Clinical aspects

Description

	• Various methods are being used to prevent or treat cerebral vasospasm.
	• Drugs used for the treatment of vasospasm are based on various concepts of the pathomechanism of vasospasm.

Principles of management of cerebral vasospasm. An overview of methods of managing vasospasm is shown in Table 1. Various pharmacological agents are shown in Table 2.

Table 1. Overview of Methods of Cerebral Vasospasm Management

I. Pharmacological agents to prevent vasospasm and to protect the brain against cerebral ischemia (see Table 2) II. Medical methods to improve cerebral blood flow and perfusion
	A. Volume expansion B. Induced hypertension
III. Adjuncts to surgery for intracranial aneurysms
	A. Irrigation of blood from subarachnoid spaces in the brain B. Application of vasodilators directly to the affected arteries C. Implantation of prolonged-release papaverine pellets in basal cisterns of the brain D. Application of low-power pulsed dye laser to the arterial wall
IV. Minimally invasive procedures
	A. Intracisternal administration of tissue plasminogen activator B. Endovascular approach: transluminal balloon angioplasty by dilatation of the spasm with an intraarterial balloon catheter with or without infusion of vasodilators C. Intraaortic balloon counterpulsation to improve cerebral blood flow D. Cervical spinal cord stimulation E. Gene therapy

Table 2. Pharmacological Agents Used for Cerebral Vasospasm According to the Concepts of Pathomechanism

Concept: Intracellular calcium ion is essential for muscle contraction in the vessel wall.
	Pharmacologic agent
	• Calcium antagonists: nicardipine, nimodipine, magnesium sulfate
	Rationale
	• Prevention or reversal of vasospasm
Concept: Oxyhemoglobin released from red blood cells has a potent direct vasoconstrictor effect on the vessel wall. A common agent that produces endothelial injury is the superoxide ion.
	Pharmacologic agent
	• Free radical scavengers: Tirilazad mesylate recombinant human superoxide dismutase
	Rationale
	• Prevention of vasospasm by preventing endothelial injury initiated by the superoxide ion
Concept: Oxyhemoglobin released from red blood cells has a potent direct vasoconstrictor effect on the vessel wall. A common agent that produces endothelial injury is the superoxide ion.
	Pharmacologic agent
	• Free radical scavengers: Tirilazad mesylate recombinant human superoxide dismutase
	Rationale
	• Prevention of vasospasm by preventing endothelial injury initiated by the superoxide ion
Concept: Endothelin-1 is a powerful endogenous vasoconstrictor substance produced by endothelial cells.
	Pharmacologic agent
	• Endothelin receptor antagonists, eg, clazosentan and prostacyclin
	Rationale
	• Prevention or reversal of vasospasm
	• Neuroprotective effect
Concept: Spasmogenic substances released from the blood clot in the subarachnoid space
	Pharmacologic agent
	• Thrombolytic: intracisternal tissue plasminogen activator
	Rationale
	• Facilitation of clearance of blood from the subarachnoid space
Concept: Vasoconstriction due to deficiency of endothelial nitric oxide
	Pharmacologic agent
	• Nitric oxide donors: sodium nitroprusside nitroglycerin
	Rationale
	• Nitric oxide is an extremely potent vasodilator and accounts entirely for the biological effect of endothelium-derived relaxing factor. It acts through cyclic guanylic acid-dependent protein kinases.
Concept: Protein-dependent inflammatory response in the vessel wall in vasospasm
	Pharmacologic agent
	• Synthetic serine protease inhibitor FUT-175 (nafamostat mesylate)
	Rationale
	• Inhibits both complement pathways and the other plasma protease cascades (coagulation, fibrinolysis, and the kinin system)
Concept: Cerebral ischemia in vasospasm leading to infarction
	Pharmacologic agent
	• Erythropoietin
	Rationale
	• Neuroprotective by antiapoptotic action
	• Erythropoietin increases brain tissue oxygen tension (19)
Concept: Clotted blood accumulated in the cerebrospinal fluid prevents clearance of spasmogens.
	Pharmacologic agent
	• Recombinant tissue plasminogen activator
	Rationale
	• Thrombolysis facilitates drainage of blood from cerebrospinal fluid and prevents vasospasm
Concept: Effective vasodilation
	Pharmacologic agent
	• Milrinone, a phosphodiesterase inhibitor, given intra-arterially
	Rationale
	• Combining vasodilating and inotropic properties is desirable
Concept: Platelet-derived growth factor-BB (PDGF-BB) is produced around the cerebral arteries following subarachnoid hemorrhage and produces vasospasm
	Pharmacologic agent
	• Trapidil, an antiplatelet agent, relieves vasospasm
	Rationale
	• Trapidil is an antagonist of PDGF-BB function and forms the basis of developing better agents to counteract cerebral vasospasm.

