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Cerebral vasospasm and delayed cerebral ischemia: Review of literature and the management approach
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.253627
Keywords: Cerebral vasospasm, delayed cerebral ischemia, endovascular intervention, medications
Cerebral vasospasm is defined as the constriction of intracranial blood vessels most commonly seen as a sequelae to aneurysmal subarachnoid haemorrhage. Although subarachnoid haemorrhage comprises only 5% of all strokes, the mortality rates are as high as 40%. Severe vasospasm and delayed cerebral ischemia (DCI) remain the most challenging aspects of management of subarachnoid hemorrhage and the largest contributor to morbidity and mortality. Apart from subarachnoid haemorrhage, other entities that may cause cerebral vasospasm are traumatic brain injury,[1],[2],[3] reversible cerebral vasoconstriction syndrome, brain tumor resection,[4],[5],[6],[7] and non-aneurysmal subarachnoid hemorrhage.[8] Cerebral vasospasm is seen on angiography in almost 70% patients with subarachnoid hemorrhage [9] and causes neurological symptoms in about 20%–40% of them.[10],[11] The time period from day 4 to day 12 from the initial hemorrhage is considered as a high risk period for vasospasm. DCI which may or may not be related to cerebral vasospasm can occur in up to 30% of patients with subarachnoid hemorrhage.DCI is more commonly seen after aneurysm clipping and doubles the risk of an adverse outcome.[12] Various pathogenic mechanisms and treatment strategies to manage cerebral vasospasm and DCI have been discussed in the literature.[13] During the course of this review, we discuss the same based on the evidence available.
Cerebral vasospasm has been as perplexing for the pathologists as it has been for the clinicians. Various mechanisms have been implicated in the onset and progression of vasospasm. Nitric oxide (NO), which is a potent vasodilator, has been studied with keen interest in the pathogenesis of cerebral vasospasm. Decreased production and attenuated response to NO in the endothelium have been proposed as probable mechanisms in the development of vasospasm.[14],[15] Other studies have concentrated on the role of hemoglobin (Hb) and its degradation products as irritants to the vascular endothelium leading to vasoconstriction. Degradation of Hb leads to increased production of endothelin-1 which is a potent vasoconstrictor and causes contraction of vascular smooth muscles. Elevated endothelin-1 levels in the plasma and the cerebrospinal fluid have been associated with cerebral vasospasm.[16],[17],[18],[19] By-products of Hb breakdown like bilirubin have been shown to cause oxidative damage leading to cerebral vasoconstriction as well. These oxidative radicals cause smooth muscle constriction and endothelial damage which lead to vasoconstriction.[20],[21] Destruction of blood–brain barrier and leakage of excitatory neurotransmitters such as glutamate lead to activation of metabotropic glutamate N-methyl-D-aspartate (NMDA) receptors causing apoptosis and cell death. More so, elevated levels of glutamate in cerebral micro-dialysis are associated with ischemia, and a similar increase is also seen in patients with aneurysmal subarachnoid hemorrhage and correlates with a poor outcome.[22],[23],[24],[25],[26] Neuroinflammation, caused by leakage of blood products, has been directly implicated in the pathogenesis of vasospasm. There is leukocyte-mediated damage through leukotrienes and cytokines to the vascular endothelium leading to increased production ofvasoconstriction factors such as endothelin-1 and increased consumption of NO.[27],[28],[29] Subarachnoid blood also increases the production of nuclear factor κ-light-chain (NF-κB) which is pro-inflammatory and increases synthesis of cytokines, adhesion molecules, and complement factors.[30] Cytokines have a role in maintaining a state of vasoconstriction and ultimately lead to a longer duration of vasospasm and poor outcomes.[31] Interleukin-6(IL-6) levels in the serum and endothelial adhesion molecules (E-selectin, intercellular adhesion molecule 1(ICAM), and vascular cell adhesion protein (VCAM-1) levels in the serum and cerebrospinal fluid (CSF) have been shown to be associated with a poor outcome in patients with subarachnoid haemorrhage [Figure 1].[32],[33],[34]
Microvascular vasospasm has also been associated with cerebral vasospasm. Large vessel vasospasm visible on angiography is usually seen after day 3 of haemorrhage, but there are various clinical studies that have documented incidence of small vessel or microvascular vasospasm in the hyperacute phase of subarachnoid haemorrhage.[34],[35],[36] It has been shown that microvascular vasospasm leads to decreased cerebral blood flow and causes red cell agglutination. The vasospasm at the level of the arterioles may not be associated with large vessel vasospasm. Studies have confirmed arteriolar vasospasm within 72 h of ictus leading to decreased capillary density and constriction of pial vessels.[37] Animal studies have also shown that the destruction of the endothelial layer is more evident in the microvasculature and hence leads to increased synthesis of pro-inflammatory vasospastic markers and decreased response to vasodilators.[38],[39] Cortical spreading depolarization (CSD) is an electrical process leading to depolarization of the neurons and glial cells in subarachnoid hemorrhage. Depolarization is primarily because of irritant molecules such as glutamate, endothelins, and electrolyte disturbances. This wave of depolarization leads to ionic changes and increases neuronal edema and injury. It produces a state of hypermetabolism in the setting of decreased cerebral blood flow and thus exacerbates neuronal damage.[34],[40],[41],[42] In non-clinical studies, the wave of depolarization has been shown to increase glutamate and lactate levels while decreasing the glucose levels. This may worsen brain hypoxia and cause neuronal death. Multiple studies have shown that CSD correlates well with the incidence of vasospasm even better than angiogram in some series.