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Chapter 4 Aneurysmal Subarachnoid Hemorrhage Trials
4 Aneurysmal Subarachnoid Hemorrhage Trials Luca Regli and Bernhard Walder
Subarachnoid hemorrhage (SAH) continues to be a common cause of worldwide morbidity and mortality among young adults of both genders. Intracranial aneurysm rupture is the most common identifiable cause of nontraumatic SAH. Although the case-fatality rates from SAH have progressively declined,1 the incidence of SAH, unlike other types of stroke, has not declined over time.2 The outcome of patients remains poor, despite rapidly evolving research regarding diagnosis, causes, and treatment of SAH. The overall mortality rate is estimated to be 25%. Approximately 50% of patients who survive the aneurysmal rupture will have significant morbidity,3 for approximately 30% of which secondary ischemia is responsible.4,5 Cerebral vasospasm after aneurysmal SAH is a major cause of disability and death. Therefore, because little can be done to ameliorate the immediate deleterious effect of aneurysm rupture, rebleeding and vasospasm are the major problems for which clinical trials have been designed. Large, multicenter prospective cohort analyses and multicenter prospective randomized trials have influenced considerably the treatment protocols for SAH patients. Nevertheless, many currently accepted treatment options are not supported by rigorous clinical scientific evidence. Some specific treatments for SAH are not amenable to testing by randomized, prospective trials because of practical or ethical considerations. In 1994, the Stroke Council of the American Heart Association published practice guidelines for the management of aneurysmal SAH to precisely address these issues.6 The reading of these guidelines is strongly recommended, as it is not the purpose of this chapter to repeat them. They can also be found on the website of the American Heart Association (www.americanheart.org). Despite these guidelines, controversies around treatment protocols for patients with SAH are ongoing. The beneficial role of calcium antagonists, the role of prophylactic treatment with hypervolemia, and the role of transluminal balloon angioplasty are just some of the controversial issues. Recent multicenter prospective randomized trials have addressed the efficacy of antioxidant and
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64 Clinical Trials in Neurologic Practice anti-inflammatory agents, mainly tirilazad mesylate. The technical development and advancement of interventional endovascular surgery has opened new avenues in aneurysm and cerebral vasospasm treatment. An international multicenter prospective randomized trial comparing treatment of ruptured aneurysm with surgical clipping versus endovascular coiling began in 1999 and is ongoing.
PREVENTION OF REBLEEDING Treatment of Ruptured Aneurysms The most extensive data on the results of modern management of ruptured aneurysms have been provided by the International Cooperative Study on Timing of Aneurysm Surgery, in which more than 3,000 patients were entered in a prospective observational study from 1980 to 1983.4,7 Surgical repair is today the firstline treatment option for ruptured aneurysms. Endovascular techniques for the treatment of intracranial aneurysms have been evolving since 1973. 8 The Guglielmi detachable coil device has been in use in North America since 1991 and in Europe since 1992.9 Significant improvement in coiling has an increased occlusion rate and a reduced complication rate. This has fueled the belief that aneurysm coiling could become the first-line treatment. The International Subarachnoid Aneurysm Trial (ISAT) compared surgery and endovascular coil treatment of ruptured aneurysms and is the largest ever randomized clinical trial in SAH management.10 The study had randomized more than 1,300 patients by mid-2000 and has planned to recruit more than 2,500 patients. The results of the ISAT study will answer two main questions. First, is aneurysm coiling as effective as clipping to protect against rebleeding? Second, is patient outcome improved with endovascular treatment? The results of this large, multicenter prospective randomized trial will have an impact on the management strategies in patients with aneurysmal subarachnoid hemorrhage.
