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Neurology India, Vol. 59, No. 2, March-April, 2011, pp. 151-153 Editorial Continuous intravertebral artery injection of fasudil hydrochloride in the treatment of cerebral vasospasm Feyzi Birol Sarica Department of Neurosurgery, Baskent University Faculty of Medicine, Ankara, Turkey Correspondence Address: Feyzi Birol Sarica, Department of Neurosurgery, Baskent University Faculty of Medicine, Adana Training and Research Hospital, Dadaloglu Mahallesi 39. Sokak No. 6, 01250, Adana, Turkey, saricafb@gmail.com Date of Submission: 14-Nov-2010 Code Number: ni11047 PMID: 21483106 DOI: 10.4103/0028-3886.79121 Angiographic vasospasm refers to the narrowing of the diameter of cerebral vessel radiologically. The clinical vasospasm is used as a synonym of delayed ischemic neurological deficit (DIND) which is more preferred in recent years and describes the syndrome that has ischemic symptoms and goes with the development of a progressive narrowing of cerebral arteries. [1] Cerebral vasospasm (CV) begins clinically on fourth day after subarachnoid hemorrhage (SAH), and has the highest level between the days of 7 and 8 and recovers toward the end of second week by decreasing the severity. [2] Fasudil hydrochloride [hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride] is a protein kinase inhibitor and acts as a potent vasodilator. It inhibits enzyme specific for cerebral vascular area such as myosin light-chain kinase and protein kinase-C. Fasudil and its active metabolite, hydroxyfasudil, inhibit Rho kinase which is responsible for CV development. Thus, it causes vasodilatation in the final stage of contraction of the smooth muscle by expanding the blood vessels. [3] In a prospective, randomized, placebo-controlled, double-blind study on 267 patients with ruptured cerebral aneurysm which was conducted by Shibuya et al. in 1992, IVF was administered (30 mg three times/day for 14 days) in order to do prophylaxis against vasospasm. Although the incidence of angiographic vasospasm is 38% in the IVF group, it is 61% in the control group. The incidence of clinical vasospasm is 35% in the IVF group and 50% in the control group. Thus, it was determined that fasudil hydrochloride reduces significantly the incidence of both angiographic and clinical vasospasm. [4] In 2001, Masaoka et al. administered IVF to 74 patients with ruptured aneurysm within 48 h after the SAH onset and reported that this treatment method is safe and effective for CV treatment in human beings. [5] In 2009, Jingjian et al. conducted a prospective, randomized, positive-controlled with Nimodipine, double-blind study on 64 patients. In this study, 30 mg of IVF (over 30 min/one time, 3 times/day for 14 days) was administered to 32 patients and 8 mg (40 mL) of Nimodipine was administered intravenously to 32 patients in the positive control group. In the CT scan that was done on 14 th day after the treatment; it was detected that there was a decline in hypodense areas that was considered to be secondary to vasospasm (IVF group: 18.7-3.1%) and a significant increase in mean blood flow velocity (with TCD) (P = 0.0002). As a result of this study, it was also reported that DIND which is developed secondary to aneurysmal SAH could be healed substantially with IVF treatment and this treatment is safe and effective. [6] In patients with severe CV, intravenous drug administration methods are ineffective at delivery of the drug to the related vessel. Balloon angioplasty and intraarterial vasodilator applications are introduced as alternative treatment methods for CV treatment with the developments in the field of endovascular technology (microcatheter, micropump, etc.). [1],[7],[8] In 1999, Tachibana et al.[7] firstly administered IAF (over 10-30 min 15-60 mg was administered via the proximal internal carotid artery or vertebral artery following standard angiography, without superselective techniques) to 10 patients with DIND. Twenty-four arterial territories (21 internal carotid artery, 3 vertebral artery) were treated, with angiographic improvement noted in vessels (66.7%). Angiographic vasospasm was improved in 9 of 10 patients (90%) and neurologic symptoms that are seen in DIND recovered without sequealae in 2 of 3 patients (66.7%). Researches emphasized that IAF administration is an effective and safe treatment method with a high success rate in CV treatment. The use of IAF for DIND after SAH, however, has been reported for only a small number of patients. In 2005, in a study that was conducted by Tanaka et al.,[8] 23 patients with DIND were treated with 34 dose of IAF injection (with doses ranging from 15 to 45 mg, for one treatment, depending on the degree of the vasospasms, injection with power injector: 1.5 mg/min, into internal carotid artery and/or M2 portion of middle cerebral artery angiography, with superselective techniques). All IAF treatments were performed between 5 and 16 days after SAH. Angiographic improvement was seen in 100% of the cases and the result of 3 months follow-up showed that there is good recovery or moderate disability in 15 of 23 patients (65.3%). Multiple IAF treatment ranging between two and four times was given to nine patients. A 3-month follow-up showed that there is good recovery or moderate disability in five of patients that were given multiple IAF treatment (55%). This results suggest that IAF injection colud be a safe, new and effective method for symptomatic treatment of cerebral vasospasm. In the article published in this issue of the journal, Liu et al.[9] conducted an experimental study on rabbits with delayed post-SAH CV by using the control group in order to show the superiority of effects of the continuous administration of IAF to intravertebral artery (30 mg: 2 mL fasudil HCL, CIV group: 1 mg/kg/24 h, 5-day and 7-day) to the IVF (30 mg: 2 mL fasudil HCL, 0.5 mg/kg, bid) treatment. In this study, continuous IAF injection was administered with the help of a micropump by placing a persistent microcatheter to vertebral artery, and thus, it was directly delivered to the vessel area with vasospasm by preventing the peripheral consumption of the drug. A rapid and safe response to the drug is obtained with this superselective technique. Another advantage of this method is to have the possibility of reducibility of necessary drug concentration for use. Maximum and reliable response were obtained by using minimum dose. In this study, both IAF injection and IVF injection were effective in the prevention of basilar artery spasm caused by SAH. In the treatment of delayed CV due to SAH, it was observed that IAF treatment is more effective than IVF treatment applied in different periods of time (P < 0.05). Furthermore, no significant difference was observed between " short-term" continuous IAF injection such as for 5 days; however, it was observed that continuous IAF injection such as for 7 days was significantly more effective than IVF injection (P < 0.05). This situation indicate that, probably, the effect of IAF cannot be obtained within 5 days, but it can be obtained with " long-term" use such as 7 days. As a result of this study, it was proved that IAF is effective in the treatment of post-SAH CV and is more effective than IVF treatment in continuous long-term use. Moreover, fasudil and the other drugs will be able to administer rapidly, with effective concentration and within the desired time by this method. In the future, the effectiveness of continuous IAF treatment in CV will be able to understood more clearly with the use of this endovascular method in the randomized clinical trials on human beings. References
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