[43],[44],[45],[46] Microcirculation thrombi formation has been postulated as another mechanism to explain worsening of vasospasm and DCI. As discussed above, there is an increased expression of pro-inflammatory markers which leads to a procoagulant state. These markers are responsible for leukocyte and platelet aggregation and lead to stasis of blood flow in the arteriolar system by forming microthrombi. Platelet microthrombi have been seen on autopsy studies and on transcranial Doppler ultrasound examination of the patients.[47],[48] There is no clear consensus on the mechanism of increased platelet aggregation, but recently Bell et al., have proposed a new hypothesis to explain this phenomenon. They discuss destruction of glycocalyx which is a gel-like substance lining the inner wall of the blood vessels. This prevents platelet aggregation as the primary cause of increased platelet clumping. Endothelial glycocalyx injury leads to a cascade of events which increases microthrombi formation [Figure 2].[49],[50],[51],[52]
Optimization of fluid status and hemodynamic variables After the aneurysm is secured, the next most important step in the management of the patient is to prevent vasospasm. The first step in the management of vasospasm is to optimize hemodynamic variables such as blood pressure and Hb in these patients. Previously popular “3H” therapy which included hypertension, hypervolemia, and hemodilution has fallen out of favor over the years. There is no role of prophylactic 3H therapy in the prevention of cerebral vasospasm.[53],[54] However, the focus has shifted to maintaining euvolemia and letting the blood pressure autoregulate to maintain adequate cerebral perfusion. Cerebral perfusion pressure (CPP) of 80–120 mmHg is helpful in improving cerebral autoregulation while decreasing complications associated with hypervolemia.[55] Therefore, the first step in decreasing the risk of vasospasm in a patient with subarachnoid hemorrhage post aneurysm treatment is maintaining euvolemia and avoiding hypotension. There is no clear consensus on the blood pressure parameters, but a maximum systolic blood pressure (SBP) of 220 and a maximum mean arterial pressure (MAP) of 140 have been used widely after aneurysm surgery. Some studies have also targeted an increase in MAP of 20–30 from the baseline for therapeutic treatment of vasospasm.[56],[57],[58] Hemoglobin and anemia Anemia is a common manifestation in patients with subarachnoid hemorrhage. About 40%–50% of patients with subarachnoid hemorrhage develop anemia during their stay in the intensive care unit (ICU).[59],[60],[61] Various factors have been implicated in the decrease in Hb concentration such as age, sex, surgery, and blood drawing for laboratory investigations. The mean decrease in Hb concentration is about 3 g/dL and anemia develops after 3.5 days.[62] Anemia has been associated with increased morbidity because of infarction, disability, and eventually death in patients with subarachnoid hemorrhage.[61],[62],[63],[64],[65],[66] Interestingly, patients with poor outcome have consistently low Hb levels between days 6 and 11 which coincides with the highest prevalence of delayed cerebral injury.[61] Various studies have linked low brain tissue oxygen (PbtO 2) because of anemia, leading to neuronal injury in patients with acute brain injury.[67],[68],[69] In normal brain, effects of low Hb (<6g%) concentration are not manifested because of compensatory cerebral autoregulation. However, in subarachnoid hemorrhage, the autoregulation is impaired, and hence it is postulated that these effects may manifest at higher Hb concentration.[70] Oddo et al., showed that Hb concentration of less than 9 g% was an independent predictor of cerebral ischemia in patients with poor grade subarachnoid hemorrhage. They verified their results based on cerebral microdilaysis parameters. In a similar study, Hb <10g% was linked to cellular dysfunction.[60],[71] Animal studies have also corroborated similar findings consistent with brain ischemia at Hb <10g%.[72] Optimal Hb concentration is still a matter of debate; however, studies have shown improved outcomes with Hb >11g%.[73] An international survey done in 2009 showed that majority of the intensivists (67% of 626) around the world target a Hb level of more than 10 in subarachnoid hemorrhage (SAH).[74] Guidelines for the management of aneurysmal subarachnoid hemorrhage also favor maintaining higher Hb levels; however, the optimal level is debatable. Based on the data available, a target Hb >10 g% is a reasonable option to consider in patients with SAH. Calcium channel antagonist Vasospasm is known to be associated with constriction of vascular smooth muscles. Calcium channel blockers are theorized to act on vascular smooth muscles thereby relaxing them and consequently reducing the effect of vasospasm. Nimodipine is the only calcium channel blocker known to reduce DCI.[75],[76],[77],[78],[79] and improve outcome and hence carries class I, level of evidence A in subarachnoid hemorrhage management guidelines.[75],[77] Although nimodipine is a calcium channel blocker, it works through various other mechanisms that may help in decreasing the incidence of DCI. Nimodipine has been postulated to have a neuroprotectant effect. It may decrease neuronal cell death by decreasing the intracellular influx of calcium by improving blood rheology.[80] Some studies have also shown an anti-platelet aggregation effect and dilatation of leptomeningeal collateral circulation that may decrease DCI.[82] Nimodipine is administered orally at a dose of 60 mg every 4 hourly as per SAH guidelines.[75] Some studies have also proposed a dose of 30 mg every 2 h to maintain blood pressure and adequate cerebral perfusion. As the incidence of vasospasm increases a day after bleed, most centres prefer to start nimodipine on day 3 post hemorrhage. Monitoring for cerebral vasospasm Various techniques have been used to monitor for vasospasm. Imaging techniques such as computed tomography (CT) angiogram, magnetic imaging (MR) angiogram, and perfusion studies have been studied with variable success. Shortcomings of radiological studies are that their daily use is not feasible and most of them are only sensitive to moderate to severe vasospasm.