in vascular smooth muscle contraction. Eicosapentaenoic acid is an omega-3 polyunsaturated fatty acid that inhibits this process and has been shown to inhibit the occurrence of cerebral vasospasm in animal models. [98][99][100] A prospective multicenter randomized trial randomized 162 patients with SAH postaneurysm clipping to 900 mg of eicosapentaenoic acid three times daily for 30 days or no trial drug. The occurrence of symptomatic vasospasm (15% vs 30%, P = .02) and cerebral infarction vasospasm (7% vs 21%; P = .01) was lower in the treatment group.
Eicosapentaenoic acid is not currently used in the clinical setting, but early reports showed positive results and further studies are needed.

| Heparin and low molecular weight heparin
Heparin and low molecular weight heparin infusions have been evaluated in aSAH with inconsistent results. [101][102][103] Heparin has antiinflammatory properties different than its role in anticoagulation. It is thought to attenuate the inflammatory response and restore bloodbrain barrier integrity. 104

| Erythropoietin
Erythropoietin is a hormone produced primarily by the kidneys and plays an essential role in the production of red blood cells. In animal studies, erythropoietin has been shown to have some neuroprotective properties through an indeterminate mechanism that seems to be unrelated to its function in erythropoiesis. [105][106][107][108] It has been reported to reduce the severity of vasospasm. A phase II randomized trial that included 80 patients who received 30 000 U of intravenous erythropoietin or placebo every 48 hours for a total of 90 000 U showed a decreased incidence of severe vasospasm from 27.5% to 7.5% (P = .037), reduced DCI from 40% to 7.5% (P = .001), and better outcome at discharge (P = .039). 109 In a study on seven patients with SAH and cerebral vasospasm, 30 000 IU of erythropoietin was injected for 3 days. This resulted in an increase in brain tissue oxygen tension significantly over baseline. 107 The overall mechanisms and role in vasospasm are still unclear as well as the effect on clinical outcomes.

| Corticosteroids
The role of inflammation is central to the development of vasospasm and early brain injury post-SAH. Corticosteroids that interfere with the glucocorticoid receptor are able to downregulate this inflammatory response. A randomized trial that administered high-dose methylprednisolone (16 mg/kg) to patients with aSAH reported better functional outcome at one year when compared to control patients (poor outcome of 15% in the treatment group vs 34% in controls, CI 95% CI 0.5%-37.9%). 110 The use of corticosteroids in aSAH warrants further investigation.

| Minocycline
Matrix metalloproteinase (MMP) is strongly involved in the pathophysiology of blood-brain barrier disruption and CNS injury. [111][112][113] MMP-9 levels are increased following SAH, and several studies have suggested a role for MMP-9 in early brain injury after SAH and correlation between MMP-9 levels and vasospasm in animal models. [114][115][116][117][118][119] Fischer et al 120 evaluated blood samples in 20 patients with aSAH and showed that MMP-9 was higher in aSAH patients compared to healthy controls (P < .001) and an increase in MMP correlated with occurrence of vasospasm (P < .05).
Minocycline is a lipophilic semisynthetic second-generation tetracycline antibiotic that is a broad MMP inhibitor, with a good safety profile, used for other indications in humans. It has antiinflammatory effects in addition to serving as an iron chelator; thus, it has the potential of mitigating early brain injury following aSAH. 121 Multiple trials have evaluated the neuroprotective role of minocycline in acute ischemic stroke and intracranial hemorrhage pa-

| Deferoxamine
The amount of blood released during aSAH has been shown to be related to the degree of neurological injury and poor outcome. 124 Abnormally high levels of iron in the brain can lead to significant oxidative damage via free radical production. [125][126][127] Recent studies showed that oxidative injury and iron overload play a significant role in brain damage after intracerebral hemorrhage. 126,127 Iron deposition after intracranial hemorrhage seems to be related to oxidative injury, resulting in brain edema, neuronal cell death, and delayed brain atrophy and secondary brain injury. [128][129][130] Deferoxamine is an iron chelator that chelates the unbound iron responsible for catalyzing the production of reactive oxygen species and blocks neurotoxic effects of hemoglobin. 131 Previous studies found that deferoxamine reduces hemoglobin-induced brain edema and decreases brain injury in experimental ICH. 130,131 Deferoxamine has currently reached clinical trials for ICH. In a rodent SAH model study, deferoxamine treatment reduced SAH-induced mortality (12% vs 29%, P < .05), brain nonheme iron concentration, iron-handling protein expression, oxidative stress, and neuronal cell death at day 3 (P < .01). 125 In another rodent study, deferoxamine injection resulted in a