Removal of blood from CSF. One of the older methods for prevention and reduction of vasospasm associated with subarachnoid hemorrhage is drainage of CSF by lumbar puncture based on the concept of removal of spasmogens in CSF. Shunting of CSF after subarachnoid hemorrhage has been observed to markedly reduce the risk of clinically evident vasospasm and its sequelae, shorten hospital stay, and improve outcome. Although CSF drainage or shunting procedures are done for hydrocephalus as a complication of subarachnoid hemorrhage, the value of early drainage of CSF on prevention of complications of subarachnoid hemorrhage (eg, vasospasm triggered by presence of blood) was tested in a phase 3 clinical trial completed in 2017 (NCT01258257). According to an earlier published protocol, this prospective randomized controlled trial investigated whether early application of a lumbar drainage after aneurysm has been secured by coiling or clipping improves clinical outcome (04). One of the secondary endpoints was angiographic vasospasm. A systematic review and meta-analysis of controlled trials concluded that external lumbar drainage was associated with a statistically significant decrease in the risk of delayed cerebral ischemia-related complications (cerebral infarctions and clinical deterioration), as well as the risk of severe disability; however, it was not translated in a lower mortality (03). Surgical removal in the acute stage of as many blood clots as possible by irrigation of all accessible cisterns can decrease symptomatic cerebral vasospasm and reduce the severity of angiographic cerebral vasospasm (36).

Tissue plasminogen activator has been administered intrathecally for intracisternal thrombolysis to facilitate removal of subarachnoid blood accumulations. Various studies using this method suggest a beneficial effect, but there is a paucity of randomized studies.

Triple-H approach. A commonly used approach to reduce the occurrence of delayed ischemic neurologic deficits consists of 3 measures: hypertension, hypervolemia, and hemodilution. Human albumin is used to induce hypervolemia; although it may increase the mortality rate in critically ill patients with subarachnoid hemorrhage. The primary rationale for the use of induced hypertension is that raising perfusion pressure may increase cerebral blood flow in high-resistance vascular beds, increase collateral flow to ischemic brain regions, or both. Dopamine-induced hypertension is associated with an increase in cerebral blood flow in patients with ischemia after subarachnoid hemorrhage. However, a potential risk of dopamine-induced ischemia exists, so the treatment should be guided by local cerebral blood flow measurements. Hypertension can be induced only in such patients if the ruptured aneurysm has been repaired so that no recurrence of hemorrhage occurs. This therapy, though, does not increase the risk of hemorrhage from unsecured, unruptured aneurysms in the acute setting or in their short-term natural history. A systematic review of studies with triple-H approach concluded that hypervolemia did not appear to be superior to normovolemia, whereas its side effects were significantly more frequent. However, hypertension was associated with higher cerebral blood flow, regardless of the status of volume, with reversal of symptoms in two thirds of patients (51).

Calcium antagonists. These were originally proposed for the prevention or treatment of vasospasm following subarachnoid hemorrhage because of their ability to block the effect of a variety of vasoconstrictor substances on cerebral arteries in vitro. They were expected to prevent or ameliorate the narrowing of major arteries in the brain and to prevent ischemic brain damage.

Nimodipine. Nimodipine was the first well-known agent of this class for the treatment of subarachnoid hemorrhage. Although it ameliorated the ischemic consequences of subarachnoid hemorrhage in controlled clinical trials, no reversal of narrowing could be demonstrated on cerebral angiography. Based on the results of older clinical trials, oral nimodipine has been used as the initial treatment in patients with aneurysmal subarachnoid hemorrhage with intravenous administration reserved for those patients who cannot take oral nimodipine.

High-dose intravenous nicardipine has been shown to reduce the incidence of angiographic and symptomatic vasospasm in patients with subarachnoid hemorrhage, but the treatment may be complicated by adverse effects such as hypotension and pulmonary edema. Intraarterial nimodipine reduces angiographic vasospasm with increase in cerebral perfusion and is more effective than intraarterial papaverine, but the effect is temporary.

Nicardipine. Nicardipine prolonged-release implants, positioned next to the large cerebral arteries at the time of surgical clipping of the ruptured aneurysm, have been shown to decrease the incidence of angiographic vasospasm from approximately 70% to less than 10% (50).

Intrathecal nicardipine is effective in the treatment of vasospasm associated with aneurysmal subarachnoid hemorrhage after other prophylactic and aggressive therapeutic management for vasospasm failed. Cisternal lavage with nimodipine by stereotactic catheter ventriculocisternostomy is a novel rescue therapy for the prevention of delayed cerebral infarction due to cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (43).

Intra-arterial nicardipine is an effective and safe treatment for cerebral vasospasm. Infusion can be performed from the cervical catheter with microcatheter infusion (37).

Verapamil. This is another calcium channel blocker that has been used intra-arterially for the treatment of vasospasm. Low doses are generally used because of the concern regarding hemodynamic effects of verapamil. High-dose intraarterial verapamil may be used to treat cerebral vasospasm without compromising hemodynamic stability or increasing intracranial pressure.