[76] Transcranial Doppler (TCD) study, thus, has emerged as the most promising non-invasive modality to screen patients for vasospasm. The ease of performing the test with minimal set up at the bed side and the freedom of doing repeated follow-up examinations makes TCD ultrasound as the preferred mode of diagnosing cerebral vasospasm; however, this modality has its short comings and is not a solution to all questions the clinicians face in the neurocritical care unit. TCD can be performed daily or every other day depending on the requirement. The authors, however, prefer daily monitoring starting from day 3 after the ictus. TCD mean velocities of 100–120, 120–200, and more than 200, correlate with mild, moderate, and severe angiographic vasospasm in the middle cerebral artery (MCA), respectively.[81] Lindergaard used MCA: internal carotid artery (ICA) [extracranial ICA] mean velocity ratio as a marker for vasospasm. The ratio increases with vasospasm as the blood flow to the brain is reduced and the flow velocity through the MCA increases. MCA: ICA ratio more than 3 corresponds to vasospasm and more than 6 corresponds to severe vasospasm.[82],[83] Lindegaard ratio has an accuracy of 89.9% for detection of angiographic vasospasm.[82] In a similar approach, Soustiel et al., compared the velocity of basilar artery (BA) with that of extracranial vertebral artery (EVA). BA/EVA >2 was associated with vasospasm.[84] The sensitivity of diagnosing vasospasm depends on the skill of the operator, presence of anatomical window, location and severity of vasospasm, course and anatomy of the blood vessel, intracranial pressure (ICP), blood pressure fluctuations, pCO 2 variations, hematocrit, and so on. TCDs have a sensitivity of 39%–94% and specificity of 85%–100% in detecting vasospasm in the MCA. Other vessels carry a lower sensitivity (13%–77%). A negative TCD study thus does not rule out vasospasm. Induced hypertension for treatment of vasospasm Prophylactic 3H therapy has fallen out of favor; however, induced hypertension in symptomatic and euvolemic patients has been found to be helpful and is recommended by recent subarachnoid hemorrhage treatment guidelines.[75] Induced hypertension has been shown to reverse the symptoms of vasospasm in up to two-thirds of patients.[81],[82] Phenylephrine, dopamine, and norepinephrine have been used to increase blood pressure. Dopamine use has been limited because of dose-related cardiac side effects and increase in ICP.[84] Phenylephrine and norepinephrine are safer in this regard in patients with normal left ventricular function. The principle behind blood pressure augmentation is based on impaired autoregulation which leads to an increase in cerebral perfusion by increasing blood pressure. Experimental studies in animals have shown an increase in cerebral blood flow in parts of the brain with impaired autoregulation with no effect on the normally autoregulated brain.[84] Milrinone, a phosphodiesterase (PDE) III inhibitor, has been used to treat cerebral vasospasm both intra-arterially and as an infusion. In a study of 88 symptomatic and euvolemic patients, milrinone infusion was helpful in reducing delayed cerebral injury and improving outcomes while reducing the need for endovascular intervention and incidence of cardiac and pulmonary complications.[85] There has been no randomized study till date though to draw definite conclusions. Arginine vasopression (AVP) has also been used as an adjunct to inotropic therapy in patients to achieve target MAP and reduce the dose of inotropic agents.[86] It has been found to be safe and effective when used in combination with phenylephrine to achieve target blood pressure. At the moment, there is no study on the effect of cerebral blood flow with various agents. There are no trials to prove the superiority of one drug over the other. Norepinephrine may have a more predictable effect on cerebral blood flow when compared with dopamine. Phenylephrine has also been used with similar efficacy.[87] Vasopressin may be preferred for patients who do not respond to pressor agents to achieve the target blood pressure.[86] Endovascular management of vasospasm Endovascular therapy to treat vasospasm is chosen when medical management has failed or when there is a risk of complications associated with it. Various options are available to treat vasospasm through endovascular route which range from infusion of drugs intra-arterially to balloon angioplasty of blood vessels. Various studies have been performed to ascertain the optimal approach and its timing.[88],[89] One of the studies looked at patients with subarachnoid hemorrhage who underwent prophylactic angioplasty within 96 h of symptom onset. Patients underwent angioplasty of bilateral M1 segments of the MCA, bilateral P1 segments of the posterior cerebral artery, and A1 segments of the anterior cerebral artery. Analysis showed non-significant reduction in delayed cerebral injury in patients undergoing prophylactic angioplasty and significant reduction in those patients requiring therapeutic balloon angioplasty as a rescue measure for vasospasm. Four patients had vessel perforation as a result of angioplasty and three of them died.[89] Rosenwasser et al., showed that patients who underwent balloon angioplasty with or without intra-arterial therapy within 2 h of onset of symptoms had a significantly better neurological improvement when compared with patients who underwent treatment after 2 h.[89] Bejjani et al., looked at patients who underwent treatment within 24 h of symptom onset when compared with patients who had delayed treatment.[90] Patients in the early treatment arm showed more improvement when compared with the delayed arm.[90] Although there is no clear consensus on the optimal hour of treatment, it does make sense to treat the symptoms as soon as possible and not delay treatment unless it is unavoidable.