Antifibrinolytics Early clipping or coiling of the ruptured aneurysm is the most efficacious prevention of rebleeding and is becoming increasingly common in neurosurgical centers. In patients with delayed surgery the use of antifibrinolytic treatment has been recommended.11 Systematic reviews have shown that antifibrinolytics reduce the rebleeding rate by approximately 45% but do not affect overall outcome because of an increase in the rate of delayed cerebral ischemia due to cerebral vasospasm.6 The trials on antifibrinolytic therapy date from over 10 years, when triple-H therapy (hypervolemia, hypertension, hemodilution) and nimodipine were not used routinely to decrease the incidence of symptomatic vasospasm. Members of the STAR study group recently conducted a prospective double-blind, placebo-controlled multicenter clinical trial12 to investigate whether antifibrinolytics, in combination with treatment to prevent cerebral ischemia, improve outcome in patients with subarachnoid hemorrhage and delayed (longer than 48 hours) occlusion of the aneurysm. The overall results of
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this study show no beneficial effect on outcome despite reduction in rebleeding rate. Actually, in patients with impaired level of consciousness on admission (World Federation of Neurological Surgeons [WFNS] grade IV or V), antifibrinolytics adversely affected outcome. In patients with normal level of consciousness (WFNS grade I–III) there was a clear trend toward beneficial effect of this treatment. However, patients with normal levels of consciousness are ideal candidates for early surgery or coiling to prevent rebleeding. Antifibrinolytic treatment needs no consideration for SAH patients, even if combined with treatment to prevent cerebral ischemia.
PREVENTION AND TREATMENT OF SYMPTOMATIC VASOSPASM Calcium Antagonists in Aneurysmal Subarachnoid Hemorrhage Several controlled randomized clinical trials have studied calcium antagonists, mainly nimodipine, in patients with aneurysmal SAH and were published between 1983 and 1993.13–23 In two trials not using nimodipine, one used AT877,23 and the other nicardipine.19 According to the AHA guidelines, these trials can be summarized as follows: (1) Oral nimodipine consistently reduced poor outcome due to vasospasm in all grades of patients; (2) the incidence of symptomatic vasospasm was not affected by nimodipine; (3) angiographic vasospasm was not affected by nimodipine; and (4) complications and side effects of the drug were minimal. Despite these recommendations supported by level I and II evidence from the individual trials, some recent reports have called the use of calcium antagonists into question,24 and controversy about their beneficial effect exists. To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH and whether these drugs reduce the frequency of secondary cerebral ischemia, structured reviews have been published in which the authors performed a meta-analysis of all the controlled clinical trials.25–27 In their meta-analysis including seven trials and 1,202 patients, Barker and Ogilvy28 demonstrated that prophylactic nimodipine is effective in increasing the odds of good outcome after aneurysmal SAH. Efficacy was both statistically significant ( p = .004) and clinically significant in magnitude, with one additional good outcome expected for every seventh patient treated. The meta-analysis also showed that nimodipine significantly increased the odds of good or fair outcome and reduced the odds of radiographically detectable infarction and permanent deficit and death from secondary ischemia. A slight decrease in overall mortality or rebleeding-related death or deficit with nimodipine was demonstrated but was not statistically significant. Due to limitation of the data in the original trials, they declined to perform a meta-analysis of the potential effect of nimodipine on arteriographic vasospasm. They failed to show significant differences in other subgroup analyses comparing oral versus intravenous administration, and low dose versus high dose. They also analyzed the potential sources of bias in such observational studies.28 The meta-analysis was not weakened by publication bias or the undue influence of any single trial. As the trials included in the metaanalysis did not specify the use of prophylactic hypervolemic-hypertensive ther-
66 Clinical Trials in Neurologic Practice apy, the efficacy of nimodipine in such a setting cannot be analyzed. Barker and Ogilvy28 concluded that the efficacy of prophylactic nimodipine in improving outcome after SAH is demonstrated by meta-analysis and that isolated retrospective trials24 that fail to show efficacy under specific conditions should not weigh heavily in decisions regarding its use. Similarly, Feigin et al.27 demonstrate in their meta-analysis, including 10 controlled trials with 2,756 patients, significant reduction of poor outcome after SAH with nimodipine treatment (27% relative risk reduction; 95% confidence interval, 13–39%), as well as secondary ischemia (33% relative risk reduction; 95% confidence interval, 25–41%). Again, there was no significant difference between route or dosage of nimodipine administration. The clinical trials and their meta-analysis demonstrate that nimodipine improves overall outcome after aneurysmal SAH. Oral administration of nimodipine 60 mg every 4 hours can be advocated.
