Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage

Vasospasm is one of the leading causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Radiographic vasospasm usually develops between 5 and 15 days after the initial hemorrhage, and is associated with clinically apparent delayed ischemic neurological deficits (DID) in one-third of patients. The pathophysiology of this reversible vasculopathy is not fully understood but appears to involve structural changes and biochemical alterations at the levels of the vascular endothelium and smooth muscle cells. Blood in the subarachnoid space is believed to trigger these changes. In addition, cerebral perfusion may be concurrently impaired by hypovolemia and impaired cerebral autoregulatory function. The combined effects of these processes can lead to reduction in cerebral blood flow so severe as to cause ischemia leading to infarction. Diagnosis is made by some combination of clinical, cerebral angiographic, and transcranial doppler ultrasonographic factors. Nimodipine, a calcium channel antagonist, is so far the only available therapy with proven benefit for reducing the impact of DID. Aggressive therapy combining hemodynamic augmentation, transluminal balloon angioplasty, and intra-arterial infusion of vasodilator drugs is, to varying degrees, usually implemented. A panoply of drugs, with different mechanisms of action, has been studied in SAH related vasospasm. Currently, the most promising are magnesium sulfate, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, nitric oxide donors and endothelin-1 antagonists. This paper reviews established and emerging therapies for vasospasm.


Introduction
Vasospasm is a common complication that follows aneurysmal subarachnoid hemorrhage (SAH). Ecker was first to point out the occurrence of arterial spasm following SAH [1]. Before him, Robertson had attributed ischemic brain lesions found on autopsy of patients with SAH to probable 'spasm of arteries' [2]. Despite growing literature, skepticism regarding the association between angiographic vasospasm and clinical findings persisted [3], until CM Fisher and colleagues published a synopsis on the matter in 1977 [4]. This seminal publication comprehensively described the deficits accompanying vasospasm and, most importantly, made the association between vasospasm and neurological deficits, also known as delayed ischemic deficits (DID).
The term vasospasm implies a reduction in the caliber of a vessel; however, in SAH it has multiple meanings. SAHinduced vasospasm is a complex entity due in part to a delayed and reversible vasculopathy, impaired autoregulatory function, and hypovolemia causing a regional reduction of cerebral perfusion to the point of causing ischemia [5,6].
Radiographic evidence of vasospasm develops in 50% to 70% of patients with SAH, but only half of those experience symptoms of DID [7][8][9][10][11][12]. Proximal vessels, situated at the base of the brain, are preferentially affected; however, more distal arteries could also develop impaired vascular reactivity (autoregulation), further reducing cerebral blood flow [5,13,14]. A tendency toward spontaneous intravascular volume contraction can further compound the deleterious effect of a marginal cerebral blood flow (CBF) caused by vasoconstriction. These factors are probably in play in a subset of patients with DID who show no evidence of radiographic vasospasm.
Vasospasm adversely affects outcome in patients with SAH; it accounts for up to 23% of disability and deaths related to SAH [8,9,[15][16][17]. However, given its predictable delayed onset between day 5 and 15 after bleeding, it is a potentially modifiable factor. Use of nimodipine, a calcium channel antagonist, and prompt recognition and treatment with hypervolemic hypertensive therapy (HHT) and endovascular interventions are likely responsible for the lower incidence of DID reported after their widespread use [17,18]. They are by no means completely effective and additional treatments are needed. The ongoing elucidation of the pathophysiology of vasospasm is crucial, as it offers targets for novel therapeutic modalities.

Pathophysiology
The pathophysiology of vasospasm is far from being completely understood. Histologically, there are structural alterations in endothelial and smooth muscle cells in the arterial wall [19]. The presence of oxyhemoglobin in the subarachnoid space seems to be necessary to produce these changes [20][21][22]. The specific mechanisms leading to vasoconstriction, however, are unknown. In vitro, oxyhemoglobin stimulates the secretion of endothelin (ET)-1, a vasoconstrictor, inhibits the vasodilator nitric oxide (NO) and produces activated oxygen species [23][24][25]. These free radicals are believed to play a role in cell membrane lipid peroxidation, possibly mediating the structural changes in the vessel wall.
Whether inflammation is simply part of the multi-organ system dysfunction encountered in SAH [26] or contributes to the development of vasospasm is unsettled. The risk of vasospasm is increased in the presence of systemic inflammatory response syndrome [27]. Furthermore, cerebrospinal fluid (CSF) levels of interleukin-1β and -6 in patients with SAH are increased during the vasospasm period and in those in whom vasospasm and ischemia develop later [28]. Genetic and racial factors are likely important; studies of SAH from Japan revealed a higher incidence of vasospasm across different diagnostic methods [29]. Also, certain endothelial NO synthase (eNOS) gene polymorphisms seem to be associated with an increased risk of vasospasm [30].
Risk factors for vasospasm and DID are amount and duration of exposure to subarachnoid blood, thick blood collections in basal cisterns and fissures, and intraventricular blood [31][32][33][34]. Interestingly, however, endovascular coiling of the ruptured aneurysm, a procedure that does not involve a craniotomy and washing out of the subarachnoid blood, does not increase the risk of vasospasm in comparison to surgical clipping [35,36]