Papaverine It is a potent vasodilator which inhibits cyclic adenosine monophosphate and cyclic guanosine monophosphate phosphodiesterase activity leading to relaxation of blood vessels in the cerebral and coronary vascular beds. Various small case studies have described vasdilatory effects of papaverine on cerebral vasculature with good angiographic outcome.[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102] Some case studies found no benefit, whereas one study reported on tha incidence of neurotoxicity with papaverine.[100] The drawback of papaverine has been its short duration of action and hence the requirement of repeated infusions. Studies have shown rebound vasospasm after papaverine treatment and thus the benefits are transient.[103],[104],[105] Vajkoczy et al., demonstrated that papaverine only transiently increases the cerebral blood flow with its benefit dissipating within 3 h of infusion.[104] Another shortcoming of papaverine is increased ICP post infusion. It has been hypothesized that diffuse vasodilatation and increase in venous capacitance lead to increased cerebral blood flow and increased ICP. In another study, papaverine infusion led to ICP elevation in 42% of the patients with a mortality rate of 10%.[106],[107] Due to these shortfalls, papaverine is not the drug of choice for intra-arterial infusions. Nicardipine Nicardipine is a dihydropyridine calcium channel blocker with selective action on blood vessels when compared with the cardiac muscles. It causes vasodilatation by preventing the influx of calcium into the cells and disrupting the actin–myosin interaction essential to muscle contraction. Its half-life is approximately 40 min. Use of nicardipine as an antispasmolytic agent has been extrapolated from the cardiothoracic surgery literature. He and Yang showed in an in vitro study that dihydropyridine group of calcium channel blockers were more potent vasodilator agents. Not only did they treat the existing spasm but they were also effective in preventing vasospasm because of influx of potassium ions.[108] Another study done by Radermecker et al., confirmed the efficacy of nicardipine as well.[109] Badjatia et al., reported improvement in clinical examination in patients treated with intra-arterial nicardipine. They reported improvement in 42% of patients undergoing intra-arterial therapy. ICP was transiently elevated in five patients and persistently elevated in one patient.[110] Another study done in 11 patients by Tejada et al., reported similar results.[111] Use of nicardipine for intra-arterial therapy is still limited when compared with nimodipine and verapamil. Verapamil Verapamil is a non-dihydropyridine calcium channel blocker that relaxes the vascular smooth muscle by inhibiting the influx of calcium. It suppresses the sino-atrial node and the atrioventricular (AV) node conduction and has a negative inotropic effect. Use of verapamil has been prevalent in cardiology to reduce nitroglycerin-resistant vasospasm in coronary arteries.[112] Verapamil was shown to improve cerebral blood flow as a linear function of arterial pressure by Joshi et al. They postulated that verapamil may thus help patients with decreased cerebral blood flow as in the case of cerebral vasospasm.[113] Animal studies have shown that the effect of verapamil is dose-dependent and stabilizes after 15–30 min.[114] Feng et al., studied the effect of verapamil in patients with subarachnoid hemorrhage in three different settings: (1) before balloon angioplasty, (2) in mild vasospasm, and (3) in moderate to severe vasospasm not responding to angioplasty. In the first two groups, 3 mg of verapamil was used per patient without any complications or side effects. Blood pressure parameters remained stable and there were no signs of increased ICP. In the group with moderate to severe vasospasm, up to 8 mg of verapamil was infused in ICA over 30 min without evidence of any hemodynamic compromise or ICP issues. Post procedural angiogram was done in only 10 patients and it confirmed an increase in vessel diameter up to 44%.[115] In another study done by Mazumdar et al., the efficacy of verapamil infusion was studied by comparing pre–post procedural vessel diameters on angiogram in 15 patients with subarachnoid hemorrhage. About 2.5–10 mg of verapamil was infused over 5–10 min. Six of the 15 patients showed significant neurological improvement within 24 h. There was no hemodynamic compromise in 14 of the 15 patients; however, 1 patient had intraprocedural hypotension which resolved once the verapamil infusion was stopped.[116] Keuskamp et al., studied higher doses of verapamil, up to 20 mg intra-arterially, and found no effect on hemodynamic parameters or ICP. There was significant improvement in vasospasm.[117] Albanese et al., observed transient and reversible blood pressure and ICP fluctuations with doses as high as 164 mg per vessel and a total intraprocedural dose of 720 mg, suggesting that verapamil was safe at very high doses as well.[118] Nimodipine Nimodipine is another calcium channel blocker that acts on L-type calcium channels and thus prevents smooth muscle contraction. Nimodipine prevents calcium ion influx and thus exhibits a neuroprotective effect on the neurons.