Magnesium sulfate. Vasodilatory effect of magnesium is mediated through blocking of calcium channels as well as by antagonism of the vasoconstricting effect of endothelin-1 and oxyhemoglobin on the cerebral vessel wall. Intravascular administration of magnesium sulfate fails to show vasodilatory effect because it does not cross the blood-brain barrier. A preliminary clinical study indicated that intra-cisternal infusion of magnesium sulfate solution has vasodilatory effect on cerebral vasospasm after subarachnoid hemorrhage and early clipping of the aneurysm (29). However, a phase 3 clinical trial and metaanalysis of other randomized trials showed that magnesium is not superior to placebo for the reduction of poor outcome after aneurysmal subarachnoid hemorrhage (12).

Dantrolene. Dantrolene sodium produces relaxation of skeletal muscle by interfering with the release of calcium from the sarcoplasmic reticulum. It is approved for the management of spasticity and is used in patients with neuroleptic malignant syndrome. In a prospective, open-label, single-dose ascending safety trial, patients with cerebral vasospasm after subarachnoid hemorrhage received a single dose of intravenous dantrolene, and low dose was shown to inhibit vasoconstriction (31). A randomized double-blind placebo-controlled safety trial showed that intravenous dantrolene was well tolerated, but due to the small number of participants, the trial was not powered to detect efficacy (30).

Colforsin daropate. This drug directly activates adenylate cyclase, which increases intracellular cAMP concentrations and facilitates calcium uptake into the sarcoplasmic reticulum, leading to depletion of the amount of calcium available for smooth muscle contraction. In a series of patients with cerebral vasospasm who received intraarterial colforsin daropate, angiographic improvement was observed following all procedures, and clinical improvement was observed following 86% of the procedures in symptomatic cases (49).

Endothelin receptor antagonists. Endothelin, a powerful endogenous vasoconstrictor, is the key mediator of vasospasm following subarachnoid hemorrhage as indicated by the increase of plasma and cerebrospinal fluid levels of endothelin-1. The function of endothelin-1, endothelin-2, and endothelin-3 is mediated via endothelin-A and endothelin-B receptors; the former generally mediates vasoconstriction, and the latter vasodilatation.

The major limitation of peptide endothelin receptor antagonists is that they do not penetrate the blood-brain barrier.

Clazosentan. This was the first highly selective non-peptide endothelin-1 receptor antagonist has proven to be effective in the treatment of cerebral vasospasm in initial clinical trials. A phase IIa multicenter study indicated that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage, with the incidence and severity of adverse events comparable to that of placebo. However, the reduction of vasospasm did not translate into improvement in clinical outcome. A metaanalysis of randomized trials demonstrated a significant decrease in the incidence of delayed ischemic neurologic deficits in patients treated with a high dose of clazosentan (15 mg/h) after aneurysmal subarachnoid hemorrhage, and it had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h), indicating the need for further study to fully understand the potential usefulness of clazosentan (44). REVERSE (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage), a phase 2 prospective, multicenter, open-label, single-arm study, was conducted to evaluate whether clazosentan (15 mg/h) has an early effect in reversing angiographically-confirmed cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage treated by endovascular coiling or surgical clipping (20). Recruitment in this trial was stopped after stage 1 in accordance with the predefined interim analysis criteria as the exploratory analysis showed a significant reversal of vasospasm or improvement over the admission status. Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, particularly, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial (NCT03585270).

A systematic analysis of randomized clinical trials has shown significant beneficial outcomes of high-dose clazosentan in preventing cerebral vasospasm and subsequent cerebral infarction compared with low-dose clazosentan, with a manageable safety profile (48). However, high doses of clazosentan had no significant effect on rescue therapy and vasospasm-related morbidity or mortality.

Prostacyclin. Prostacyclin is an endothelin receptor antagonist and platelet inhibitor as well as a vasodilator. A randomized, blinded, pilot clinical trial of prostacyclin was conducted to evaluate prevention of delayed ischemic neurologic deficits, which are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage (41). It was well tolerated but did not increase cerebral blood flow. Incidence of delayed ischemic neurologic deficits and angiographic vasospasm was markedly higher in the placebo group, although this difference was not statistically significant.

Iron-chelating agents. The use of iron chelators in vasospasm associated with subarachnoid hemorrhage is based on the experimental evidence that iron in the oxyhemoglobin causes vasospasm by generating free radicals and lipid peroxides. Although it is the ferrous state (Fe++) of the iron that catalyzes these reactions, proponents of the free radical hypothesis have studied only chelators of ferric (Fe+++) or free iron, such as deferoxamine, as potential therapies for vasospasm with limited success.

Deferoxamine. Oxyhemoglobin released from the lysis of red blood cells produces vasospasm and is a mechanism of the production of free radicals. The Haber-Weiss reaction resulting in singlet oxygen formation is catalyzed by the presence of free ferric ion. Deferoxamine, a selective ferric chelating agent, was shown to protect against vasospasm in animal models of vasospasm, pointing to a role of ferric ion in the development of vasospasm.

Deferoxamine chelates the free ferric ion (Fe+++) but has no effect on iron bound to proteins such as heme or transferrin. Deferoxamine renders iron nonreactive to free-radical generating reactions that damage biomolecules and tissues. Currently, no practical application of deferoxamine in preventing vasospasm is available, although the drug is marketed for another indication.