Clinical diagnosis
The diagnosis of vasospasm is primarily clinical. Vasospasm can be asymptomatic; however, when the net result of vasoconstriction, impaired autoregulation, and inadequate intravascular volume is a CBF below ischemic threshold, symptoms ensue. They typically develop subacutely, and because of the dynamic interplay between the inciting factors, they might fluctuate. Symptoms range from vague and non-specific, such as excess sleepiness, lethargy, and stupor, to a spectrum of localizing findings like hemiparesis or hemiplegia, abulia, language disturbances, visual fields deficits, gaze impairment, and cranial nerve palsies [4]. Although localizing, these signs are not diagnostic of any specific pathological process; therefore, alternative diagnoses, such as rebleeding, hydrocephalus, seizures and metabolic derangements, should be promptly excluded using radiographic, clinical and laboratory assessments. On the other hand, the neurological changes can be subtle or unapparent, as many individuals have an abnormal exam related to the initial hemorrhage. Detection of clinical signs of vasospasms is particularly difficult in poor grade patients because of the limited exam that is possible [44]. The frequent use of sedatives in SAH patients further complicates this task. Thus, the evaluation frequently includes transcranial doppler ultrasonography (TCD) and angiography. Angiography can be both diagnostic and therapeutic (see below).

Cerebral angiography and transcranial doppler ultrasonography
Cerebral angiography is the gold standard for visualizing and studying cerebral arteries. The non-invasive nature of TCD, however, makes it an appealing method for monitoring for, and to help confirm, the clinical diagnosis of vasospasm. It detects elevation in mean CBF velocities, mainly in middle and internal cerebral arteries [45,46]. Although it is almost as sensitive as angiography in detecting symptomatic vasospasm [47-49], inadequate insonation window in a proportion of patients, unacceptably high rate of false negatives [48], and failure to account for altered autoregulation during hemodynamic manipulation [13] limit its utility (Table 1).

Reducing the impact of vasospasm
The typical temporal course of vasospasm and its high incidence make prevention an attractive therapeutic approach. However, the process is a difficult one to study and despite investigation of a myriad of compounds, very few have made it to the clinical arena (Additional data file 1).

Nimodipine
Nimodipine is a dihydropyridine that blocks calcium influx through the L-type calcium channels. It is the most rigorously studied and only drug approved by the US Food and Drug Administration for use in treatment of vasospasm. It is safe [12,59], cost-effective [60], and most importantly reduces the risk of poor outcome and secondary ischemia after aneurysmal SAH [7,10-12,61]. A major randomized controlled trial, the British aneurysm oral nimodipine trial, showed a significant reduction in the incidence of cerebral infarction and poor outcome at three months compared to placebo [12].
How nimodipine exerts its beneficial effects is not well understood and may involve neuronal as well as vascular factors, although, of note, it does not significantly reverse angiographic vasospasm [62]. Nimodipine is administered in a dose of 60 mg every 4 hours for 14-21 days after SAH. In Europe, nimodipine is also used as a continuous intravenous infusion, although this is often associated with hypotension.

Tirilazad mesylate
Tirilazad, a non-glucocorticoid 21 amino-steroid free radical scavenger, was studied in several controlled trials [69-73] following promising results in primate vasospasm models [74][75][76]. It was well tolerated but had inconsistent effect on overall outcome across the different studies, possibly related to gender differences in drug metabolism and an interaction with phenytoin.

Prophylactic hypervolemia
In large prospective controlled studies, prophylactic volume expansion therapy failed to reduce the incidence of clinical or TCD-defined vasospasm, did not improve CBF, and had no effect on outcome [77-79]. In one of those studies, costs and complications were higher in the group treated with prophylactic hypervolemia [77]. A small retrospective cohort reported worsening outcome after discontinuing routine use of albumin to induce hypervolemia in SAH [80].

