Vasospasme merupakan komplikasi terbanyak yang terjadi pada pasien dengan SAB/SAH.

Vasospasme paling sering terjadi pada 3 hari pertama setelah timbulnya gejala khas pada SAH.
Dan akan mereda setelah hari ke 7 dan 8.
Beberapa jurnal meneliti hubungan antara menurunnya kadar trombosit dengan terjadinya
vasospasme ini. Vasospasme terjadi paling sering pada kadar trombosit <150.000/mm 3 dengan
risiko 5 kali lebih besar. Ini terjadi sebagian besar antara hari ke 3 sampai ke 7.

http://dx.doi.org/10.3340/jkns.2013.54.4.289

Significance

of

C-Reactive

Protein

and

Transcranial Doppler in Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage.

Copyright 2013 The Korean Neurosurgical Society

[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.
Pathogenesis:
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 relaxation.
Treatment:
Current
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 160200mm 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.
Tirilazad
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 SAHincluding 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.
Future Treatments
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.

Conclusion:
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.

References:

1. Hall ED: Efficacy and mechanisms of action of the cytoprotective lipid peroxidation inhibitor
tirilazad mesylate in subarachnoid haemorrhage. Eur J Anaesth 13:279-289, 1996.

2. Hall ED, McCall JM, Means ED: Therapeutic potential of the Lazaroids (21-aminosteroids) in
acute central nervous system trauma, ischemia and subarachnoid hemorrhage. Advances in
Pharmacology 28:221-268, 1994.

3. Smith SL, Scherch HM, Hall ED: Protective effects of tirilazad mesylate and metabolite U-89678
against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative
neuronal injury. J Neurosurg 84:229-233, 1996.