Current Thinking and Future Trends
Deepak Awasthi, MD
Department of Neurosurgery, Louisiana State University Medical Center
New Orleans, Louisiana
[Definitions & Epidemiology | Pathogenesis | Treatment | Tirilazad | Future | Conclusion | References]
This review on cerebral vasospasm was supported in part by an educational grant from Pharmacia &Upjohn.
Cerebral vasospasm remains a significant source of morbidity and mortality in patients with subarachnoid hemorrhage (SAH) after an aneurysmal rupture. This article will briefly review this important topic in neurosurgery and highlight some of the recent research. For a complete and thorough review of this topic, the reader is referred to a recent chapter authored by Joseph Zabramski (Vasospasm after Subarachnoid Hemorrhage, in Subarachnoid Hemorrhage: Pathophysiology and Management. Neurosurgical Topics series of the American Association of Neurological Surgeons, 1997, pp127-156).
Definitions and Epidemiology:
The term "cerebral vasospasm" is commonly used to refer to both the clinical picture of delayed onset of ischemic neurological deficits associated with aneurysmal SAH ("symptomatic vasospasm") and the narrowing of cerebral vessels documented by angiography or other studies ("angiographic or arterial vasospasm"). Arterial vasospasm typically appears 3 to 4 days after rupture and reaches a peak in incidence and severity at 7- 10 days. The incidence and time course of symptomatic vasospasm parallels that of arterial vasospasm. However, while 40% to 70% of patients have evidence of arterial narrowing (angiography or Doppler ultrasound), only 20% to 30% develop the clinical symdrome. The most imprtant factors in determining the clinical effect of vasospasm are the severity and extent of vessel narrowing. Symptomatic vasospasm typically begins 4-5 days after the hemorrhage and is characterized by the insidious onset of confusion and a decreasing level of consciousness. When the arterial narrowing is marked, these symptoms may progress to focal neurological deficits, infarction, coma and death. In less severe cases, neurological recovery can be expected as the arterial narrowing resolves.
The exact mechanism(s) by which SAH induces arterial vasospasm continues to be a subject of considerable research and debate. As a matter of fact as many as 100 articles are published each year on the topic of cerebral vasospasm.
Arterial spasm most likely involves some alteration
in the structure of the vessel wall. Studies have shown that arterial
vasospasm results primarily
from prolonged smooth muscle contraction. Hypertrophy, fibrosis, and degeneration
as well as other inflammatory changes in the vessel wall are secondary effects
that occur on a delayed basis. Extensive research has shown that the big
event that leads to the initiation of vasospasm is the release of oxyhemoglobin
(blood breakdown product). However, the exact mechanism by which oxyhemoglobin
induces vasocontriction is unknown. This mechanism appears to be a multifactorial
process that involves the generation of free radicals, lipid peroxidation
and activation of protein kinase C as well as phospholipase C and A2 with
resultant accumulation of diacylglycerol and the release of endothelin-1.
These events appear to create a positive feedback loop that, in turn, produces
a tonic state of smooth muscle contraction and inhibition of endothelium-dependent
The main goal of current treatment plan is to prevent or limit the severity of arterial and symptomatic vasospasm. To this end, only two treatments are generally accepted to be of substantial value in reducing the ischemic complications related to vasospasm: 1) Treatment with cerebroselective calcium channel blocker nimodipine- Nimotop (30-60mg po q4h); note: mild volume expansion is maintained to minimize the effects on systemic arterial pressure. Nimodipine is designed to prevent signs and symptoms of vasospasm. If, however, these signs and symptoms develop despite this regimen, patients are then treated with aggressive hypervolemic, hypertensive, hemodilution (HHH) therapy. 2) Hypervolemic, hypertensive therapy is used to elevate the cerebral perfusion pressure and thus provide blood to regions of the brain with marginal perfusion because of arterial spasm. By clipping the aneurysm early, one can be more aggressive with this therapy without concern of aneurysm re-rupture and subsequent rebleeding. Some centers also advocate prophylactic HHH therapy in patients at high risk for spasm (for example, thick subarachnoid blood clots). Thus, prophylactically one raises the blood pressure (in the range of 160-200mm Hg systolic with pressor agents like Neosynephrine) and volume expansion (with colloids) while monitoring the central venous pressure (CVP) or pulmonary capillary wedge pressure (PCWP).
In our center, we prophylactically treat patients at high risk for vasospasm, while the others we closely follow for clinical signs or symptoms of vasospasm correlating them with daily transcranial doppler studies (TCDs)- spastic arteries exhibit a higher than normal velocity. In addition, hyponatremia is also an early sign (which we monitor) of impending vasospasm.