[119],[120],[121],[122] In an experimental study, nimodipine was shown to be more effective than papaverine.[123] Biondi et al., treated 25 patients with symptomatic vasospasm with nimodipine and observed neurological improvement in 76% patients. Out of those, 42% patients had angiographic improvement in vasospasm suggesting a possible underlying effect in terms of neuroprotection and microcirculation.[120] Hui and Lau injected 3.3 mg of intra-arterial nimodipine in a series of 11 patients with good neurological improvement in 8 patients after the procedure.[119] Hanggi and Steiger infused 0.8–3.6 mg nimodipine in 26 patients and observed that 8 patients had no improvement in symptoms and 6 patients experienced a transient reversible moderate decrease in blood pressure. The increase in brain perfusion was transient and 61% patients suffered additional neurological injury.[123] Milrinone Milrinone is a vasodilator with positive inotropic activity. It inhibits cyclic adenosine monophosphate (cAMP)-specific PDEIII isoenzyme in the cardiac and vascular muscles. It enhances the uptake of intracellular calcium ion by sarcoplasmic reticulum thereby reducing the calcium ion available for contraction and thus relaxes the vascular smooth muscle.[124] Arakawa et al., studied the effect of milrinone in seven patients who received intra-arterial drug at a concentration of 0.25 mg/mL and at a rate of 1 mL/min to a total dose that ranged from 5 to 15 mg. This therapy was followed by 2 weeks on intravenous milrinone infusion as well. All patients showed angiographic improvement in vasospasm with a mean increase of 78% in vessel diameter. Around 58.3% had neurological improvement after milrinone therapy without any hemodynamic compromise.[124] Fraticelli et al., studied the effect of milrinone in 22 patients who received both intra-arterial and intravenous therapies and observed angiographic improvement in vasospasm.[125],[126] Fasudil Fasudil is a potent vasodilator with specificity to cerebral vessels. It inhibits the action of free intracellular calcium ion and thereby reduces vascular contraction. Fasudil also inhibits myosin light chain kinase and protein kinase C, both of which help in muscle contraction. It also acts against rho kinase which is involved in the pathogenesis of cerebral vasospasm.[127],[128] Intra-arterial fasudil was studied in 10 patients with angiographic vasospasm. Three of the 10 patients were symptomatic. The maximum dose of fasudil that was used was 60 mg, and diffuse cerebral vasodilatation was seen in 60% of the patients. Two of the three symptomatic patients had neurological improvement; however, the third one progressed with a large stroke. There were no embolic complications. The decrease in blood pressure was never greater than 20 mmHg.[128],[129],[130] Tanaka et al., reported favorable outcomes in their study on 23 patients with cerebral vasospasm who received 15–45 mg (mean: 22.9 mg) of fasudil intra-arterially. The medication was diluted in 20 mL of saline and infused at a rate of 1.5 mg/min. Only 11.8% of patients had complete resolution of vasospasm and 44% patients showed neurological improvement. Six patients had a blood pressure decrease of >20 mmHg and two patients developed transient mental status changes after the treatment. An increase in ICP ranging from 1.1 to 5.2 mmHg (mean: 2.4 mmHg) was also observed.[128] Another study done by Iwabuchi et al., showed similar results.[130] Colforsin daropate hydrochloride Colforsin is a forskoilin derivative that activates adenylate cyclase, resulting in elevation of the intracellular concentration of cAMP. It has positive chronotropic, inotropic, and vasodilatory effects.[131],[132] Corlforsin has been shown to be beneficial in a study when used as an adjunct to intravenous fasudil. Good angiographic and clinical improvement (100 and 86%, respectively) was observed after the therapy; however, most of the patients in the study required multiple treatments.[132]
NeuroFlo catheter (Coaxia, Maple Grove, MN, USA) This device has been approved by the Food and Drug Administration (FDA) for the treatment of subarachnoid hemorrhage-induced vasospasm. The device works on mechanical diversion of blood flow by occluding the aorta above and below the renal arteries thereby increasing the blood flow to cerebral vasculature. This device was studied in 24 patients with symptomatic cerebral vasospasm. The authors documented improvement in clinical examination, increased mean velocities on TCD, and better parenchymal opacification on angiography.[133] The device had a good safety profile. Advanced version of this device will enable simultaneous intra-arterial infusion of medications as well. Brains Gate device This device works on the principle of neurostimulation and is intended for sphenopalatine ganglion (SPG). Anatomically, the SPG is responsible for parasympathetic nerve supply to the anterior circulation and causes vasodilatation on stimulation. SPG ganglion stimulation has been shown to reverse vasospasm in animal models. The safety of this device was established in a pilot trial (ImpACT-1) where 98 patients with acute ischemic stroke underwent SPG stimulation within 24 h of stroke onset. At this point, the use of the Brains Gate system remains purely investigational and no human use in cerebral vasospasm has yet been reported.