Therapeutic approaches to vasospasm in subarachnoid hemorrhage Nicholas W.C. Dorsch, FRCS, FRACS

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1 Therapeutic approaches to vasospasm in subarachnoid hemorrhage Nicholas W.C. Dorsch, FRCS, FRACS Delayed vasospasm as a result of subarachnoid blood after rupture of a cerebral aneurysm is a major complication. It is seen in over half of patients and causes symptomatic ischemia in about one third. If left untreated, it leads to death or permanent deficits in over 20% of patients. The essential cause and the relative contribution of true muscle spasm and other changes in the vessel wall remain uncertain. The mainstays of treatment are careful maintenance of fluid balance, induced hypervolemia and hypertension, calcium antagonists, balloon or chemical angioplasty, and, in some centers, cisternal fibrinolytic drugs. Promising future lines of treatment include gene therapy, nitric oxide donors, magnesium, sustained release cisternal drugs, and several other drugs that are under experimental or clinical trial. Curr Opin Crit Care 2002, 8: Lippincott Williams & Wilkins, Inc. Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia. Correspondence to Nicholas W.C. Dorsch, FRCS, FRACS, Department of Surgery, Westmead Hospital, Westmead NSW 2145, Australia; nick_dorsch@wsahs.nsw.gov.au Dr. Dorsch has received support from pharmaceutical companies, including Bayer AG, Pharmacia & Upjohn, Sterling-Winthrop, and Roche, for attendance at meetings where vasospasm was discussed. The Neurosurgery Department at Westmead Hospital has benefited by its participation in several related clinical trials. Current Opinion in Critical Care 2002, 8: Abbreviations CGRP calcitonin gene-related peptide DID delayed ischemic deficit HHH hypervolemia, hypertension, and hemodilution SAH subarachnoid hemorrhage TCD transcranial Doppler ISSN Lippincott Williams & Wilkins, Inc. Delayed cerebral ischemia as a result of arterial spasm is the most common cause of death and disability due to aneurysmal subarachnoid hemorrhage (SAH) after recurrent hemorrhage. The reported incidence of this complication varies widely, but angiographic vasospasm is seen in over 67% of untreated patients with angiography at the time of maximum spasm around the end of the first week [1]. Symptomatic vasospasm, or delayed ischemic deficit (DID), affects nearly one third. Without specific treatment, the outcome of DID is devastating it results in death in 30% and permanent disability in 34% of patients (Table 1). Until recently, despite many reports that aroused initial optimism but the results of which could not be duplicated, there was no effective treatment. In the 1980s, two large reviews by Wilkins [2,3] discussed well over 100 different drugs and other treatments a sure sign that none were effective. This was not quite the case by the time of the second article, because the use of variations of hypervolemia, hypertension, and hemodilution (HHH) therapy was well under way by then. Prediction of vasospasm No treatment for vasospasm is entirely safe or without side effects, and it would be useful if an accurate predictor of which patients are most at risk were available. Although cerebral angiography is accepted as the most accurate diagnostic standard, it is an invasive procedure with occasional complications, and also can miss vasospasm altogether if the spasm is restricted to small vessels that are not seen angiographically. In some centers, postoperative angiography after early aneurysm clipping is scheduled for 5 to 7 days after SAH when vasospasm is most likely [4]. It is well known that vasospasm is more likely in patients classified in a poor clinical grade (in whom it is, incidentally, more difficult to detect subtle early deterioration) or with a thicker subarachnoid clot. In addition, a sudden increase in flow velocity or a high velocity measured by transcranial Doppler (TCD) sonography may warn of spasm development. TCD itself is not entirely accurate; the technique is quite operator dependent, and increased velocity due to hyperemia can be misleading [5]. 128 Attempts have been made from time to time to improve prediction, largely without success. In a recent example, 283 control subjects from a drug trial were analyzed [6].