| Intrathecal and intraventricular therapy
The major advantage of delivery of treatment through an intrathecal or intraventricular route is the ability to achieve higher drug concentrations directly around the area of vasospasm and minimizing systemic toxicity.
Nicardipine is a calcium channel blocker used for treatment of hypertension, commonly utilized in its intravenous form.
Intraventricular nicardipine in aSAH has been studied in small case series. 134 Intraventricular milrinone and sodium nitroprusside have been evaluated as well in small studies. 139,140 In addition, studies have investigated the administration of intrathecal thrombolytics in aSAH to help with the clearance of blood from the basal cisterns and ventricular system. One trial randomized 49 patients to placebo and 51 patients to intracisternal tPA at the time of aneurysm clipping. The incidence of angiographic vasospasm between the seventh and eleventh day following SAH was similar between the two groups (74.4% in the placebo group vs 64.6% in the rtPA group), with a trend toward a lower rate of vasospasm in the tPA group. Furthermore, the group that received tPA with a thick subarachnoid clot had a 56% relative risk reduction of severe vasospasm compared to placebo (P < .02). 141  A meta-analysis that included 652 patients reported positive results with an absolute risk reduction in DCI of 14.4% (P < .001), in poor clinical outcome of 9.5% (P < .01), and in death of 4.5% (P < .05). 143 Intrathecal/intraventricular administration of these various agents cannot be currently recommended as level I evidence is lacking to support the routine use of locally administered therapy.
Further prospective randomized trials evaluating safety and efficacy are required.

| Intraarterial treatment and angioplasty
Symptomatic cerebral vasospasm refractory to medical treatment and DCI requires further interventions. Mechanical dilation using percutaneous transluminal balloon angioplasty has become the mainstay of treatment for symptomatic focal vasospasm of the larger cerebral arteries that is refractory to medical treatment. 5 The suggested mechanism of this approach is related to disruption of smooth muscle cells or extracellular matrix with resultant dilatation of the vessel and increased cerebral blood flow. 144 In 1984, Zubkov et al 145  Angioplasty has high success rates in proximal arteries including the internal carotid and vertebral arteries. [146][147][148] In a review by Hoh and Ogilvy, angioplasty resulted in clinical improvement in 62% of patients, significantly improved mean TCD velocities (P < .05), significantly improved cerebral blood flow in 85% of patients, and was associated with a 5% complication rate. 149 One report identified that institutions that use interventional modalities such as balloon angioplasty for vasospasm had a 16% reduction in risk of in-hospital death (RR, 0.84, P = .03). 150 In clinical practice, and despite strong level I evidence, transluminal balloon angioplasty is often pursued in patients with severe vasospasm and symptoms refractory to medical treatment.
Prophylactic use of angioplasty, however, is not recommended.
One multicenter randomized trial that included 170 patients with the Fisher grade III SAH randomized 85 patients to prophylactic angioplasty. The study did not show benefit in clinical outcomes from prophylactic intervention and showed a procedure-related complication rate of 5%. 151 Per the current AHA/ASA recommendations, balloon angioplasty before the development of angiographic vasospasm is not recommended but is reasonable in patients with symptomatic vasospasm, particularly those who are not rapidly responding to hypertensive therapy. 5 Chemical angioplasty consisting of intraarterial administration of vasodilators is also an option that is generally used for diffuse vasospasm involving smaller arterial branches. Intraarterial nicardipine, papaverine, milrinone, nimodipine, and verapamil have been utilized in treatment of symptomatic vasospasm. [152][153][154][155][156] Intraarterial papaverine causes vasodilatation, likely related to alteration in cAMP. It can result in transient reversal of cerebral hypoperfusion with improvement in blood flow velocities and CBF. 83,157,158 There are significant limitations with its use. It has a short-lived effect, and patients may require multiple treatments. It also has some neurotoxic effects and may result in increased intracranial pressure, brainstem depression seizures, altered mental status, and hypotension.
Given these limitations, papaverine is not routinely recommended for the treatment of vasospasm and its use is limited in aSAH.
The primary limitation of vasodilator therapy is related to the shorter duration of benefit and an increased incidence of recurrent vasospasm. Intraarterial verapamil, nicardipine, nimodipine, and milrinone appear to be safer than papaverine and provide a more durable response. Most of these agents have been tested in case series and have become widely adopted in clinical practice despite lack of strong established evidence. Randomized trials are still needed to establish safety and efficacy and to compare the different intraarterial treatments.