[134],[135] Intra-aortic balloon pump This device has only been used in small case series in patients where standard therapy is not able to maintain the desired blood pressure in cases of refractor vasospasm.[133] Intrathecal administration of drugs Intrathecal administration of drugs has been studied in various case series and multiple drugs have been tried. Shibuya et al., administered nicardipine intrathecally in 50 high-grade subarachnoid hemorrhage patients and observed 26% decrease in symptomatic cerebral vasospasm. Post-operative angiogram showed that the effect of nicardipine was more noticeable locally and the vessels close to the catheter tip, in the basal cistern responded better. A2 and M2 vessels did not respond to the treatment. Radioisotope cisternography suggested that nicardipine might not reach the subarachnoid space around A2 and M2 segments. Headaches were common because of vasodilatation and two patients developed meningitis.[136] In another study by Suzuki et al., 177 patients with subarachnoid hemorrhage post clipping were administered intrathecal nicardipine (4mg twice daily) from day 3 to day 14.[137] There was a four- to six-fold reduction in the incidence of vasospasm with 89.2% of patients achieving a good outcome. A total of 33 patients (18.6%) required shunt operation and 11 patients (6.2%) had intracranial infection. Again, most of the vasospasm was seen in peripheral A2 and M2 arteries.[137] Fujiwara et al., studied five patients with aneurysmal subarachnoid hemorrhage who underwent continuous cisternal infusion of nicardipine at a daily dose of 8 mg (12 mL) for 14 days. They did not report symptomatic vasospasm in any of these cases. One patient had transient neurological deficits and there was one patient who suffered from meningitis.[138] Intrathecal administration of urokinase to decrease the clot burden and decrease spasmogenic blood products was carried out by Sasaki et al. In all, 217 patients with Fisher grade III SAH post aneurysm surgery within 72 h from the onset of SAH were enrolled in the study.[139] Patients had irrigation tubes placed in the Sylvian fissure (inlet) unilaterally or bilaterally, and in the prepontine or chiasmal cistern (outlet). Lactated ringer and urokinase solution (120 IU/mL) was circulated through the tubes for 10 days. Symptomatic vasospasm was observed in only six cases (2.8%), two of which had permanent sequelae (0.9%). Complications occurred in only eight patients. Two patients (0.9%) experienced seizures because of occlusion of the drainage tube in the subdural space. Two patients (0.9%) developed meningitis with complete recovery after intrathecal antibiotics. Four patients also suffered from intracranial hemorrhage because of local trauma. Lumbar drainage The incidence of vasospasm has been related to the amount of blood in the subarachnoid space. Both ventricular drain and lumbar drain have been used to reduce the amount of blood in the CSF space and thus the incidence of cerebral vasospasm.[140],[141] Early application of a lumbar drain was shown to reduce the incidence of vasospasm and improve outcome in preliminary studies.[76],[142] On the other hand, excessive removal of CSF through a ventricular drain was not shown to decrease the incidence of vasospasm and may lead to a higher incidence of post-hemorrhagic shunt dependency.[143] Irrigation of blood while performing aneurysm clipping has not yielded satisfactory results either.[140],[141] Lumbar drainage was shown to be safe and effective in patients undergoing aneurysmal clipping and endovascular coiling. Both studies led to a markedly diminished incidence of angiographic vasospasm and improvement in clinical outcome. The Lumbar Drainage in Subarachnoid Haemorrhage (LUMAS) trial was performed, which showed a decrease in the incidence of DCI and improvement in early clinical outcome. There was, however, no effect on clinical outcome after 6 months.[143] The Early Lumbar Cerebrospinal Fluid Drainage in Aneurysmal Subarachnoid Haemorrhage (EARLYDRAIN) trial is currently underway.[142],[144] Mechanical angioplasty Endovascular mechanical angioplasty has been tried in patients who do not respond to medical management and intra-arterial dilatation of blood vessels.[144] It is currently advocated for patients with refractory vasospasm and carries a low level of evidence.[145],[146],[147] Angioplasty has been performed with both compliant and non-compliant balloons with similar results.[147] The Invasive Diagnostic and Therapeutic Management of Cerebral Vasospasm After Aneurysmal Subarachnoid Haemorrhage (IMCVS) trial is currently underway to address the efficacy of endovascular management of vasospasm when compared with medical management.[148] Kinetic therapy Kinetic therapy is based on the principle of clearing blood from the subarachnoid space with the help of mechanical agitation. It uses a head shaker or lateral rotational therapy in combination with local thrombolytic therapy. Few studies have yielded positive results in decreasing the incidence of vasospasm and delayed cerebral injury;[149],[150] however, its use has been limited.