2 Therapeutic approaches to vasospasm Dorsch 129 Table 1. Summary of the natural history of vasospasm; hypervolemia, hypertension, and hemodilution therapy; and nimodipine and nicardipine Incidence of DID No. patients % DID Natural history 32, HHH prophylaxis Nimodipine prophylaxis Oral Intravenous Nicardipine prophylaxis Outcome of DID No. patients % Dead % Permanent deficit % Recovery Natural history HHH treatment Nimodipine treatment Continued from prophylaxis De novo for DID Nicardipine treatment DID, delayed ischemic deficits; HHH, hypervolemia, hypertension, and hemodilution. Data from [1,15]. An index based on four significant variables thickness of subarachnoid clot, early increase in TCD velocity, initial Glasgow Coma Scale score under 14, and carotid or anterior cerebral artery aneurysms was still only 68% sensitive in identifying those who would develop DID, limiting the utility of this index. Other studies have used TCD assessment of impaired autoregulation [7,8], cerebral microdialysis [9,10], and measurement of tissue oxygen and other parameters [11,12] with some success to improve the accuracy of prediction of vasospasm or of ischemia. Hypervolemia, hypertension, and hemodilution therapy The first report on the use of induced systemic hypertension was published in 1976 [13]. This was strictly for the treatment of established DID and was followed by other open studies with similar, apparently successful results. Later, HHH (triple-h) treatment became widespread. It was not until several years later that the vital importance of at least maintaining a normal fluid intake was realized. Following evidence that patients with SAH had reduced blood volume, plasma volume, erythrocyte mass, and many other metabolic and electrolyte disturbances [14], HHH or its variations began to be used also for the prophylaxis or prevention of vasospasm. In a review of the management of vasospasm, the incidence of DID with HHH prophylaxis was reduced by almost half compared with the natural history (Table 1) [15], but further comparison is not statistically valid. Similarly, in reports of HHH therapy for the treatment of established DID, outcome was apparently better than would be expected in untreated cases and, in particular, was characterized by a lower death rate (Table 1). The usefulness of HHH treatment is generally accepted, but it has never been unequivocally demonstrated by a randomized controlled trial to be superior to simple moderate fluid loading. An early controlled study showed less DID and a better outcome with volume expansion, but control patients received daily diuretics as part of their hypertension treatment and were probably kept relatively dehydrated [16]. In a more recent trial with 82 patients, no effect of hypervolemia on either cerebral blood flow or DID incidence was found; daily fluid intake averaged 530 ml more in the hypervolemia group, but patients in both groups received over 3000 ml per day for much of the study period [17]. Another controlled trial with 1-year outcome as a primary endpoint showed no difference in TCD-determined or clinical vasospasm or in outcome and noted higher costs and more complications in the hyperdynamic group; again, although that group received considerably more fluids over the 12-day study period, the control group still averaged 3000 ml or more daily [18 ]. It seems likely, then, that in recent studies control patients have, in fact, been receiving at least hypervolemia, certainly in comparison with the situation with SAH 25 years ago, when most patients were kept quite dehydrated, and delayed ischemia was much more common. In my view, adequate fluid loading is the most important aspect of early treatment and vasospasm prophylaxis. It is reasonable to reserve the more vigorous loading and induced hypertension for when DID occurs. It is common with hypervolemic treatment to find it difficult to maintain the desired blood pressure, venous pressure, pulmonary capillary pressure, or whatever one is monitoring. This is particularly the case in young, fit people with normal renal function, and large volumes of

