SAH-Induced Vasospasm Refractory to Medical Treatment: A Mini Review and Role of Intraventricular Agents

Editorial

Aneurysmal Subarachnoid Hemorrhage (SAH) is a common cause of intracranial vasospasm with major disabilities and death due to delayed cerebral ischemia with an overall incidence of 33-67% and 10-13% incidence of cerebral infarct [1,2].

The pathogenesis of vasospasm in SAH appears to be multifactorial with various theories being put forward to explain the occurrence of vasospasm. Oxyhemoglobin, a breakdown product of hemoglobin from lysed RBC in the cisternal CSF, is believed to be the spasmogen involved in the genesis of vasospasm [1]. Lately, vasoactive endothelium derived peptide, called Endothelin-1 (ET-1), was isolated and its effect on smooth muscle contraction demonstrated. Oxyhemoglobin liberated after SAH appears to be simultaneously capable of activating the gene for this potent vasoconstrictor, increasing levels of ET-1 mRNA in the CSF and of also removing the influence of the potent vasodilator NO, the physiological antagonist of ET-1, from the blood vessel walls by direct binding. ET-1 and NO are important factors in maintaining dynamic equilibrium in vasomotor tone. Disequilibria between the vasomotor effects of these molecules results in unmitigated vasoconstriction.

Factors significantly associated with vasospasm are age of 40 to 59 years, history of hypertension, worse neurological grade, thicker blood clot on cranial CT scan obtained on hospital admission, larger aneurysm size, presence of IVH, and prophylactic use of induced hypertension [3]. Transcranial Doppler (TCD) and angiography are the two main tools for the diagnosis of vasospasm.

Various treatment options for vasospasm are calcium channel blockers (nimodipine, 60mg q4hr PO or 2mg/hr IV), triple-H therapy (hypertension, hypervolemia, hemodilution), balloon angioplasty, and papaverine infusion. Although the effectiveness has still not been proven, these modalities are widely accepted as rescue therapies [4-6]. The goal is CPP levels greater than 120 mm Hg and a central venous pressure over 10 mm Hg. Other proposed but less certain modes of treatment are the non-glucocorticoid 21 aminosteroid, tirilazad, and Magnesium sulfate.

However, all medical therapies have their own limitations, including risk of rebleeding of the unclipped aneurysm after triple-H therapy, unavailability of balloon angioplasty in urgent conditions in all neurosurgical institutions, etc. Therefore, there is still the need for further last resort therapies.

Intraventricular agents has been showed as appealing options as many of SAH patients already have ventricular drains in place, they can be safely administered at the bedside, and can be used in patients for whom conventional therapies are either not effective or not tolerated. The following agents have been used: 1) Calcium channel blockers: nicardipine (4 mg bid x 5-17 days) and nimodipine (bolus of 0.4 mg, followed by Intrathecal (IT) infusion of 0.4 mg/h) has been shown to reduce mean cerebral blood flow velocity over 24 h with continued administration [7-10]. 2) Sodium Nitroprusside (SNP): Some promising efforts have been reported with intraventricular SNP (10-40 mg bolus followed by 2-8 mg/h infusion or 2-5 mg q3-12 h) with benefits shown clinically and by TCD [11-17]. It is possible that this agent exerts its effects through release of NO and playing a role in ET-1/NO equilibrium. 3) Magnesium sulfate.

As SAH is a life threatening and debilitating disease with a high personal, social, and economic burden, it really needs more research to better understand the complications and promote therapeutic options.

References

1. Weir B. The pathophysiology of cerebral vasospasm. Br J Neurosurg. 1995; 9: 375-390.
2. Dorsch NW. Cerebral arterial spasm--a clinical review. Br J Neurosurg. 1995; 9: 403-412.
3. Macdonald RL, Rosengart A, Huo D, Karrison T. Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage. J Neurosurg. 2003; 99: 644-652.
4. Weyer GW, Nolan CP, Macdonald RL. Evidence-based cerebral vasospasm management. Neurosurg Focus. 2006; 21: E8.
5. Rinkel GJ, Feigin VL, Algra A, van Gijn J. Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews. 2004: CD000483.
6. Eskridge JM, McAuliffe W, Song JK, Deliganis AV, Newell DW, Lewis DH, et al. Balloon angioplasty for the treatment of vasospasm: results of first 50 cases. Neurosurgery. 1998; 42: 510-516.
7. Webb A, Kolenda J, Martin K, Wright W, Samuels O. The effect of intraventricular administration of nicardipine on mean cerebral blood flow velocity measured by transcranial Doppler in the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2010; 12: 159-164.
8. Kasuya H, Onda H, Sasahara A, Takeshita M, Hori T. Application of nicardipine prolonged-release implants: analysis of 97 consecutive patients with acute subarachnoid hemorrhage. Neurosurgery. 2005; 56: 895-902.
9. Hänggi D, Beseoglu K, Turowski B, Steiger HJ. Feasibility and safety of intrathecal nimodipine on posthaemorrhagic cerebral vasospasm refractory to medical and endovascular therapy. Clin Neurol Neurosurg. 2008; 110: 784-790.
10. Goodson K, Lapointe M, Monroe T, Chalela JA. Intraventricular nicardipine for refractory cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care. 2008; 8: 247-252.
11. Thomas JE, Rosenwasser RH, Armonda RA, Harrop J, Mitchell W, Galaria I. Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke. 1999; 30: 1409-1416.
12. Thomas JE, McGinnis G. Safety of intraventricular sodium nitroprusside and thiosulfate for the treatment of cerebral vasospasm in the intensive care unit setting. Stroke. 2002; 33: 486-492.
13. Raabe A, Zimmermann M, Setzer M, Vatter H, Berkefeld J, Seifert V. Effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm. Neurosurgery. 2002; 50: 1006-1013.
14. Raabe A, Vatter H, Zimmermann M, Seifert V. Reversal of tissue hypoxia by a single intraventricular dose of sodium nitroprusside in a patient with severe medically refractory cerebral vasospasm after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2002; 72: 123-124.
15. Pathak A, Mathuriya SN, Khandelwal N, Verma K. Intermittent low dose intrathecal sodium nitroprusside therapy for treatment of symptomatic aneurysmal SAH-induced vasospasm. Br J Neurosurg. 2003; 17: 306-310.
16. Kumar R, Pathak A, Mathuriya SN, Khandelwal N. Intraventricular sodium nitroprusside therapy: a future promise for refractory subarachnoid hemorrhage-induced vasospasm. Neurol India. 2003; 51: 197-202.
17. Agrawal A, Patir R, Kato Y, Chopra S, Sano H, Kanno T. Role of intraventricular sodium nitroprusside in vasospasm secondary to aneurysmal subarachnoid haemorrhage: a 5-year prospective study with review of the literature. Minim Invasive Neurosurg. 2009; 52: 5-8.