| Animal models of SAH
Animal models are essential to the study of SAH and its effects.
There are numerous studied animal models of SAH. 159 Some involve the puncture or perforation of a cerebral vessel involving the use of a needle or catheter, or via a suture tied around the vessel. 160 Endovascular approaches have also been utilized using intraluminal filaments advanced into a cerebral vessel with subsequent puncture.
Other models use injection of blood into a cistern. The cisterna magna is the most common site for blood injection in animal models.
Blood may be introduced into the cisterna magna via a microcatheter or by direct puncture. 161 Models of SAH in the anterior circulation have also been developed using injection of blood into the perichiasmatic cistern. 162 In addition, there are single and double injection models.
Direct injection of blood is often the preferred method, given the ability of the investigator to control the initiation, volume, and rate of hemorrhage, into the cisterna magna or the prechiasmatic cistern. 163 Originally, large animal models of SAH such as dogs and primates were used. In particular, primates were the preferred model because of similarities in their brain structure to humans. The first animal model of SAH that was developed was in primates. 164 The basilar artery was exposed by craniotomy, and autologous blood was injected into the subarachnoid space surrounding it. However, high cost and the small number of animals that can be tested have limited this use of this model.
Canine models represent a popular model to study SAH given the large size of the animal and relatively lower cost than primates.
More recently, the rat model has become one of the most utilized animal models of SAH due to low cost and ability to use large numbers of animals. 165 Other model species studied in SAH include mice, rabbits, cats, and pigs.
Although many therapeutic agents were met with great success in preclinical animal studies, the failure in translation of these findings into clinical trials could be related to a wide variability in animal models and lack of standardized methodology. Some of the variables include volume of blood injected, the method of injection, with or without withdrawal of CSF, injection times, the use of single vs double injection models, and vascular perforation techniques.
More recently, there has been an increase in acute SAH models focusing on early brain injury given the increasing clinical interest in this entity.
To note, the recently described glial-lymphatic or glymphatic pathway, a fluid clearance pathway that subserves the flow of CSF into the brain along arterial perivascular spaces, has been found to be impaired in SAH. 166 There appears to be impaired CSF inflow starting at 24 hours after the insult attributed to the occlusion of perivascular spaces by blood components. 167 This could represent another target that warrants investigation in animal models of SAH.

| CON CLUS ION
Available treatments for aSAH continue to expand. Vasospasm and resultant DCI continue to be a significant cause of morbidity and mortality after SAH. No single-treatment algorithm has shown to be uniformly effective in preventing post-aSAH complications. Vasospasm after aSAH appears to be a multifactorial process, and the etiology of cerebral vasospasm remains incompletely understood.
Oral nimodipine continues to be the primary medication routinely used in practice given its neuroprotective properties and data supporting improvement in clinical outcomes. There have been many studies evaluating the role of other medical and interventional treatments for aSAH and particularly vasospasm prevention and treatment. Many of these treatments have crossed into clinical practice. There is growing evidence supporting that early brain injury in aSAH may be related to significant morbidity and mortality. This needs to be explored further. Many of the current experimental drugs may have significant roles in the treatment algorithm of aSAH, early brain injury, and vasospasm and further trials are needed.

ACK N OWLED G M ENT
None.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.