3 130 Neuroscience fluid can lead to electrolyte disturbance (particularly hyponatremia), pulmonary edema, and other complications. Suggested measures to counteract this include fludrocortisone [19] or albumin solution [20] to minimize sodium and fluid loss. Calcium antagonists Calcium antagonists have been in use since the mid- 1980s, and, by far, the most experience has been with the dihydropyridine analogue nimodipine, which was tested in several controlled trials. These studies were reviewed by Barker and Ogilvie [21] in a well-organized metaanalysis, which showed notable improvements in good and good-plus-fair outcomes and reductions in death due to vasospasm and computed tomography detected infarcts with nimodipine. Although it has never been tested formally, in a review of several thousand reported cases, the overall incidence of DID (15.9%) was somewhat lower when intravenous rather than oral nimodipine was used. When used de novo for the treatment of established DID, outcome was better than the expected natural history 13% of patients died and 20% experienced permanent deficits (Table 1). Controlled trials have also been performed on nicardipine. Although the largest trial showed a considerably lower rate of DID, the overall outcome was not improved [22]. It was noteworthy that therapeutic or rescue HHH was used much more often in the control group, which may explain the lack of difference in outcome. This problem did not occur in the trials of nimodipine, which were performed earlier when HHH treatment was not so widely used. Other calcium antagonists have also been used from time to time. An interesting recent series showed a 20% incidence of DID when oral diltiazem was used and favorable outcome in 75% of 123 consecutive cases [23 ]. Also noteworthy in this series was the limited use of intensive care monitoring and aggressive HHH treatment. Angioplasty First described for vasospasm in 1984, transluminal angioplasty was initially performed with the use of specially designed balloons that could be passed into a spastic vessel and then inflated [24]. This technique requires special equipment and a highly skilled and experienced interventional neuroradiology team. An alternative is chemical angioplasty, in which the angiography catheter is used to instill a vasodilator, usually papaverine. Each technique has its proponents and advantages and disadvantages. In general, angioplasty is recommended for angiographic vasospasm or at an early stage in DID (ie, if there has been no improvement after a trial of vigorous HHH). It is possibly more effective if used within 2 hours of DID onset [25]. Balloon angioplasty is generally more effective at reversing spasm, and the dilatation is also much more prolonged. However, it can only be used for fairly proximal arteries, and there is a risk of rupturing an artery (this can be reduced if the patient is kept intubated and paralyzed to prevent movement [26]) or an unclipped aneurysm. Chemical angioplasty often has to be repeated within hours or days [4] and carries complications including pupil changes, seizures, and respiratory arrest with vertebral artery injection. In many centers, both forms are used, often in combination, depending on the size of vessel affected. In a recent review of 41 publications on angioplasty (unpublished data), immediate clinical improvement was seen in 55% of nearly 400 reported patients who underwent balloon angioplasty (occasionally combined with chemical angioplasty) as compared with 40% of those undergoing drug angioplasty. An interesting trial of prophylactic balloon angioplasty is under way: patients with thick layers of subarachnoid clot undergo early aneurysm surgery, which is followed immediately by another angiogram and angioplasty on all the major arteries regardless of their state at the time. This is based on evidence of the involvement of endothelium in the development of vasospasm and the endothelial disruption caused by angioplasty. So far, in 18 patients there has been no symptomatic vasospasm, but there were three deaths one resulted from arterial rupture during angioplasty. In a nonrandomized control group of nine cases, there were four deaths [26]. Cisternal therapy There has been great interest over the last decade in the cisternal injection or infusion of fibrinolytic agents, which are most commonly recombinant tissue plasminogen activator or urokinase. In an early multicenter trial of tissue plasminogen activator in 100 patients, there were trends toward reduced angiographic spasm (significant in those with thick subarachnoid clot), a lower incidence of DID, and improved outcome in the treated group, with no increase in bleeding complications [27]. Studies of these treatments were discussed at length at a recent conference (Seventh International Conference on Cerebral Vasospasm, Interlaken, Switzerland, 2000), by V. Seifert and others; it was concluded that more study is needed regarding the best agent, dosage and timing of treatment, complications, efficacy, and the situation after coiling versus clipping of aneurysms. One recent report concerned patients with coiled aneurysms, with urokinase infused via a cisternal catheter after coiling treatment for several doses until CT scanning showed clearance of blood [28]. One of 15 patients developed a transient DID, and all made a good recovery. None of 16 aneurysms bled again, and no patient developed significant hydrocephalus.

