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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 2  |  Page : 423-425

Vasospasm following aneurysmal subarachnoid hemorrhage: The search for the elusive wonder-drug

Department of Neurosurgery, Kasturba Medical College, Manipal, Karnataka, India

Date of Web Publication15-Mar-2018

Correspondence Address:
Dr. Girish Menon
Department of Neurosurgery, Kasturba Medical College, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.227285

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How to cite this article:
Menon G. Vasospasm following aneurysmal subarachnoid hemorrhage: The search for the elusive wonder-drug. Neurol India 2018;66:423-5

How to cite this URL:
Menon G. Vasospasm following aneurysmal subarachnoid hemorrhage: The search for the elusive wonder-drug. Neurol India [serial online] 2018 [cited 2020 Jun 7];66:423-5. Available from:

Cerebral vasospasm (CVS) and its sequelae, delayed cerebral ischemia (DCI), are the single most important prognosticators for a poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). Angiographic spasm is detected in 75% of the patients with aSAH but DCI and morbid complications develop only in 17–40% cases.[1] Rational thinking suggests that the complications secondary to vasospasm can be mitigated by identifying this subgroup of patients early and instituting appropriate treatment. Unfortunately, the last three to four decades have failed to provide a safe, effective and sustained cerebral vasodilatory drug to counter vasospasm. It is in this context that this attempt by Narayan et al., to add valuable positive evidence to one of the few available modes of treatment becomes noteworthy.[2] The authors share their experience with the use of intrarterial nimodipine in twenty-three patients with DCI. A favorable angiographic response was seen in 22 (95.7%) patients and a satisfactory clinical response in 20 (87%) patients. Their observation, which is similar to other published reports, highlights the need for aggressive management with intra-arterial spasmolytics in preventing disability caused by DCI. This paper is also important at a time when considerable debate is going on over the benefits of IAVT over routine hemodynamic therapy.[3]

Cerebral vasospasm constitutes a unique clinicopathological entity characterized by reversible vasculopathy, impaired autoregulatory function, and hypoperfusion resulting in cerebral ischemia and infarction, if left unchecked. The exact pathogenesis is still unclear and the possible culprits include depletion of nitric oxide (NO), excess of endothelin 1, free radical oxidation of bilirubin to bilirubin oxidation products (BOXes), proinflammatory mediators and leukocyte infiltration, adhesion molecules such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion protein 1), E-selectin and cytokines including TNF-a (tumor necrosis factor alpha), IL-1 (interleukin-1), IL-6, and IL-8.[1]

Treatment modalities have, therefore, been directed towards oral, intravenous, or intra-arterial administration of antagonists of these mediators. Experimental trials with several new molecules have yielded variable results in preventing and reverting vasospasm. Notable among them have been the CONSCIOUS trials with clazosentan (an endothelin receptor agonist), magnesium sulfate infusion, statins, fasudil (a potent rho-kinase inhibitor), erythropoietins, intracisternal implantation of nicardipine prolonged-release pellets, sildenafil, dantrolene and nitric oxide donors. None of these molecules, however, have provided consistent results and acceptable side effects to be considered for routine clinical use.

The aim of vasospasm management is to optimize cerebral blood flow in order to prevent delayed cerebral ischemia (DCI) and medical treatment is usually the initial step when vasospasm is suspected. The current treatment for CVS revolves around oral nimodipine – a calcium channel blocker, and the triple “H” (hypertension, hypervolemia, and hemodilution therapy. However, vasospasm is often refractory to these treatments. The British aneurysm nimodipine trial and other clinical trials confirmed that nimodipine reduces the risk of cerebral infarction from 33% to 22% and there is class I evidence proving that oral nimodipine is definitely beneficial for aSAH patients.[1] It is, however, to be noted that nimodipine improves neurological outcome but not cerebral vasospasm through its neuroprotective mechanism rather than its vasodilatory effect. Triple “H” therapy, however, has only level B evidence in the management of patients suffering from aSAH and there is an increasing shift toward double “H” avoiding the hemodilutional part and maintaining euvolemia. The hypertensive regime too is being questioned and some studies have shown that employing continuous milrinone infusion instead of triple “H” therapy yielded similar results with the requirement of less invasive monitoring and resources. In addition, triple 'H” therapy can result in volume overload, pulmonary edema, myocardial ischemia, hyponatremia, and cerebral edema. The doubtful efficacy as well as the side effects of the currently practiced management protocol has necessitated the adoption of interventional or endovascular management.

Angioplasty, either mechanical or chemical, appears to be the most effective solution available currently. Balloon angioplasty is suitable for proximal large arteries in the circle of Willis and distal vessel balloon angioplasty is typically not feasible. Balloon angioplasty provides sustained vasodilatation and retreatment is rarely necessary, unlike the situation in chemical angioplasty. The vessel tortuosity, preventing endovascular navigation, and the risk of fatal vessel rupture in 1% of cases, are its potential limitations. An alternative to balloon angioplasty is the intra-arterial vasodilator therapy (IAVT), which can be safely administered to smaller vessels. The therapy too can easily be repeated with little risk of severe side effects. Several intra-arterial agents have been assessed for chemical angioplasty which include phosphodiesterase inhibitors (papaverine and milrinone) or calcium channel blockers (nimodipine, verapamil, nicardipine). Papaverine, which was first used in 1992, was found to reverse vasospasm in the majority of cases (78%).[4] However, this angiographic improvement was associated with cerebral blood flow augmentation in only 46% of the cases and resulted in a major clinical improvement in only 26% of them. Papaverine was also reported to have significant side effects when used for IAVT. Verapamil, another calcium channel blocker, is not preferred due to the risk of causing profound hypotension, an increase in the intracranial pressure and seizures. Nimodipine, nicardipine and milrinone remain the three commonly used drugs for IAVT and superiority of any one of these agents has not been established yet.