Papaverine. Papaverine is 1 of the strongest of the nonspecific vasodilatory agents and has been used for the prevention and treatment of clinical and experimental vasospasm with administration via the intravenous, intraarterial, and intrathecal routes as well as direct application to the arteries during neurosurgical procedures. Intravenous infusion is usually not effective, and intraarterial infusion produces hypotension. Subarachnoid injection is more effective. In a study on patients with delayed-onset post-subarachnoid hemorrhage vasospasm, intraarterial papaverine led to angiographic improvement of cerebral vasospasm in 80% of the patients (21). The initial detrimental effects of the endovascular procedure itself were outweighed by an improved cerebral metabolism within 10 hours thereafter. This improvement is temporary, and repeated interventions or continuous application should be considered.

Statins. This category of drugs may reduce vasospasm by increasing levels of endothelial nitric oxide. In simvastatin, another mechanism of action is that it decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. Randomized, placebo-controlled trials have shown that acute treatment with pravastatin after subarachnoid hemorrhage is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related delayed ischemic deficits Prophylactic use of simvastatin has also attenuated serum biomarkers associated with brain injury and decreased the incidence of radiographic vasospasm and delayed ischemic deficit. Some studies of statins, however, did not show significant clinical improvement in patients with vasospasm after subarachnoid hemorrhage. A randomized controlled trial of pitavastatin, a long-acting statin, after repair of a ruptured aneurysm did not show statistically significant differences in the outcome than the placebo group, although there was definite, statin-induced amelioration of cerebral vasospasm on digital subtraction angiograph (34). The authors of this study did not recommend administration of any type of statin in the acute phase of aneurysmal subarachnoid hemorrhage. A systematic review and metaanalysis of randomized controlled trials concluded that statins significantly reduced cerebral vasospasm and mortality and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage (45).

Thromboxane A2 synthetase inhibitor. The effects of thromboxane A2 synthetase inhibitors on delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage have been inconsistent in various studies. Thromboxane synthetase A2 probably does not play a part in the pathogenesis of chronic vasospasm although some thromboxane A2 synthetase inhibitors have a strong antiplatelet and antithrombotic activity. It is unlikely that monotherapy with drugs of this class will be effective in the treatment of cerebral vasospasm.

Free radical scavengers.

Tirilazad mesylate. Tirilazad mesylate is a free radical scavenger for the treatment of ischemic stroke. Free radicals released by oxyhemoglobin are 1 of the factors causing vasospasm, and, therefore, the effect of this compound was investigated on the intraluminal narrowing of the basilar artery in experimental subarachnoid hemorrhage. In a phase III study, a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, but the primary endpoint (mortality rate at 3 months post-subarachnoid hemorrhage) was not affected by the study drug. Further development of this drug has been discontinued.

Antivasospasm substance or "AVS" [(+/-)-N, N’-propylenedinicotinamide; nicaraven]. This is a hydroxyl radicals scavenger that has shown marked ameliorative effects on cerebral vasospasm and ischemic brain damage in animal experimental studies as well as clinical trials. No significant adverse reaction attributable to treatment was observed. The usefulness of antivasospasm substance in therapy for subarachnoid hemorrhage is strongly indicated by the fact that the agent significantly ameliorated delayed ischemic neurologic deficits and produced a reduction in the cumulative incidence of death by 3 months. It was tested in clinical trials in Japan and has not been introduced into clinical practice in any other country.

Nitric oxide donors. There is experimental and clinical evidence of positive effects of nitric oxide donors such as nitroglycerin on cerebral vasospasm. Thus, nitroglycerin influences the cerebral vascular tone and increases cerebral blood flow. However, the short half-life of nitric oxide and the unwanted effects of nitric oxide donors (eg, hypotension) limit their clinical usefulness. Transdermal nitroglycerin therapy for vasospasm associated with subarachnoid hemorrhage is possible without increasing the risk of delayed ischemic neurologic deficit. The exact timing of onset, duration, and reduction of nitroglycerin administration in respect to the appearance of vasospasm may have a strong impact on the success of such a therapy.

Intrathecally administered sodium nitroprusside and nitroglycerin, both donors of nitric oxide, can rapidly and completely reverse endothelin-1–induced cerebral vasoconstriction in experimental animals without causing hypotension. In an open clinical trial, intrathecal sodium nitroprusside was shown to be a safe and potentially effective treatment for established delayed cerebral vasospasm and cerebral ischemia refractory to conventional treatment, but this method has not been adopted for clinical use, and there have been no publications regarding further research on this topic during the past decade. However, animal experimental studies on intrathecal nitroglycerine have continued. Prophylactic, continuous intrathecal administration of glyceryl trinitrate prevents vasospasm of the basilar artery in the rabbit model of subarachnoid hemorrhage.

Hemoglobin, released from breakdown of red blood cells in the subarachnoid space, destroys nitric oxide synthase-containing neurons in the cerebral arteries, leading to deficiency of nitric oxide, which initiates delayed vasospasm. This provides the rationale for exogenous nitric oxide delivery. As an alternative to exogenous delivery of nitric oxide, inhibition of the L-arginine-methylating enzyme or stimulation of asymmetric dimethyl arginine-hydrolyzing enzyme may provide new therapeutic modalities to prevent and treat vasospasm.