4 Therapeutic approaches to vasospasm Dorsch 131 A much larger group was treated with cisternal irrigation with urokinase and ascorbic acid (to accelerate the breakdown of oxyhemoglobin); this was administered to patients with thick subarachnoid clot after early operation via bilateral cisternal catheters (with a third catheter for drainage) for up to 10 days [29]. This obviously requires intensive medical and nursing management because of the associated risks of raised intracranial pressure, infection, and hemorrhage. Of the 217 patients treated, six developed DID, which was reversible in four. Complications included meningitis in two and bleeding in four, with no permanent sequelae. Outcome was excellent or good in 175, and only six (3%) patients died. Interestingly, 39% needed shunts for hydrocephalus. Other treatments Space does not allow for adequate discussion of many other treatments (eg, the phosphodiesterase inhibitor milrinone [30], the platelet-activating factor receptor antagonist E5880 [31], or the protein kinase inhibitor fasudil hydrochloride [32]) that are under continuing investigation. Of considerable initial interest was the modified steroid free radical scavenger tirilazad mesylate, which was used in four large, controlled trials in the 1990s [33]. In the first, it appeared likely to be effective in reducing spasm, but later metaanalysis showed only a trend, whereas outcome was improved only in patients categorized in clinical grades IV and V [34]. The future Dietrich and Dacey [35 ] recently published a very interesting and comprehensive review of the vast amount of research into the molecular biology of cerebral vascular regulation, microcirculatory regulation in relation to ischemia, intracellular mechanisms in blood vessels, the pathways of regulation of vascular smooth muscle tone, stretch-induced smooth muscle contraction, and receptor activation. The metabolic pathways of nitric oxide and other endothelium-derived relaxing factors, and of endothelin and other endothelium-derived constricting factors, and the effect of blood and cerebrospinal fluid components on these pathways are discussed, together with gene activation, potential gene therapies, and so forth. Several potential future therapies and modifications for the prevention and treatment of vasospasm are described below, in a list that is not at all exhaustive. Experimental therapies (1) The capsaicin-derived glyceryl nonivamide has a vasodilating effect via the release of calcitonin generelated peptide (CGRP). In a rabbit study, cisternal instillation after SAH reduced or prevented basilar artery narrowing in a dose-dependent manner [36]. (2) In another study concerning CGRP, pretreatment of rabbits by CGRP gene transfer by adenovirus transfection reduced post SAH basilar artery constriction [37 ]. A more rapid effect was seen when a cytomegalovirus promoter was used, which allowed treatment after SAH. (3) Another gene transfer study looked at induction of heme oxygenase-1 by adenovirus-mediated gene transfection via cisternal injection in rats and found that vasoconstriction after hemoglobin injection was less, and blood flow was higher, than in control subjects [38]. Other studies have used a nitric oxide synthase gene. (4) Controlled-release polymer containing a nitric oxide donor placed in the periadventitial space has been studied; in a rat model of femoral artery spasm caused by autologous blood, vasospasm was significantly reduced [39]. Other researchers have used a collagen-based delivery system containing a thrombin inhibitor. Another novel delivery system involved cutaneous tape containing nitroglycerine as a nitric oxide donor. (5) Following preliminary studies with prolongedrelease implants containing papaverine, further trials with cisternal implants containing nicardipine successfully prevented vasospasm induced by autologous blood clot in dogs [40]. Clinical therapies (1) In early reports, the use of intrathecal sodium nitroprusside as a nitric oxide donor had impressive results, with little or no hypotension (as occurs with systemic administration) [41,42]. Of 10 patients with thick