Endothelin 1 antagonist Endothelin-1 is a potent vasoconstrictor and is implicated in the pathogenesis of cerebral vasospasm. Experimental studies have shown improvement in cerebral vasospasm with blockade of endothelin receptors (A and B). Clazosentan is one such drug that has been studied in various trials to reverse cerebral vasospasm in patients with SAH.[151] The Clazosentan to Overcome Neurological iSChemia and Infarct Occurring after Subarachnoid haemorrhage (CONSCIOUS-1) study showed improvement in vasospasm, DCI and strokes without any effect on patient mortality.[152] The study was underpowered, and hence the CONSCIOUS-2 and CONSCIOUS-3 trials were designed to validate this issue further. In the CONSCIOUS-2 trial, patients were assigned to clazosentan (5 mg/h, in 768 patients) or the placebo groups (389 patients) for more than 14 days. This trial did not show any improvement in mortality or functional outcome.[153],[154] In the CONSCIOUS-3 trial, a total of 571 patients were managed (placebo group = 189 patients, clazosentan 5 mg/h = 194 patients, and clazosentan 15 mg/h = 188 patients) after endovascular coiling of their aneurysms. Poor outcome was seen in 24% of the patients receiving placebo, in 25% of the patients receiving clazosentan (5 mg/h), and in 28% of patients receiving high-dose clazosentan. The study showed no benefit in functional outcome with clazosentan although some improvement in vasospasm was seen.[153],[154] Magnesium Magnesium is a divalent cation that works by inhibiting voltage-dependent calcium channels to inhibit smooth muscle contraction. Magnesium also inhibits glutamate release and may have a neuroprotectant role. The role of magnesium has been studied in various clinical studies and the observations have been discussed here. In 2002, Veyna et al., published a study of 20 patients who were given intravenous magnesium and had nonsignificant trend toward favorable outcomes when compared with a placebo.[155] In another study by Muroi et al., a similar trend was seen with increased incidence of hypocalcemia and hypotension.[156] The magnesium in the Aneurysmal Subarachnoid Hemorrhage (MASH) trial, a randomized trial, demonstrated nonsignificant reduction in DCI [34%, hazards ratio (HR) = 0.66, confidence interval (CI) = 0.38–1.14] and 3-month poor clinical outcomes [23%, relative risk (RR) = 0.77, CI = 0.54–1.09] among 283 patients who received a 14-day continuous intravenous magnesium infusion.[157] Following this, the Intravenous Magnesium Sulfate for Aneurysmal Subarachnoid Haemorrhage (IMASH) trial was published which showed no improvement in outcomes in patients who received magnesium.[158] The MASH2 trial showed similar outcomes as well.[159],[160] The current data available do not support the routine use of intravenous magnesium therapy for the treatment of cerebral vasospasm. Statins Statins have been shown to have anti-inflammatory effects which may also help in reducing cerebral vasospasm. Tseng et al., conducted a trial using pravastatin in patients with subarachnoid hemorrhage and observed 32% reduction in TCD-diagnosed vasospasm when compared with a placebo.[161] Lynch et al., observed similar benefits when they used simvastatin (26.3% vs 60% incidence of vasospasm).[162] Trials done subsequently were not able to replicate these findings and no effect on the incidence of vasospasm or the long-term outcome was observed.[163],[164] A meta-analysis published in 2010 involving 309 patients found that although statins reduced the incidence of ischemic neurological deficits [OR 0.38 (0.23–0.65)], there was no effect on the outcome or mortality.[165] Simvastatin in the Aneurysmal Subarachnoid Haemorrhage (STASH) trial, a multicentre randomised phase 3 trial, was published in 2014 which did not detect any benefit in the use of simvastatin for long-term or short-term outcome in patients with aneurysmal subarachnoid hemorrhage. Despite demonstrating no safety concerns, the patients with subarachnoid hemorrhage should not be treated routinely with simvastatin during the acute stages.[166] Nitric oxide analogues NO is a potent vasodilator and its role in cerebral vasospasm has been studied extensively. Blood degradation products decrease the endothelial production of NO and impair its effects on vascular endothelium leading to vasoconstriction. Thus, theoretically NO analogues should help with vasodilatation by increasing NO production. NO donors such as sodium nitrite (NaNO2) have been studied in animals and have shown promising effect on vasodilatation.[167],[168],[169] Role of adinopectin in subarachnoid hemorrhage has been reported by Osuka et al.[167] Adinopectin has been postulated to cause activation of AMP-activated protein kinase α and endothelial NO synthase signaling pathway.[169],[170] L-citrulline has been found to be safe and efficacious in a few experimental studies. It has been shown to increase the expression of e-NOS and thus the availability of NO.[171] Further studies are needed to confirm the use of NO analogues in subarachnoid hemorrhage. Erythropoietin Erythropoietin (EPO) has been studied recently for its role in preventing cerebral vasospasm. Although initial studies have been encouraging, there is still a lot to prove when it comes to using it routinely in patients with SAH. The mechanism of action is not clearly understood and multiple hypotheses have been proposed such as inflammation limitation, apoptosis inhibition, oxidative damage limitation, and neurogenesis upregulation.