Lumbar drainage of CSF and intracisternal thrombolysis
The amount of blood in the subarachnoid space is a strong predictor for the development of vasospasm. Several interventions to facilitate the clearance of blood from the CSF following SAH have been studied. Cisternal irrigation by tissue plasminogen activator [81] was relatively safe [82,83] but had no impact on incidence of angiographic vasospasm [84]. Intraand post-operative cisternal irrigation with tissue plasminogen activator combined with continuous post-operative cisternal drainage was associated with a low incidence of vasospasm [85]. Intracisternal infusion of urokinase has also been studied in a small retrospective randomized, but not placebocontrolled trial [86,87]. Incidence of vasospasm was significantly reduced and outcome improved.
Lumbar CSF drainage following SAH is another appealing technique to clear blood from the subarachnoid space. A non-randomized, controlled-cohort study enrolled 167 patients in whom CSF drainage reduced the incidence of clinical vasospasm, the use of angioplasty, and vasospasmrelated infarction [88]. Larger placebo controlled studies are needed to determine if these interventions produce sustained clinical benefits.

Aggressive treatment of vasospasm
Given the limited impact of established and developing preventive measures, more aggressive interventions are often implemented. The threshold for instituting these interventions varies widely across centers. Some actively intervene in the setting of rising TCD velocities; others may treat angiographic vasospasm in asymptomatic patients, while some require a neurological deterioration before instituting aggressive measures. The ideal therapeutic combination would improve CBF, reverse or attenuate DID, and have low potential for adverse events. While this intervention has yet to be defined, varying combinations of medical and endovascular approaches are widely used to treat vasospasm.
Medical therapy HHT, also described as hemodynamic augmentation, is the cornerstone of medical therapy for vasospasm. The varying nomenclature reflects the fact that it is unclear which specific intervention is most effective.

Intra-arterial vasodilators
Papaverine is a potent smooth muscle relaxant; its use in SAH related vasospasm has been extensively studied. It is infused intra-arterially through a micro-catheter proximal to the vasospastic vessel. In most cases, its effect on angiographic vasospasm is immediate and dramatic [103][104][105][106] but reversal of clinical deficits is variable [91]. Papaverine has been shown to transiently improve regional CBF [103,107]. The effect of papaverine on outcome is unknown. In one study, when compared to patients with similar characteristics and degree of vasospasm, patients who were treated with papaverine had similar outcome at three months [108].
In most centers, use of papaverine has been relegated to a secondary role or altogether abandoned because of its shortlived effect and a myriad of complications. The most serious are increased intracranial pressure [109], brainstem depression [110], worsening of vasospasm [111,112], neurological deterioration with gray matter changes on MRI [113], and seizures [114].
This has led to growing use of intra-arterial nicardipine, verapamil, nimodipine, and milrinone as alternatives to papaverine. Nicardipine reverses angiographic vasospasm and significantly reduces mean peak systolic velocities in treated vessels, with no sustained effect on intracranial pressure or cardiovascular function [115]. Verapamil is reported to reduce angiographic spasm and produce clinical improvement in a third of cases without significant adverse events [116]. Nimodipine showed similar favorable results in two small retrospective series [117,118]. Controlled clinical trials are lacking.

Future directions
A number of therapies are currently being developed and are at different stages of testing. They include magnesium sulfate (Mg ++ ), statins, NO donors, and ET-1 antagonists.

Magnesium sulfate
Hypomagnesemia on admission occurs in 38% of individuals with SAH [119]. Whether it independently predicts the development of DID is controversial [119,120]. The appeal of Mg ++ in SAH stems from its biochemical properties as a physiological antagonist of calcium [121], ease of administration, low cost, the ability to measure and regulate concentration in body fluids [122,123], and favorable safety profile.
There have been a number of encouraging reports on the effect of Mg ++ in animal models of SAH related vasospasm [124][125][126][127]. In patients with stroke and SAH, administration of Mg ++ is practical and safe [122,123,[128][129][130][131]. In a pilot, randomized, double blind study comparing Mg ++ to saline there was a trend toward less symptomatic vasospasm with Mg ++ [129]. Yet a large controlled trial of continuous Mg ++ infusion did not find conclusive effects on DID or outcome [132]. In a small, single-center trial Mg ++ was similar to intravenous nimodipine in preventing DID [133]. On the other hand, Mg ++ was of no added benefit in patients receiving prophylactic hypervolemia/hemodilution [134]. Interestingly, a TCD study showed no improvement in elevated mean flow velocities in middle cerebral arteries of patients with clinical vasospasm after receiving a bolus infusion of Mg ++ [135].
The proposed mechanism of neuroprotection in vasospasm is related to induction of the NOS pathway, leading to dilation of cerebral vessels and improved CBF [136][137][138].
Two small randomized placebo-controlled, single-center studies investigated the safety and feasibility of statins in SAH. In one study, pravastatin reduced the incidence of TCD-defined vasospasm and shortened the duration of severe vasospasm [139]. Another randomized controlled trial used simvastatin in a smaller group of patients [140]. The incidence of TCD-defined vasospasm and DID was significantly reduced in the simvastatin group. The routine use of statins in SAH is awaiting larger, multi-center clinical trials showing clear reduction in DID and improvement in overall outcome.