subarachnoid clots who received prophylactic intraventricular sodium nitroprusside, none developed vasospasm. In other patients with severe DID and failed HHH therapy, sodium nitroprusside, sometimes combined with balloon angioplasty, showed reversal of angiographic spasm and symptomatic improvement. (2) With cisternal placement of controlled-release pellets containing papaverine, treated patients had significantly less vasospasm and better outcomes than nonrandomized control subjects [43]. (3) An interesting case report described two patients in whom symptoms persisted despite HHH therapy and angioplasty, and cardiac ischemia was limiting the possible intensity of HHH [44]. Aortic balloon counterpulsation was started, with improvement in cardiac function and in the neurologic state. Eventual recovery was better than expected. (4) Based on experimental data showing relief of vasospasm and neuroprotection, two small series were reported in which, in addition to the usual treatment, intravenous magnesium sulfate was also given, a bolus followed by continuous infusion to

5 132 Neuroscience raise serum magnesium to twice baseline (or to 2.0 to 2.4 mmol/l) in one paper [45], and infusion to maintain plasma levels of 1.0 to 1.5 mmol/l in the other [46]. Five of 10 patients in the first study developed spasm on TCD and three had symptomatic spasm, but, eventually, eight made a good recovery. In the study conducted by Chia et al. [46], the infusion was started as early as possible; the 13 treated patients had less angiographic vasospasm than 10 historical controls. Importantly, there were no adverse effects from magnesium in either study. Randomized trials were recommended. Cervical spinal cord electrical stimulation [47] and mild hypothermia [48] have also been recommended after SAH for prophylaxis and treatment, respectively. Conclusions Although major advances have been made in the management of what is now probably the most significant complication of cerebral aneurysm rupture, the problem is by no means solved. Much research is continuing to be devoted to elucidating the complex pathophysiology of vasospasm itself and of the consequent, but less common ischemia. Because vasospasm is such a multifactorial problem, it is likely that prevention and treatment will continue to require application along several different lines, as is done at present with clearance of blood, hypervolemia, calcium antagonists, and, if necessary, intensive HHH and balloon or chemical angioplasty. Another recent review by Treggiari-Venzi, Suter, and Romand [49 ] is well worth reading. It includes a wideranging discussion of the diagnosis of vasospasm and the problems with various diagnostic modalities including TCD, as well as the common difficulty with distal artery spasm. The early trials of HHH are reviewed, and the continuing lack of definite evidence from large trials, along with the lack of standardization of blood pressure or wedge pressure goals, and complications of HHH are discussed. The different calcium antagonists are also discussed, along with fibrinolysis, antioxidants, immunosuppression, and other experimental and clinical treatments not mentioned here. The current, generally accepted recommendations for prevention and treatment of delayed vasospasm include careful fluid management and maintenance of hypervolemia, use of a calcium antagonist, and, in some centers, cisternal therapy. For more difficult situations, full HHH treatment and angioplasty are standard. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: Of special interest Of outstanding interest 1 Dorsch NWC, King MT: A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage. I: Incidence and effects. J Clin Neurosci 1994, 1: Wilkins RH: Attempted prevention or treatment of intracranial arterial spasm: a survey. Neurosurgery 1980, 6: Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 1986, 18: Morgan MK, Jonker B, Finfer S, et al.: Aggressive management of aneurysmal subarachnoid haemorrhage based on a papaverine angioplasty protocol. J Clin Neurosci 2000, 7: Clyde BL, Resnick DK, Yonas H, et al.: The relationship of blood velocity as measured