[170] EPO has been shown to inhibit the JAK2/STAT3 signaling pathway, thus inhibiting vascular apoptosis.[172] It also induces the antioxidant and detoxifying enzymes by acting on the Nrf2-ARE pathway.[173] EPO may also increase brain tissue oxygenation.[174] Free radical scavengers The damage caused because of oxidative damage from Hb by-products has raised the interest in the role of free radical scavengers in SAH. Tirilazad is one such drug that inhibits lipid peroxidation and scavenges free radicals. A large multicenter international trial that enrolled 819 female patients showed a decreased incidence of symptomatic vasospasm (33.7% vs 24.8%) without affecting mortality.[175] The trial specifically enrolled female patients as the effect on tirilazad was found to be more beneficial in women in previous trials.[176],[177],[178] An extension of the same trial was conducted in North America which found no significant differences in symptomatic vasospasm or clinical outcome between patients who received tirilazad and those who received a placebo. The patients with high-grade SAH was the only subgroup which showed some mortality benefit.[179] A subsequent meta-analysis that included 3821 patients showed no improvement in outcomes in patients who received tirilazad.[180] Nicaraven is a hydroxyl radical scavenger and has shown promising results in a study of 162 patients where decreased or delayed neurological deficits and improvement in functional outcome were observed.[181] Other drugs such as edarava one and ebselen (antioxidant) have shown improvement in functional outcome to various degrees, but definitive evidence is still lacking to recommend their use in patients with SAH.[181],[182] Nicardipine prolonged release implants Intracisternal implantation of nicardipine implants has shown promising results.[183] In various studies, the incidence of vasospasm and delayed neurological deficits were found to be significantly decreased in patients who received intracisternal implantation. Barth et al., reported a significant decline in the incidence of angiographic vasospasm (73% in the control group to 7% in the treatment group) with improved clinical examination.[184] Krischek et al., observed similar positive effects and concluded that the implants were more effective for proximal parts of the blood vessels when compared with distal arteries.[185] Use of nicardipine prolonged release implant has also been studied in patients undergoing endovascular coiling. The authors noticed no adverse outcomes related to this therapy.[184],[185] This therapy does offer a new approach to treating cerebral vasospasm but still lacks the data to validate its efficacy. Sildenafil citrate Sildenafil is a PDE inhibitor which is directly involved in metabolism of cyclic guanosine monophosphate (cGMP) which is a potent vasodilator. Sildenafil has been hypothesized to inhibit PDE V, thereby increasing cGMP concentration and causing vasodilatation. Animal studies have shown the vasodilator effect of sildenafil on cerebral vessels; however, further research is needed to document its utility in human subjects.[186],[187],[188] Thrombolytic drugs Clearance of blood products from the ventricles has always been studied with great interest as it correlates directly with the incidence of vasospasm. In the same league, the role of tissue plasminogen activator (tPA) and urokinase has been looked at and had shown encouraging results. In a study of 51 patients, there was a 56% relative risk reduction in severe vasospasm in patients who received a single bolus of intracisternal tPA post clipping.[189] In another study, cistern magna injection of urokinase injected after endovascular coiling showed a significant decline in vasospasm (8.8% vs 30.2%) and improvement in functional outcome.[190] A meta-analysis conducted in 2004 showed a significant reduction in neurological deficits as well as a poor outcome and mortality in patients who received thrombolytic therapy. The therapy was considered safe without any increase in procedure or drug-related complications.[191] Although encouraging, this therapy has still not been tested in a randomized control trial and thus the results still need to be validated. Protocol-based management The flow-chart of amangement of vasospasm and DCI is presented in [Figure 3].
Cerebral vasospasm has been one of the most difficult clinical conditions to understand and treat. It is responsible for high morbidity and mortality rates among subarachnoid hemorrhage patients. Various clinical mechanisms have been described in the literature to explain the pathogenesis and progression of vasospasm; however, a clear explanation remains elusive. The fact that pathogenesis of this syndrome has not been understood also limits our ability to treat it effectively. Time-proven approaches have been challenged and new lines of treatment ranging from endovascular approach to antioxidants have now been studied. The management of cerebral vasospasm has definitely grown with the endovascular options now being available and better understanding of cerebral hemodynamics, but it still remains a clinical entity that is difficult to treat and carries a high mortality rate. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1]
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