Nitric oxide donors
NO is a free radical gas formed by the enzyme NOS from the substrate L-arginine. It was discovered in 1987 [141] and appears to have a crucial role in controlling cerebral vasomotor tone. Tonic release of NO is an important regulator of resting CBF; inhibition of NOS constricts cerebral arteries and decreases CBF [142][143][144].
Intraventricular administration of sodium nitroprusside, a NO donor, to patients with medically refractory vasospasm had variable effects on CBF and a high rate of adverse events [145]. Partial to complete reversal of angiographic vasospasm was seen in ten patients after sodium nitroprusside [146], and symptoms completely resolved in two. Vomiting was the most common adverse effect (in seven out of ten) and three patients had mild fluctuation in blood pressure. In three patients administered intrathecal sodium nitroprusside, clinical and angiographic improvement and excellent outcome with no systemic or neurological complications was reported [147].
Finally, transdermal nitroglycerin was tested in SAH. There were no differences in terms of DID and TCD velocities between the nitroglycerin group (nine patients) and the control group (eight patients). CBF, measured by perfusion computed tomography, was increased in the nitroglycerin group [148]. Large randomized and controlled trials of NO donors in SAH are in the planning stage.

Endothelin-1 antagonists
ET-1 was identified in 1988 [149]. It is a 21 amino acid peptide generated in the endothelium of blood vessels and has an important role in vascular tone regulation. ET-1 exerts its effects through two receptor subtypes, ET A and ET B . ET A receptors are found on vascular smooth muscle cells and mediate vasoconstriction of small and large blood vessels. ET B receptors, on the other hand, are found in brain, aorta, lung and kidney vascular endothelial cells where they modulate vasoconstriction in response to ET-1, through the production of vasodilator substances like prostacyclin and NO. They are also found on vascular smooth muscle cells where they can mediate vasoconstriction [150][151][152][153].
A phase IIa trial of clazosentan (an ET A antagonist) demonstrated reduction in the incidence and severity of angiographic vasospasm [154]. Adverse events were comparable to placebo. An ET A/B antagonist, TAK-044, was also tested in a phase II trial [155]. The drug was very well tolerated. Delayed ischemic deficits occurred in 29.5% of patients receiving active treatment and 36.6% of patients on placebo (risk reduction 0.8, 95% confidence interval of 0.61 to 1.06).
Most recently, clazosentan was tested in a controlled clinical trial enrolling 413 patients with SAH [156]. Moderate to severe angiographic spasm was significantly reduced, although there was no effect on outcome.

Other therapies
Enoxaparin, a low molecular weight heparin, was studied in a randomized clinical trial in SAH [157]. Although the incidence of DID and infarcts was reduced, the admission characteristics of the two groups were not well balanced.
Nicardipine prolonged-release implants (NPRI s ) are placed in the subarachnoid space at the time of surgical clipping of aneurysm. Two case series describing the use of such implants are of interest [158,159]. In one, Kasuya and colleagues report an incidence of DID of 6% when they were applied in 69 patients with thick subarachnoid clots [158].
Recently, a randomized double-blind trial of the implants showed a dramatic reduction in incidence of angiographic vasospasm and infarctions [160].
A randomized, controlled trial compared dapsone to placebo (n = 49) in Fisher grade 3 and 4 SAH [161]. It is thought to act as a glutamate receptor antagonist and reduced the incidence of DID (26.9% versus 63.6%, p = 0.01) and significantly improved outcome at discharge and three months (modified Rankin scale).

Conclusion
There is a great need for new preventive strategies and therapies to lessen the impact of vasospasm following SAH. Unfortunately, to date the available literature provides few definitive answers. A number of factors conspire to make the task of better defining treatment exceedingly challenging. They include the complex, incompletely understood mechanisms operating in SAH, the relatively low frequency of the disease, and most importantly, the large number of other factors that influence outcome is this population. To properly study interventions in SAH, very large multi-center, prospective, tightly controlled studies are needed; unfortunately, their design and execution remains a major challenge.
This lack of definitive answers leads to a wide variation in the specifics of managing patients with SAH. Yet in general, current management focuses on screening patients at risk for DID, implementing multiple preventive measures and more aggressive interventions in selected patients. A number of neuroprotective approaches as well as the use of multimodal treatment regimens [162] are under active development and hold promise in the treatment of vasospasm.

Competing interests
SGK declares that he has no competing interests. MND consults for Novo Nordisk and Astellas Pharma.

Additional data file
Additional file 1 Major controlled trials of prevention and treatment of vasospasm following subarachnoid hemorrhage.