by transcranial Doppler ultrasonography to cerebral blood flow as determined by stable xenon computed tomographic studies after aneurysmal subarachnoid hemorrhage. Neurosurgery 1996, 38: Qureshi AI, Sung GY, Razumovsky AY, et al.: Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med 2000, 28: Lam JMK, Smielewski P, Csosnyka M, et al.: Predicting delayed ischemic deficits after aneurysmal subarachnoid hemorrhage using a transient hyperemic response test of cerebral autoregulation. Neurosurgery 2000, 47: Rätsep T, Asser T: Cerebral hemodynamic impairment after aneurysmal subarachnoid hemorrhage as evaluated using transcranial Doppler ultrasonography: relationship to delayed cerebral ischemia and clinical outcome. J Neurosurg 2001, 95: Schulz MK, Wang LP, Tange M, et al.: Cerebral microdialysis monitoring: determination of normal and ischemic cerebral metabolisms in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2000, 93: Unterberg AW, Sakowitz OW, Sarrafzadeh AS, et al.: Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 2001, 94: Khaldi, A, Zauner A, Reinert M, et al.: Measurement of nitric oxide and brain tissue oxygen tension in patients after severe subarachnoid hemorrhage. Neurosurgery 2001, 49: Charbel FT, Du X, Hoffman WE, et al.: Brain tissue PO 2, PCO 2, and ph during cerebral vasospasm. Surg Neurol 2000, 54: Kosnick EJ, Hunt WE: Postoperative hypertension in the management of patients with intracranial arterial aneurysms. J Neurosurg 1976, 45: Maroon JC, Nelson PB: Hypovolemia in patients with subarachnoid hemorrhage: therapeutic implications. Neurosurgery 1979, 4: Dorsch NWC: A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage. II: Management. J Clin Neurosci 1994, 1: Rosenwasser RH, Delgado TE, Buchheit WA, et al.: Control of hypertension and prophylaxis against vasospasm in cases of subarachnoid hemorrhage: a preliminary report. Neurosurgery 1983, 12: Lennihan L, Mayer SA, Fink ME, et al.: Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke 2000, 31: Egge A, Waterloo K, Sjøholm H, et al.: Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 2001, 49: A complex, but well-designed, randomized, controlled trial in which those involved were blinded as much as possible. Patient numbers were small, with a possible type II error. Complications were significantly higher in the hyperdynamic group even after correction for multiple testing. Several interesting and pertinent comments are provided (pp ), and it is pointed out that these results must not be extrapolated to the use of therapeutic HHH for established DID. 19 Mori T, Katayama Y, Kawamata T, et al.: Improved efficiency of hypervolemic therapy with inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 1999, 91: Mayer SA, Solomon RA, Fink ME, et al.: Effect of 5% albumin solution on sodium balance and blood volume after subarachnoid hemorrhage. Neurosurgery 1998, 42: Barker FG II, Ogilvie CS: Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis. J Neurosurg 1996, 84: Haley EC Jr, Kassell NF, Torner JC, et al.: A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage: a report of the Cooperative Aneurysm Study. J Neurosurg 1993, 78:

6 Therapeutic approaches to vasospasm Dorsch Papavasiliou AK, Harbaugh KS, Birkmeyer NJ, et al.: Clinical outcomes of aneurysmal subarachnoid hemorrhage patients treated with oral diltiazem and limited intensive care management. Surg Neurol 2001, 55: A large, consecutive series of patients with aneurysms mostly treated outside the intensive care situation and without invasive monitoring, but who received fluids and oral diltiazem, and therapeutic HHH if DID developed. This occurred in only 24 of 123 patients, with poor outcome due to DID in 5.7%. Overall, 75% of patients had a good outcome or moderate disability on the Glasgow Outcome Scale. This study shows that good results can be obtained in a standard neurosurgical ward setting with ICU backup when needed. 