Triple-H Therapy (Hypervolemia, Hypertension, Hemodilution) A popular concept of cerebral vasospasm prevention, as well as of cerebral vasospasm treatment in patients experiencing SAH, is the induction of a hypervolemic, hemodiluted, and hypertensive/hyperdynamic state (triple-H therapy). Triple-H therapy can be used in prevention of cerebral vasospasm or as a treatment of symptomatic vasospasm and is based on the hypothesis that an increase in arterial pressure and cardiac output and a decrease of blood viscosity optimize cerebral blood flow, thereby decreasing the incidence of symptomatic vasospasm. However, it is not clear in the literature which component of triple-H therapy impacts prevention or treatment of cerebral vasospasm. Similarly, it is not well established how to define an induced hypertensive, hypervolemic, and hemodiluted state.
Triple-H Therapy as Prevention Clinically relevant reduction of cerebral vasospasm was reported in observational studies using preventive triple-H therapy compared with observational studies not using preventive therapy.29 Only small randomized, controlled studies were conducted of triple-H therapy as a preventive treatment analyzing clinically relevant end points, such as symptomatic cerebral vasospasm, neurologic disability, and mortality.30–32 Rosenwasser et al.31 compared preoperative hypervolemia (n = 15) (administering blood [aim: hematocrit 45%], albumin, and crystalloid) with preoperative normovolemia (n = 15) in patients scheduled for late surgical aneurysm treatment. Their results showed that the incidence of symptomatic cerebral vasospasm was significantly decreased in the group treated with preventive hypervolemia. Mayer et al.32 compared the outcome of 19 hypervolemic patients with 19 normovolemic patients using central venous pressure measurements to evaluate the state of intravascular volemia. Hypervolemia was defined as a central venous pressure greater than 8 mm Hg, and normovolemia was defined as a central venous pressure greater than 5 mm Hg. Patients in both groups received 0.9% saline solution
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1,920 ml per day, as a baseline; hypervolemia was achieved by additional 5% albumin administration to increase central venous pressure as needed. Five of 19 patients in the hypervolemic group and seven of 24 patients in the normovolemic group developed symptomatic cerebral vasospasm with delayed cerebral ischemia (29% versus 26%; no significant difference). Pulmonary edema requiring treatment was observed in one patient in the hypervolemic group. The same research group published a more recent trial, using the same methodological design, randomizing 41 patients into the hypervolemic and 41 patients into the normovolemic groups.30 The incidence of symptomatic vasospasm was 20% in both groups, and no side effects were reported from induction of hypervolemia. Solenski et al.33 reported, however, in a large prospective observational study, that 104 of 457 (23%) treated with triple-H therapy experienced pulmonary edema. A confounding factor in the judgment of the potential complications induced by triple-H therapy may be the frequent presence of neurogenic pulmonary edema associated with SAH. In fact, Solenski et al.33 observed an increased incidence of pulmonary edema among patients presenting in high clinical grades (WFNS IV and V), which may support the hypothesis that other factors besides induction of hypervolemia could play a role in the development of pulmonary edema. The lack of randomized controlled trials enrolling a significant number of patients (as estimated by power analysis) implies that the efficacy and safety of triple-H therapy are not well established. Guidelines, recommendations, and clinical implementation of triple-H therapy as a preventive treatment of cerebral vasospasm can therefore not be based on evidence.