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one]. This is a lipid-soluble, seleno-organic compound that potently inhibits lipid peroxidation through a glutathione peroxidase-like action. As it is effective against membrane hydroperoxides (such as phospholipid hydroperoxide glutathione peroxidase) but not against glutathione peroxidase, this agent effectively inhibits both nonenzymatic and enzymatic (the lipoxygenase pathway of the arachidonate cascade) lipid peroxidation in vitro. Results of a study of ebselen versus nimodipine on cerebral vasospasm following experimental subarachnoid hemorrhage in rats showed that it has neuroprotective effects by acting to prevent vasospasm. It was shown to be neuroprotective in stroke and is approved in Japan for this indication but not in Europe or the United States. Based on numerous in vitro and in vivo research, mechanisms are proposed to understand the biomedical and molecular actions of ebselen in health and disease, and it is currently under clinical trials for the prevention and treatment of various human disorders (52).

Erythropoietin. This cytokine plays an important role in the brain's response to neuronal injury. Systemic administration of recombinant human erythropoietin protects neurons from injury after middle cerebral artery occlusion. Its neuroprotective action is likely due to inhibition of apoptosis. Although it has proven effective in experimental subarachnoid hemorrhage in animals, the erythropoietic effects may limit the clinical use of recombinant human erythropoietin, and development of selective erythropoietin-derived neuroprotective agents is needed.

Fasudil hydrochloride. This is an orally available inhibitor of Rho kinases, which are involved in a variety of biochemical signal transductions in cells. Inhibition of Rho-kinase facilitates relaxation of blood vessels. Intra-arterial administration of fasudil hydrochloride is safe and effective for patients with vasospasm following subarachnoid hemorrhage (22). It is widely used in Japan. Intraarterial infusion of fasudil hydrochloride has been successfully used for relief of posttraumatic cerebral vasospasm (32).

Phosphodiesterase inhibitors. Because nitric oxide-cyclic GMP vasodilatory pathway is strongly implicated in its pathophysiology, phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role. This is the basis for use of PDE5 inhibitors for treatment of cerebral vasospasm.

Sildenafil. Sildenafil is approved for the treatment of erectile dysfunction, attenuates an increase in PDE5 activity and restores cGMP levels after subarachnoid hemorrhage, making it a promising new therapy for vasospasm and neurologic deficits in cerebral vasospasm (18).

Milrinone. This is a phosphodiesterase inhibitor and a potent vasodilator that is marketed for the treatment of heart failure. A clinical study has shown that intraarterial milrinone is effective and safe for reversal of cerebral vasospasm after subarachnoid hemorrhage and recommended that it should be further tested in large randomized trials.

Cilostazol. This is a quinolinone-derivative and a selective inhibitor of phosphodiesterase 3 that is marketed for the treatment of intermittent claudication. A randomized, double-blind, placebo-controlled trial has shown the efficacy of cilostazol in preventing symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage and improved outcomes without serious adverse effects (28).

Clinical trials of therapies for vasospasm. As of November 4, 2020, the Clinical Trials database lists 141 clinical trials. These cover trials planned, those in progress, trials discontinued, as well as those already completed.

Treatment of vasospasm in conjunction with surgery for intracranial aneurysms. Surgery on intracranial aneurysms provides an opportunity to visualize and treat the vasospasm during surgery. Application of papaverine to the vasospastic segment of the artery is a common practice. Various methods of application of papaverine are used, of which the simplest is application of a gelfoam or cotton strip soaked in papaverine solution to the artery. Controlled-release papaverine pellets can be implanted during aneurysm surgery in cisterns containing arteries in patients considered to be at risk of developing vasospasm. Nicardipine prolonged-release implants can also be placed adjacent to the arteries during surgery.

Washing out the subarachnoid blood clot at surgery has been practiced, with some evidence of efficacy in reducing cerebral vasospasm.

Laser-induced vasodilation is a mechanical phenomenon created by absorption of laser light energy, which induces cavitation bubble formation with mechanical disruption of the contractile protein in the vascular smooth muscle cells. The vasodilatation induced is sustained after extravascular irradiation. This method has a potential application in the treatment of vasospasm during surgical procedures. However, technical refinements and safety studies have not been carried out and this approach is not in clinical use.

In view of the depletion of nitric oxide, stored blood transfusion during aneurysm surgery should be kept to a minimum. The use of nitric oxide donor compounds may be considered.

Minimally invasive procedures for the treatment of vasospasm. Two procedures are worth consideration: (1) infusion of tissue plasminogen activator into the subarachnoid space and (2) dilatation of vasospasm by a balloon catheter or retrievable stent. The term “endovascular intervention” covers both angioplasty and intraarterial administration of therapeutic substances.

Intrathecal tissue plasminogen activator. Tissue plasminogen activator is now a recognized treatment as a thrombolytic agent in acute stroke. Before approval for this indication, its use for lysis of blood in the subarachnoid space was investigated in clinical trials. Intraoperative cisternal irrigation with tissue plasminogen activator combined with cisternal drainage is safe and effective for the prevention of symptomatic vasospasm following subarachnoid hemorrhage.