24 Zubkov YN, Nikiforov BM, Shustin VA: Balloon catheter technique for dilatation of constricted cerebral arteries after aneurysmal SAH. Acta Neurochir 1984, 70: Rosenwasser RH, Armonda RA, Thomas JE, et al.: Therapeutic modalities for the management of cerebral vasospasm: timing of endovascular options. Neurosurgery 1999, 44: Muizelaar JP, Madden LK: Balloon prophylaxis of aneurysmal vasospasm. Acta Neurochir Suppl 2001, 77: Findlay JM, Kassell NF, Weir BKA, et al.: A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 1995, 37: Hamada J, Mizuno T, Kai Y, et al.: Microcatheter intrathecal urokinase infusion into cisterna magna for prevention of cerebral vasospasm: preliminary report. Stroke 2000, 31: Kodama N, Sasaki T, Kawakami M, et al.: Cisternal irrigation therapy with urokinase and ascorbic acid for prevention of vasospasm after aneurysmal subarachnoid hemorrhage: outcome in 217 patients. Surg Neurol 2000, 53: Arakawa Y, Kikuta K, Hojo M, et al.: Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: report of seven cases. Neurosurgery 2001, 48: Hirashima Y, Endo S, Nukui H, et al.: Effect of a platelet-activating factor receptor antagonist, E5880, on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: open clinical trial to investigate efficacy and safety. Neurol Med Chir 2001, 41: Shibuya M, Asano T, Sasaki Y: Effect of fasudil HCl, a protein kinase inhibitor, on cerebral vasospasm. Acta Neurochir Suppl 2001, 77: Kassell NF, Haley EC Jr, Apperson-Hansen C, et al.: Randomized, doubleblind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996, 84: Dorsch NWC, Kassell NF, Sinkula MS, et al.: Metaanalysis of trials of tirilazad mesylate in aneurysmal SAH. Acta Neurochir Suppl 2001, 77: Dietrich HH, Dacey RG Jr: Molecular keys to the problem of cerebral vasospasm. Neurosurgery 2000, 46: A good analysis of the complex molecular biology of the changes leading to vasospasm. 36 Lin C-L, Lo Y-C, Chang C-Z, et al.: Prevention of cerebral vasospasm by a capsaicin derivative, glyceryl nonivamide, in an experimental model of subarachnoid hemorrhage. Surg Neurol 2001, 55: Toyoda K, Faraci FM, Watanabe Y, et al.: Gene transfer of calcitonin generelated peptide prevents vasoconstriction after subarachnoid hemorrhage. Circ Res 2000, 87: An interesting experimental study on a possible line of treatment that appears to be full of potential. For editorial comment see pp Ono S, Komuro T, Macdonald RL: Adenovirus-mediated heme oxygenase-1 gene transfection prevents hemoglobin-induced contraction of rat basilar artery. Acta Neurochir Suppl 2001, 77: Tierney TS, Clatterback RE, Lawson C, et al.: Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer. Neurosurgery 2001, 49: Kawashima A, Kasuya H, Sasahara A, et al.: Prevention of cerebral vasospasm by nicardipine prolonged-release implants in dogs. Neurol Res 2000, 22: Thomas JE, Rosenwasser RH: Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intraventricular sodium nitroprusside in humans. Neurosurgery 1999, 44: Thomas JE, Rosenwasser RH, Armonda RA, et al.: Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke 1999, 30: Dalbasti T, Karabiyikoglu M, Ozdamar N, et al.: Efficacy of controlled-release papaverine pellets in preventing symptomatic cerebral vasospasm. J Neurosurg 2001, 95: Rosen CL, Sekhar LN, Duong DH: Use of intra-aortic balloon pump counterpulsation for refractory symptomatic vasospasm. Acta Neurochir 2000, 142: Boet R, Mee E: Magnesium sulfate in the management of patients with Fisher grade 3 subarachnoid hemorrhage: a pilot study. Neurosurgery 2000, 47: Chia RY, Hughes RS, Morgan MK: Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. J Clin Neurosci 2002, 9, in press. 47 Takanashi Y, Shininaga M: Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurol Med Chir 2000, 40: Nagao S, Irie K, Kawai N, et al.: Protective effect of mild hypothermia on symptomatic vasospasm: a preliminary report. Acta Neurochir Suppl 2000, 76: Treggiari-Venzi MM, Suter PM, Romand J-A: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care. Neurosurgery 2001, 48: A comprehensive review of the pathogenesis, diagnosis, and management of vasospasm. The authors point out the problems of extrapolating experimental results to the clinical situation. The rationale of the present mainstays of treatment and possible future developments are discussed. Comments are provided (pp ).