Nicardipine is a dihydropyridine calcium antagonist, similar to nimodipine. Badjatia et al.,[5] reported the experience with the use of intra-aterial nicardipine in the treatment of aSAH-induced vasospasm in 18 patients and observed neurological improvement in 42% of the patients coinciding with a reduction in the transcranial Doppler (TCD) velocities.[5] Hejcl et al., solely evaluated the effect of milrinone on cerebral arteries and observed an increase in the arterial diameter by 13% of the distal segment of the ICA, and by 41% of both A1 and M1 arteries.[6] They corroborated these findings with TCD measurements where sequential TCDs have shown a decrease in the flow velocity following the administration of intrarterial milrinone. Similarly, Biondi et al., have reported the efficacy of intra-arterial nimodipine in preventing infarcts in 25 consecutive patients with symptomatic vasospasm.[7] This report by the authors, Narayan et al., corresponds with the published results of angiographic improvement in 40–100% cases and clinical improvement in 61–89% cases and reiterates the efficacy of intrarterial nimodipine in treating cerebral vasospasm.[2]

The success of IAVT depends on its timely administration and these modalities are effective only if initiated before an infarct sets in. Unlike ischemic stroke which is abrupt in onset, CVS presents in a subtle and stuttering manner. The predictors for vasospasm include an old age, fever, leukocytosis, hyponatremia, as well as circulating fibrin degradation products, and a high velocity on transcranial Doppler is not the absolute sign of impending clinical vasospasm. However, neurological deterioration remains the foremost warning sign indicating the onset of vasospasm and the need for repeated clinical examination cannot be over-emphasized. In conscious patients, it is relatively simple to assess for clinical deterioration, but in a sedated ventilated patient, the assessment of neurological deterioration is challenging. The timing of angiographic intervention remains critical and the policy of the authors of the paper in focus, to subject all patients with suspected DCI and an infarct-free computed tomographic scan to angiography seems appropriate. Hejcl et al., confirmed a good efficacy of nimodipine and milrinone when administered to conscious patients presenting with a focal deficit, resulting in angiographic improvement in 94% of the procedures and a clinical improvement in 82% of the patients.[6] In comatose and sedated patients on a ventilator, diagnosing vasospasm is more complicated. Hejcl et al., have suggested the use of adjunct diagnostic tools like microdialysis.[6] Metabolic changes are known to precede the symptoms of DCI by several hours and tools like microdialysis may help in its early detection.[7] The other major drawback with IAVT is that it too carries a 5% risk of clinical deterioration. Moreover, the dilatory effect is often short-lived, mandating continuous evaluation and repeated administration of the medication, as highlighted by Narayan et al.[2] This can be practically challenging in most of the institutes.

A few factors of interest would be the assessment of timing of infusion after detection of clinical vasospasm, and whether or not cisternal/ventricular lavage was done using nimodipine during the aneurysmal clipping. Continuous infusion of nimodipine, as was done in this study, has been shown to have a better outcome than administraiton of intermittent bolus doses.[8] Another confounding variable would be the fact that all patients in this study received nimodipine via the oral route also. Inclusion of the above factors in future studies would help in establishing better evidence on the role of intra- arterial nimodipine.

The war against vasospasm is far from over. IAVT can be recommended for all patients with an evidence of clinical deterioration along with TCD features of vasospasm. Intra-arterial nimodipine is a value addition to our armamentarium but not the ultimate weapon yet. The search for that mystery drug needs to go on.

  References Top

Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke 2007;38:2315-21.  Back to cited text no. 1
Narayan V, Pendharkar H, Indira Devi B, Bhat ID, Shukla DP Aggressive management of vasospasm with direct intra-arterial nimodipine therapy. Neurology India 2018;66:414-20.  Back to cited text no. 2
Goel R, Aggarwal A, Salunke P, Kumar A, Chhabra R. Is intra-arterial nimodipine really beneficial in vasospasm following aneurysmal subarachnoid haemorrhage? Br J Neurosurg 2016;30:407-10.  Back to cited text no. 3
Eun-Sung Park, Dae-Won Kim, Sung-Don Kang. Endovascular treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: A three-year experience. J Cerebrovasc Endovasc Neurosurg 2017;19:155-61.  Back to cited text no. 4
Badjatia N, Topcuoglu MA, Pryor JC, Rabinov JD, Ogilvy CS, Carter BS, et al. Preliminary experience with intra-arterial nicardipine as a treatment for cerebral vasospasm. AJNR Am J Neuroradiol 2004;25:819-26.  Back to cited text no. 5
Hejčl A, Cihlář F, Smolka V, Vachata P, Bartoš R, Procházka J, et al. Chemical angioplasty with spasmolytics for vasospasm after subarachnoid hemorrhage. Acta Neurochir (Wien) 2017;159:713-20.  Back to cited text no. 6
Gupta DK, Singla R, Kale SS, Sharma BS. Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India. Neurol India 2016;64:259-64.  Back to cited text no. 7
[PUBMED]  [Full text]  
Biondi A, Ricciardi GK, Puybasset L, Abdennour L, Longo M, Chiras J, et al. Intra-arterial nimodipine for the treatment of symtomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: Preliminary results. AJNR Am J Neuroradiol 2004;25:1067-76.  Back to cited text no. 8


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