Effect Of Fasudil Hydrochloride, A Protein Kinase Inhibitor, On Cerebral Vasospasm And Delayed Cerebral Ischemic Symptoms After Aneurysmal Subarachnoid Hemorrhage

Objective:Cerebral vasospasm is one of the main causes of mortality and morbidity following aneurysmal subarachnoid hemorrhage (SAH). Neurocritical care has been greatly improved over the past decades and the use of both medical and surgical measures has reduced the incidence of clinical deficits in patients recovering from SAH. However, poor outcome attributed to secondary ischemia remains a major problem. For this reason, endovascular treatment of refractory cerebral vasospasm has become part of the standard treatment protocol in many neurosurgical centers. The most frequently used techniques aim to achieve arterial vessel dilatation by means of mechanical balloon angioplasty,local intra-arterial administration of papaverine, or a combination of the two.Mechanical angioplasty has demonstrated permanent reversal of vasospasm in treated vessels, but it can be applied to only proximal vessel segments, and it must be performed by experienced interventional neuroradiologists. Pharmacologic dilation by means of intra-arterial papaverine has the advantage of also acting on smaller distal branches and diffuse vasospasm. However, its beneficial effects are transient, and repeat treatment sessions are often necessary.Nimodipine is a calcium antagonist that reduces the influx of calcium in the smooth muscle cell through the blockage of the voltage-operated calcium channels. This may lead to reduced vascular smooth muscle constriction and a decrease in the release of vasoactive substances from endothelium and platelets. The molecular mechanism of vasospasm has now been partly elucidated, phosphorylation of myosin light chain is one of the most important signal transduction pathways in the arterial smooth muscle contraction-relaxation processes. The activations of Rho kinase and myosin light chain kinase promote the phosphorylation of myosin light chain and cause the contraction of arterial smooth muscle. Fasudil hydrochloride is a new potent vasodilator discovered and developed in Japan. The mechanism of action is different from that of calcium channel blockers such as nimodipine, which are widely used clinically for the treatment of cerebral vasospasm. Fasudil hydrochloride inhibits protein kinases such as Rho kinase, myosin light chain kinase, and protein kinase C, resulting in the inhibition of myosin light chain phosphorylation. The results of multi- center, prospective, randomized, double-blind trials using placebo as the control revealed that fasudil hydrochloride suppresses cerebral vasospasm after subarachnoid hemorrhage. The present study evaluated the efficacy and safety of fasudil hydrochloride for suppressing cerebral vasospasm and subsequent cerebral ischemic symptoms following subarachnoid hemo- rrhage, compared to nimodipine in a randomized open trail.Methods:This randomized open trial with nimodipine as the control included 60 patients with aneurysmal SAH, devided into nimodipine group and fasudil group. All patients were administered eigher 60mg of fasudil hydrochloride by intravenous injection over a period of 30 minutes two times a day or 10mg of nimoton by continuous intravenous infusion for 14 days following surgery or intravascular therapy. Comparison of clinical datas between per and post-therapy in the two groups was done by the statistical analysis, such as CT,TCD, clinical outcome as GOS,BI,MRS,ESS.Results: (1) This study showed significantly better clinical outcome in the patients receiving nimoton or fasudil(P>0.05);(2) CT: There were the lowdensity area on CT 7th day 4 cases in nimodipine group, 5 cases in fasudil group;14th day 1 cases in nimodipine group,1 cases in fasudil group after treatment;(3) TCD: The mean blood flow of MCA (unit: cm/s) was 94.27±23.24 before treatment in nimodipine group, reduced to 89.27±22.38(7th day),82.07±19.85(14th day), separately after treatment. 97.67± 21.82 before treatment in fasudil group reduced to 85.80±17.44 (7th day),p=0.506>0.05 to 82.43±21.39 (14th day),p=0.945>0.05, separately after treatment. But there was no significant difference between two groups, p>0.05;(4) Prognosis: Both drugs significantly improved the clinical outcome as GOS,BI,MRS,ESS. However, there were no significant difference between two groups, p>0.05;(5) There were no any poisonous, adverse reactions and other side effects.Conclusion:This clinical trial demonstrated that both fasudil hydrochloride and nimodipine suppressed cerebral vasospasm and associated cerebral ischemic symptoms. However, there were no significant difference between two groups. Fasudil hydrochloride is effective to prevent vasospasm following subarachnoid hemorrhage. The effect of fasudil hydrochloride on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage basing on the four aspects:1) Clinical outcome: the clinical outcome was evaluated according to the Glasgow Outcome Scale(GOS), Barthel Index(BI), Modified Rankin Scale(MRS), the European Stoke Scale(ESS). The functional outcome observed 3 month after the onset of disease is shown exactly effective according to GOS, BI, MRS, ESS, although the clinical outcome was statistically not significant between two groups(p>0.05);2) CT: There were the lowdensity area on CT 7th day 4 cases in nimodipine group, 5 cases in fasudil group;14th day 1 cases in nimodipine group,1 cases in fasudil group after treatment. This phenomenon showed that the early administration of fasudil hydrochloride and nimodipine prevent cerebral vasospasm following subarachnoid hemorrhage, improving disturbance of the intracerebral microcirculatory system may be involeved in cerebral ischemia due to vasospasm, and newly appeared low density areas on CT. No statistically significant difference was observed within the groups or between the two groups(p>0.05);3)TCD (transcranial doppler sonography): The mean blood flow of MCA (unit: cm/s) was reduced 7th day and 14th day after SAH in two groups, nimodipine group have a better improvement than fasudil group. These decreases were not statistically significant (p>0.05); 4) Adverse reactions and safety: There were no any poisonous, adverse reactions and other side effects between two groups. But there was no significant difference between two groups (p>0.05).This clinical trial demonstrated that fasudil hydrochloride is a safe and effective agent for preventing and treating patients after subarachnoid hemorrhage for ruptured cerebral aneurysm, but further study of larger numbers of patients is required to clarify the superiority of this drug. This drug may provide a new therapeutic modality for treating patients suffering from cerebral vasospasm following subarachnoid hemorrhage and for improving the functional prognosis of these patients.