Dilatation of vasospasm by balloon catheter or retrievable stents. Percutaneous transluminal angioplasty is performed for carotid artery stenosis as an alternative to carotid endarterectomy. Catheter navigation of intracranial arteries is now a routine procedure. Balloon catheter has been used for dilatation of the vasospasm. Real-time angiographic perfusion imaging is feasible during endovascular procedures for vasospasm, and perfusion analysis may aid in assessment of efficacy of the intervention (26).

Supplementation of balloon dilatation with superselective intraarterial infusion of papaverine for the treatment of cerebral vasospasm can achieve improvement in cerebral oxygenation and in the prevention of cerebral lactic acidosis. Normalization of oxygen supply after endovascular treatment needs to be supported by optimal hypervolemic hemodilution and controlled hypertension.

Combination of transluminal balloon angioplasty with infusion of vasodilators via the arterial catheter is somewhat controversial. According to 1 viewpoint, transluminal balloon angioplasty followed by intraarterial infusion of vasodilators leads to a more durable proximal therapy and treats distal vasospasm as well by improving access to infused vasodilators. Balloon angioplasty is generally considered to be an effective technique in treating vasospasm and results in durable clinical improvement, but it should be used judiciously because of a small risk of vessel rupture associated with intracranial angioplasty. Simultaneous endovascular management of ruptured cerebral aneurysms and vasospasm is a viable approach in patients presenting with subarachnoid hemorrhage and severe vasospasm (08). For example, nimodipine can be infused continuously during the coil embolization.

In a preliminary study on 4 patients, self-expandable retrievable stents were used successfully for vasodilation in patients with delayed cerebral vasospasm secondary to subarachnoid hemorrhage (05). There were no complications from the procedure, which produced long-lasting vasodilation and in 2 cases resulted in reversal of neurologic deficits due to cerebral ischemia. A retrospective review of endovascular treatment of patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage by using angioplasty, alone or in combination with vasodilator infusion, showed a modest rate of functional independence at time of discharge from hospital, and initial use of angioplasty reduced the need for subsequent retreatment of vasospasm (47).

Intraaortic balloon counterpulsation. This method has been used to improve cerebral blood flow significantly in patients with cardiac dysfunction and severe cerebral vasospasm that is refractory to traditional treatments.

Cervical spinal cord stimulation. This can be carried out via a percutaneously inserted lead and has been shown to be beneficial for vasospasm associated with subarachnoid hemorrhage. It can be done following surgical repair of the aneurysms. According to 1 hypothesis, vasodilatory effect of spinal cord stimulation may be due to modulation of activity of phosphodiesterases 5 and nitric oxide synthase (eNOS), resulting in enhancement of nitric oxide-cyclic guanosine monophosphate pathway (54). The phase 1 nonblinded study is evaluating the use of cervical spinal cord stimulation for treatment of patients with Hunt and Hess grade 1 to 2 subarachnoid hemorrhage and evidence of cerebral vasospasm (NCT02426827).

Gene therapy. This has been described in the Medlink article on gene therapy for cerebrovascular disease.

The 2 main goals are as follows:

(1) Prevention or relief of vasospasm (2) Cerebral protection against ischemia resulting from vasoconstriction.

Results of a retrospective case-control study indicate endogenous protective mechanisms against cerebral vasospasm in patients with preexisting occlusive cerebrovascular disease or previous cerebral infarct, which may be due to preconditioning effect or the effect of atherosclerosis of vessels (24). This knowledge and further investigations may help in the prognosis of patients with subarachnoid hemorrhage and their susceptibility to develop vasospasm, but it is unlikely to have any therapeutic applications.

Indications

Patient selection would include individuals with vasospasm due to subarachnoid hemorrhage caused by ruptured intracranial aneurysms. Symptomatic vasospasm can be detected by thermal-diffusion flowmetry, particularly in patients with high-grade subarachnoid hemorrhage who cannot be assessed neurologically. In addition, symptomatic vasospasm is more reliable than transcranial Doppler ultrasonography. Findings of cerebral imaging studies, particularly CT angiography and CT perfusion, should be taken into consideration in deciding about the treatment of cerebral vasospasm.

Single-nucleotide polymorphism studies have shown that patients with the T allele of the endothelial nitric oxide synthase gene are more prone to develop severe cerebral vasospasm following subarachnoid hemorrhage. The presence of this genotype is an indication for early treatment of vasospasm to improve outcome.

Contraindications

Patients with clinical grade V (Hunt and Hess classification) should not receive any treatment requiring an invasive procedure. These patients receive medical support, and if they have vasospasm, they can be treated with medical therapy provided that no specific contraindication is known for the drug chosen. Management would be like that of a patient with massive cerebral infarction and edema.

Results

No entirely satisfactory method is available for the treatment of vasospasm. The role of events other than vasospasm, such as early brain injury and cortical spreading depression, and of their contribution to overall mortality and morbidity should also be considered. There is room for trial of innovative procedures. Reversal of vasospasm is possible, but multimodal therapy may be required for overall neurologic improvement of the patient.

