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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 5  |  Page : 1290-1291

Aneurysmal SAH “A Riddle Wrapped Up in Enigma”

Neurosurgery, AIIMS, Delhi, India

Date of Web Publication19-Nov-2019

Correspondence Address:
Dr. Ramesh Sharanappa Doddamani
Neurosurgery, AIIMS, Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.271282

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How to cite this article:
Doddamani RS, Chandra PS. Aneurysmal SAH “A Riddle Wrapped Up in Enigma”. Neurol India 2019;67:1290-1

How to cite this URL:
Doddamani RS, Chandra PS. Aneurysmal SAH “A Riddle Wrapped Up in Enigma”. Neurol India [serial online] 2019 [cited 2020 Jul 12];67:1290-1. Available from:

Ruptured cerebral aneurysm is one of the most devastating neurosurgical diseases. The success story of the survivors seldom ends with successful securing of the aneurysm. Delayed cerebral ischemia (DCI) is the most dreaded sequelae, ensuing within the first few weeks following subarachnoid hemorrhage (SAH). DCI is one of the most important preventable cause of mortality and morbidity, arising in upto 30% patients with aneurysmal SAH.[1],[2]

  Pathophysiology of Vasospasm Top

Neuroinflammation takes the center stage and numerous inflammatory mediators have been implicated in the development of cerebral vasospasm (CVS). Disruption of the blood–brain barrier following subarachnoid bleed (SAH) and the presence of blood degradation products triggers the cascade. The occurrence of vasospasm is directly proportional to the amount of blood in the subarachnoid space as observed with the Fishers grading.[3] Oxyhemoglobin, a potent inflammatory mediator leads to the formation of endothelin-1, reduced synthesis of prostacyclin (PGI2), reduced nitric oxide synthase (NOS) in the vessel wall, thereby producing vasoconstriction. Traditionally, CVS involving large arteries is the most commonly cited culprit in the development of DCI. The recent literature suggests varied mechanisms; like early brain injury at the time of aneurysmal rupture, loss of autoregulation at the level of microvasculature, cortical spreading depolarization, and microthrombosis (as a part of inflammation), leading to DCI.[4],[5] This is evidenced by the fact that angiographic CVS though prevalent in almost 70% of patients SAH, only 20–30% progress to symptomatic CVS, indicating multifactorial etiologies. Treatment of angiographic vasospasm does not always ensure a good outcome or reduction in the occurrence of DCI.[2]

  Strategies to Prevent Vasospasm and Dci Top

The understanding of the mechanisms of vasospasm still remains incomplete and with the available evidence and improvement in the critical care facilities there has been a significant reduction in the mortality of patients with SAH. Maintenance of hypertension, euvolemia and hemodilution (Triple H therapy) along with a nebulae of pharmacologic agents to circumvent CVS have been tried in the literature: nimodipine, clazosantan, simvastatin, milrinone, cilostazol magnisium sulfate, fasudil, with variable success rates. Nitric oxide synthase analogues (Citrulline, Adenopectin), erythropoietin, sildenafil, free radical scavengers (Tirilizad), fibrinolytic agents (tPA) have all been tried with variable success.[5] Large numbers of trials have tested the efficacy of each one of these drugs in the prevention of CVS and DCI. The CONSCIOUS-1, 2, and 3 trials evaluating the role of Clazosantan, an Endothelin 1A receptor antagonist failed to show any benefits on the outcomes of patients with SAH.[6] A meta-analysis evaluating six RCTs on the role of Statins in prevention of CVS found no benefit.[6] However, on subgroup analysis there was reduced occurrence of DCI and mortality suggesting possible beneficial effect. Currently, phase-3, STASH trial is under progress evaluating the role of simvastatin in aneurysmal SAH.[7] Similarly MASH, a phase-3 trial did not show any clinical benefit of magnesium sulfate over placebo.[8]

Till date, nimodipine (Oral) is the only drug shown to be associated with better outcome (Class-1 evidence). A double-blinded placebo controlled randomized trial showed the efficacy of oral nimodepine in reducing cerebral infarction and outcomes.[9]

A disturbed balance between thrombaxanes and prostacyclins leads to the incidence of CVS, with thromboxanes possessing a potent smooth muscle contracting and platelet aggregatory properties. Ozagrel, a thromboxane synthase inhibitor has been tried in cases of aneurysmal SAH. Sasaki et al. first demonstrated a beneficial effect on vasospasm in dog models.[10] This led to the first double-blind randomized controlled trial performed by Suzuki et al. in 1989.[11] This trial showed excellent outcomes in terms of limiting low-density areas on CT brain and improvement in vasospasm-related symptoms. Very few non-randomized studies comparing combinations of Ozagrel with other drugs have shown beneficial effects of Ozagrel.[12] Mostly, these studies were restricted in the past to Japan followed by China and Korea due to non-availability of this drug in other parts of the world.

In the current study, Narayan et al., studied the efficacy of ozagrel in patients of aneurysmal SAH. They found no significant difference in the outcome between ozagrel and the standard medical therapy group. However, a significant benefit in terms of favorable outcomes at 3 months was observed in patients with preoperative evidence of vasospasm on subgroup analysis with a better safety profile. This might well suggest a possible role of this drug in patients with preoperative angiographic vasospasm. These findings need further validation with large randomized multicentric trials. The management of vasospasm and DCI following aneurysmal SAH still remains “a riddle wrapped up an enigma.”

  References Top

Narayan V, Shukla D, Bhat DI, Prabhuraj AR, Devi BI. Ozagrel for postoperative management of aneurysmal subarachnoid hemorrhages. Neurol India 2019;67:1286-89.  Back to cited text no. 1
  [Full text]  
Bederson JB, Connolly EJ, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009;40:994-1025.  Back to cited text no. 2
Lindvall P, Runnerstam M, Birgander R, Koskinen LO. The Fisher grading correlated to outcome in patients with subarachnoid haemorrhage. Br J Neurosurg 2009;23:188-192.  Back to cited text no. 3
Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2014;85:1343-53.  Back to cited text no. 4
Chugh C, Agarwal H. Cerebral vasospasm and delayed cerebral ischemia: Review of literature and the management approach. Neurol India 2019;67:185-200.  Back to cited text no. 5
[PUBMED]  [Full text]  
Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): Randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 2008;39:3015-21.  Back to cited text no. 6
Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): A multicentre randomised phase 3 trial. Lancet Neurol 2014;13:666-75.  Back to cited text no. 7
Van den Bergh WM, Algra A, Dorhout Mees SM, van Kooten F, Dirven CMF, van Gijn J, et al. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: The MASH Study. Stroke 2006;37:2326-30.  Back to cited text no. 8
Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British Aneurysm Nimodipine Trial. BMJ 1989;298:636-42.  Back to cited text no. 9
Sasaki T, Wakai S, Asano T, Takakura K, Sano K. Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY-1581. J Neurosurg1982;57:74-82.  Back to cited text no. 10
Suzuki S, Sano K, Handa H, Asano T, Tamura A, Yonekawa Y. Clinical study of OKY-046, a thromboxane synthetase inhibitor, in prevention of cerebral vasospasms and delayed cerebral ischaemic symptoms after subarachnoid haemorrhage due to aneurysmal rupture: A randomized double-blind study. Neurol Res1989;11;79-88.  Back to cited text no. 11
Suzuki Y, Shibuya M, Satoh S. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: Sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo) 2008;48:241-7.  Back to cited text no. 12


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