Despite the above management options, morbidity and mortality from vasospasm remains high. Recently, free radical induced lipid peroxidation has been identified as a potentially important contributor to both the arterial narrowing of vasospasm and the final cascade of ischemic cell death. The 21-aminosteroid tirilazad mesylate was developed (by Pharmacia & Upjohn) as a potent inhibitor of lipid peroxidation. Indeed, in experimental models of SAH and focal cerebral ischemia tirilazad has been shown to ameliorate vasospasm and improve cerebral blood flow as well as reduce the size of cerebral infarction. In addition, preliminary studies with this drug have shown it to be safe and unassociated with side effects such as hypotension, mental status changes or glucocorticoid toxicities. Tirilazad mesylate is a nonglucocorticoid 21-aminosteroid that exerts its anti-lipid peroxidation action through cooperative mechanisms: a radical scavenging action (i.e., chemocal antioxidant effect) and a physicochemical interaction with the cell membrane that serves to decrease membrane fluidity (i.e., membrane stabilization). Several multicenter, randomized, double-blind, vehicle-controled clinical trials have been organized throughout the world to test the efficacy of tirilazad mesylate in patients with aneurysmal SAH- including a North American study which involved LSU Medical Center as one of the study centers. The primary hypothesis to be tested was whether treatment with tirilazad reduced symptomatic vasospasm and improved overall outcome 3 months after SAH. Recently (February 1996), the findings from the first concluded trial conducted by investigators from Europe, Australia and New Zealand was published in the Journal of Neurosurgery (Kassell NF et al. 84:221-228,1996). This trial showed a reduction in symptomatic vasospasm in the group that received 6mg/kg per day of tirilazad. However, the difference was not statistically significant and the benefits were predominantly shown in men rather than than in women. The lack of statistical significance and the less benefit in women may be explained by increased clearance of tirilazad in middle-aged women (as compared to men) as well as use of phenytoin (administration of phenytoin or Dilantin with tirilazad increases clearance to approximately 50% in healthy male volunteers). Thus, additional phase III studies are nearing completion to evaluate the efficacy of higher doses of tirilazad in the treatment of SAH. We feel tirilazad is a promising drug which may help reduce the morbidity/ mortality associated with vasospasm. As a further support of the potential beneficial role of tirilazad, it has been shown to be of benefit in other forms of brain injury (which may involve lipid peroxidation) including traumatic brain injury. References at the end of this article will guide the reader to further study the role of tirilazad.
Intracisternal (within the CSF spaces) thrombolytic and endovascular therapies have a potential role in future therapy of vasospasm. The theory behind thrombolytic therapy is that there is an intimate association between lysis of blood and the release of oxyhemoglobin and vasospasm. Thus, by removing the blood, one can possibly prevent vasospasm. Recombinant tPA has been used in several clinical trials with moderate success. Thus, we feel that use of intracisternal thrombolytic therapy should be viewed with caution.
On the other hand, we feel that endovascular therapies may be potentially more beneficial as a treatment option. Encouraging results have been reported with intra-arterial administration of papaverine and angioplasty of accessible spastic vessels. Timing of endovascular treatment is critically important to be effective. Intervention should be performed soon after it is apparent that a patient is progressing or failing to improve despite maximal medical therapy and before the onset of cerebral infarction. Indeed, cerebral angiography with the possibility of angiopalsty has become a routine part of our protocol in the management of symptomatic vasospasm. Figure 1 shows an example of a patient with symptomatic basilar artery vasospasm who made a significant recovery (from obtundation to following commands) after angioplasty.
Left pict: Right vertebral artery injection (AP view) showing moderate spasm of the basilar artery (red arrow). Right pict: Right vertebral artery injection (AP view) post-angioplasty showing improvement in the caliber of the basilar artery (red arrow). The patient also improved clinically.
Despite being a significant source of morbidity and mortality, death and disability from vasospasm have declined from approximately 35% in the early 1970's, to between 15% and 20% in the 1980's to <10% in the 1990's. The decline can be attributed in large part to changes in perioperative management (aggressive treatment and prevention of vasospasm), early surgical intervention as well as improvement in our understanding of the pathophysiology of vasospasm.
Although the identity of the primary spasmogen is still controversial, the bulk of the evidence points to oxyhemoglobin and the involvement of oxygen free radicals in initiating a cascade of reactions that culminate in prolonged vascular smooth muscle contraction. Beyond this point, however, the pathophysiology is uncertain and likely involves multiple pathways. Clarification of these pathways will lileky lead to more effective treatment and improved outcomes in the future.