In a retrospective study to evaluate the outcome of continued treatment, patients with long-lasting vasospasm, ie, longer than 14 days, had a better outcome than regular-lasting vasospasm following subarachnoid hemorrhage (25). Risk factors for an unfavorable outcome were elderly patients, poor status on admission, and the presence of small intracerebral hematoma.

Vessel volumes are an objective parameter for the interpretation of computed tomography angiography data and can thereby improve multimodal assessment of vasospasm in patients with subarachnoid hemorrhage (35).

Refractory vasospasm. Refractory vasospasm is defined as vasospasm refractory to therapies requiring 3 or more endovascular interventions. Critical hypoperfusion and metabolic derangement are frequently encountered with refractory vasospasm. Endovascular rescue therapy, eg, angioplasty, can be used for refractory vasospasm after subarachnoid hemorrhage, and treatment efficacy can be quantified by multimodal event neuromonitoring (02). A systematic review and metaanalysis of randomized controlled trials and prospective as well as retrospective studies of clinical outcomes of targeted treatments of cerebral vasospasm following aneurysmal subarachnoid hemorrhage concluded that endovascular treatment may improve the outcome of patients with severe-refractory cerebral vasospasm (06). High doses of intravenous milrinone can be used effectively to control refractory cerebral vasospasm and high dose intraarterial nimodipine and milrinone infusion can be used as a rescue therapy for exceptionally resistant cases (14).

Adverse effects

Adverse effects of treatments for vasospasm are usually not serious, considering the seriousness of the basic disease. Volume expansion and induced hypertension carry the risk of rebleeding if the aneurysm has not been repaired. Most of the medical therapies, such as nimodipine, have the same adverse effect profile as when used for other indications. Tissue plasminogen activator infusions in the subarachnoid space may produce a local wound or extradural hematoma if the infusion is given after surgery. Nitric oxide donors, such as nitroprusside, cannot be given systemically due to resulting hypotension, and intrathecal use is safer. Balloon dilatation carries a risk of restenosis at the site of spasm. Seizures are infrequently reported when intraarterial papaverine infusion is given in conjunction with balloon angioplasty. This potential complication should be considered when this route of papaverine administration is entertained in the treatment of vasospasm after subarachnoid hemorrhage. In a review of 188 intraarterial procedures in 88 patients with vasospasm following subarachnoid hemorrhage, ischemic complications occurred in about 6% of patients treated intraarterially for cerebral vasospasm and in 3% of those who underwent transluminal balloon angioplasty (01). As an additional benefit for patients treated with this therapy has not be proven, these authors recommend intraarterial treatment of cerebral vasospasm only in carefully selected cases.

As none of the complications of the various treatments are serious, prognosis of recovery from complications of treatment is good.

Special considerations

Drugs used for vasospasm should be used with caution during pregnancy, as no data are available about their effect on the outcome of pregnancy.

Scientific basis

• Treatments are targeted to the molecular changes in the brain; the vascular endothelium and the vascular smooth muscle cells play an important role in the pathophysiology of vasospasm induced by subarachnoid hemorrhage.

A clinical, prospective study has confirmed that CT angiography detected angiographic vasospasm in 100% patients with aneurysmal subarachnoid hemorrhage, and statistically significant positive correlation was found between the intensity of radiological cerebral vasospasm and appearance of new neurologic deficits and deterioration of 2 points or more per modified Glasgow Coma Scale (11).

Pathomechanism of vasospasm. Vasospasm following subarachnoid hemorrhage is an important cause of cerebral ischemia and is the most frequent serious complication in survivors of subarachnoid hemorrhage. Delayed ischemic deficits due to vasospasm complicate the course of 15% to 36% of patients after aneurysmal subarachnoid hemorrhage and account for 13.5% of in-patient mortality and morbidity. Various pathogenetic agents have been isolated, and oxyhemoglobin is considered the main culprit. Oxyhemoglobin derived from lysis of the red blood cells in the subarachnoid space has several mechanisms of action for producing vasospasm. These include the release of free radicals, the initiation and propagation of lipid peroxidation metabolism to bilirubin (another spasmogenic), the release of vasoactive eicosanoids and endothelin from the vessel wall, perivascular nerve damage, the inhibition of endothelium dependent relaxation, and the induction of structural damage in the vessel wall. Peroxidative membrane damage in the arterial smooth muscle cell leads to prolonged arterial contraction that occurs during vasospasm.

Trauma of manipulation of the arteries during surgery for intracranial aneurysms has been suspected to aggravate vasospasm, but no significant difference in outcome has been observed between those patients who had surgery or endovascular management of their aneurysms.

Experimental studies have shown that perivascular hemolyzed blood, eg, in traumatic brain injury, can also elicit vasoconstriction in isolated basilar and middle cerebral arteries, which can be reversed by nifedipine and high concentration of CO2 (10). The presumed pathomechanism involves an increase in intracellular Ca2+—findings that can contribute to the refinement of local treatment of subarachnoid hemorrhage.

