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 ultra-sonography (TCD) and angiography. Angiography can be both diagnostic and therapeutic (see below).

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 4546. Although it is almost as sensitive as angiography in detecting symptomatic vasospasm 474849, 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).

The ability of other imaging modalities, like perfusion computed tomography 5051, Xenon computed tomography 5253, diffusion weighted magnetic resonance imaging 5455, and single photon emission computed tomography (SPECT) 5156 in detecting vasospasm are under investigation. These imaging techniques could soon become routine in the diagnosis of vasospasm 57. Unlike cerebral angiography and TCD, these techniques measure regional perfusion, not merely arterial diameter or flow velocities. Online micro-dialysis is another new technique currently being studied in vasospasm 58. It involves measuring extracellular cerebral fluid levels of an array of substances like glucose, glutamate, lactate, and pyruvate.

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 1259, cost-effective 60, and most importantly reduces the risk of poor outcome and secondary ischemia after aneurysmal SAH 710111261. 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.

Nicardipine 62636465 and diltiazem 62636667 have both been studied, but only nicardipine in a controlled fashion. In a large randomized trial nicardipine decreased the incidence of DID, reduced the use of HHT and reduced angiographic vasospasm, yet it did not improve overall outcome at 3 months 626465. An unblinded small study of prophylactic, serial intrathecal nicardipine was conducted in 50 patients with SAH. This approach reduced the incidence of both angiographic and clinical vasospasm and improved good clinical outcome at 1 month by 15%. Adverse events were frequent; nine patients developed headache and two had meningitis 68.

Phase I and II safety studies of diltiazem in SAH demonstrated safety but no effect on vasospasm 67. A recently published paper describing a series of 123 SAH patients treated with oral diltiazem instead of nimodipine reported a 19.5% incidence of DID 66. Favorable outcome (Glasgow Outcome Scale of 4 or 5) was achieved in 75% of patients.

Tirilazad, a non-glucocorticoid 21 amino-steroid free radical scavenger, was studied in several controlled trials 6970717273 following promising results in primate vasospasm models 747576. 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.

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 777879. 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.

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 8283 but had no impact on incidence of angiographic vasospasm 84. Intra-and 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 placebo-controlled trial 8687. 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 vasospasm-related infarction 88. Larger placebo controlled studies are needed to determine if these interventions produce sustained clinical benefits.

Following promising experimental results, a pilot study of prophylactic transluminal balloon angioplasty (TBA) was undertaken in a group of 13 patients with Fisher grade 3 SAH 89. None of the patients developed DID. Recently, a multi-center randomized trial evaluated the use of prophylactic TBA in a larger group of patients 90. The procedure showed no benefit, and was responsible for 3 deaths (4%) from vessel rupture, an incidence higher than the 1.1% reported in the literature 91.

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. Studies of CBF in SAH patients undergoing HHT have yielded varying results. While acute volume expansion in patients with symptomatic vasospasm increased CBF in areas of brain most vulnerable to ischemia on positron emission tomography (PET) 92, prophylactic hypervolemia did not produce such a response when SPECT 77 or ¹³³Xe clearance 78 were used. HHT appears safe following endovascular coiling of aneurysm 93, and even in patients with prior cardiac disease 94.

In clinical practice, attempts to keep symptomatic patients hypervolemic using crystalloids or colloids should be made. Although exact criteria have been hard to establish, hypertension is induced using vasopressors until there is clinical improvement, a preset limit is reached, or adverse effects occur. Clinical improvement can be dramatic 94, but is an inconsistent finding across case series. Prospective controlled outcome studies of hemodynamic interventions are lacking. Yet, such clinical trials are unlikely to be completed given the widespread use of these interventions.

Endovascular techniques frequently play a role in the aggressive treatment of vasospasm 9596. They include TBA and intra-arterial infusion of vasodilators. Both methods have their unique associated risks and benefits and are usually undertaken after a trial of medical therapy except in patients with severe cardiac disease.

Hypomagnesemia on admission occurs in 38% of individuals with SAH 119. Whether it independently predicts the development of DID is controversial 119120. 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 122123, and favorable safety profile.

There have been a number of encouraging reports on the effect of Mg⁺⁺ in animal models of SAH related vasospasm 124125126127. In patients with stroke and SAH, administration of Mg⁺⁺ is practical and safe 122123128129130131. 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.

Statins, or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, appear to have a promising role in vasospasm prevention. The proposed mechanism of neuroprotection in vasospasm is related to induction of the NOS pathway, leading to dilation of cerebral vessels and improved CBF 136137138.

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.

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 142143144.

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.

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 150151152153.

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.

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 158159. 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).