Pathophysiology of vasospasm at the molecular level. Molecular changes in the brain, the vascular endothelium, and the vascular smooth muscle cells play an important role in the pathophysiology of vasospasm induced by subarachnoid hemorrhage. Molecular mechanisms are involved in smooth muscle contraction, endothelial dysfunction, and inflammatory changes in the genesis of vasospasm following aneurysmal subarachnoid hemorrhage.

The Hp2-2 genotype is associated with a higher risk of vasospasm after subarachnoid hemorrhage. Glutamate concentrations increase after aneurysm rupture and correlate with vasospasm in experimental subarachnoid hemorrhage. S-4-CPG, a glutamate receptor inhibitor, prevents vasospasm after experimental subarachnoid hemorrhage in Hp2-2 mice and is a potential therapeutic agent for vasospasm (17).

Changes in the brain. Subarachnoid hemorrhage induces activation of immediate early genes and expression of stress proteins and heat shock proteins such as HSP70. Heme present after subarachnoid hemorrhage is metabolized by heme oxygenase to biliverdin and carbon monoxide. Subarachnoid hemorrhage induces heme oxygenase-1 in the glia without affecting its isoform, heme oxygenase-2. Heme oxygenase-1 is normally detectable in the neuronal populations but increases in response to oxidative stress. It is likely that heme itself, rather than ischemia induced by vasospasm, plays a pivotal role in the expression of heme oxygenase-1. Hemolysate-induced heme oxygenase-1 and HSP70 expression may be used as biomarkers for cell damage in infarcted brain associated with subarachnoid hemorrhage and vasospasm.

According to another view, occurrence of cerebral vasospasm depends on disturbance of balance between free radical formation (oxidative stress) and antioxidant activity (53). Isoprostanes, products of free-radical peroxidation of polyunsaturated fatty acids, are not only biomarkers of oxidative stress, but also have vasoactive, inflammatory, and mitogenic actions via activation of the thromboxane A2 receptor.

Hyperoxemia. Within 72 hours postaneurysmal rupture, hyperoxemia is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage (42). It is a variable that can be readily controlled by adjusting the delivered FiO2 and may represent a modifiable risk factor for vasospasm.

Glial cell dysfunction. A concept that has been proposed is that cerebral vasospasm is not primarily a problem of the cerebral vasculature but a consequence of glial cell dysfunction following spreading depression, which is the response of cerebral cortical tissue to noxious stimuli from subarachnoid hemorrhage (33).

Inflammatory response. Poly(ADP-ribose) polymerase is important in modulating inflammation, as inflammation has been implicated in cerebral vasospasm after subarachnoid hemorrhage. Inhibiting ADP-ribosylation attenuates cerebral vasospasm after subarachnoid hemorrhage in animal models. A review of the literature indicates that leukocyte-endothelial cell interactions play a significant role in the pathophysiology of cerebral vasospasm, and experimental therapeutic targeting of the inflammatory response can prevent vasospasm when timed correctly (40).

Changes in the endothelium. These are the major changes that contribute to vasospasm and include impaired endothelium-dependent relaxation and increased production of endothelins. Excessive concentration of oxyhemoglobin has already been shown to increase production of endothelin and intracisternal injection of endothelin-produced vasospasm in this model, rather than inducing heme oxygenase-1. This observation has implications for the application of endothelin receptor antagonists in reducing vasospasm. Endothelin‑1 and its receptors are involved in the pathogenic mechanism of cerebral vasospasm following subarachnoid hemorrhage. Its expression in CSF may be used as a biomarker of cerebral vasospasm and its receptors may provide novel therapeutic targets (07).

Changes in vascular smooth muscle. Following subarachnoid hemorrhage, depolarization of the vascular smooth muscle cells takes place and may be due to depletion of energy metabolism and impaired potassium channel activity. Various agents acting at potassium channels can partially reverse vasospasm. However, activation of calcium channels can cause smooth muscle contraction and contribute to vasospasm. The rise of intracellular calcium observed after subarachnoid hemorrhage is explained by oxyhemoglobin-induced depletion of intracellular calcium; this leads to an influx of extracellular calcium through the voltage-dependent calcium channels. This has been proposed, but not proven, as the basis of the beneficial effect of calcium channel blockers in vasospasm associated with subarachnoid hemorrhage. Protein kinase C is activated and may interact with other signaling pathways such as myosin-light chain kinase, nitric oxide, intracellular calcium, and protein tyrosine kinase.

Role of nitric oxide in vasospasm. Impairment of nitric oxide production and vasodilator function is an important mechanism associated with the pathogenesis of cerebral vasospasm, accompanied with decreased endothelial nitric oxide synthase mRNA level, loss of neuronal nitric oxide synthase immunoreactivity, and diminished cyclic guanosine monophosphate formation. Consequently, experimental vasospasm can be alleviated with nitric oxide or nitric oxide donors because of their potent relaxing function.

Patients given blood transfusion during surgery for intracranial aneurysms have worse cerebral vasospasm. The explanation is that normally red blood cells deliver the nitric oxide required for vasodilatation of arteries, which is depleted in stored blood.