Triple-H Therapy as Treatment Triple-H therapy as a treatment of symptomatic cerebral vasospasm consists of a more aggressive implementation of triple-H therapy in patients with established symptomatic cerebral vasospasm. A step-by-step concept of triple-H therapy (progressive from prevention to treatment) was proposed by Levy et al.34: First, in all patients with SAH, a hypervolemic state is induced. Second, in patients manifesting neurologic compromise, additional infusions of colloids are started to achieve a pulmonary artery wedge pressure of 14 mm Hg. Third, in patients without improvement of neurologic status over the next few hours, cardiac output (cardiac index greater than or equal to 3.5) and arterial pressure (20– 30%) are increased with intravenous infusion of dobutamine, a beta-1-adrenergic receptor agonist. In a prospective observational study applying this protocol, a reversal of the delayed ischemic symptoms was obtained in 18 of 23 patients (78%). Whereas Levy et al.34 support a hyperdynamic model to decrease delayed ischemic deficits (i.e., increase of cardiac output to increase cerebral blood flow), other authors support a hypertensive model (i.e., an increase of systemic arterial pressure). Miller et al.35 administered phenylephrine, a selective alpha1-adrenergic receptor agonist, to increase mean arterial pressure by 20–25% above the patient’s baseline and even up to 35% above the patient’s baseline, if the neurological deficit is not reversed. With such a regimen, these authors observed neurologic improvement in 21 out of 24 patients (88%). However, dobutamine and phenylephrine both increase cardiac oxygen consumption and may, therefore, induce cardiac ischemia or infarction, contributing to the increased
68 Clinical Trials in Neurologic Practice risk of lung edema.33 None of the catecholamines has proven advantageous over the others in vasospasm treatment. Safety of triple-H therapy as treatment in patients with symptomatic cerebral vasospasm after SAH is reported rarely in the literature and is never investigated systematically.36 As already mentioned under Triple-H Therapy as Prevention, there is a lack of randomized controlled trials analyzing efficacy and safety of triple-H therapy as treatment of delayed ischemia. Furthermore, there is a lack of consensus in defining the intermediate aims of triple H-treatment (blood pressure versus cardiac output), the type and amount of fluid to administer, and the type and dose of vasoactive drugs to use. Guidelines, recommendations, and clinical implementation of triple H-treatment cannot be based on evidence. Clinicians have to base their decisions on clinical experience and local protocols until randomized controlled trials with sufficient group sizes are available. Triple-H therapy can, however, be recommended for prevention and treatment of delayed ischemic deficits, based on the step-by-step concept of triple-H therapy as proposed by Levy et al.34 Patients receiving triple-H therapy must be monitored closely in an intensive care setting for hemodynamic function and electrolyte balance.
Tirilazad in Prevention of Vasospasm The use of tirilazad mesylate, a 21-aminosteroid free-radical scavenger, in animal models of subarachnoid hemorrhage and focal cerebral ischemia has shown a reduction of cerebral vasospasm and cerebral infarct.37,38 Several powerful randomized controlled clinical trials with a multicenter design, including more than 3,500 patients, were conducted to test efficacy and safety of this drug.39–42 The results of these large trials have been difficult to interpret, mainly because of differences in drug effectiveness within the studies. Despite a very similar trial design, tirilazad mesylate was more effective in the cooperative study in Europe, Australia, New Zealand, and South Africa39 than in North America.40 In the former study, tirilazad mesylate at a dose of 6 mg/kg per day improved overall outcome and reduced mortality at 3 months, particularly in men with admission grades IV and V. These results are at odds with the cooperative study conducted in North America that showed no statistical benefit on mortality rate, functional outcome, or ischemic symptoms. The reasons for the differing results are unclear but could include differences in epidemiologic characteristics or standard care of patients. In the North American trials, there were more patients with a history of arterial hypertension (40% and 44% versus 25% and 27%), with triple-H therapy as prevention (75% and 74% versus 45% and 60%), and with triple-H therapy as treatment (30% and 34% versus 18% and 24%). Similarly, nimodipine was more often administered per os in the North American trial compared to the European, Australian, New Zealand and South African trial. Differences were also observed in the results of the control groups. Mortality among men in North America, for example, was half that among men in the European, Australian, New Zealand, and South African trial. Alternatively, the authors suggested the possibility of lower blood levels of the study drug in the North American patients as compared to the other trial, due to broader use of antiepileptic medications as well as gender difference. For these reasons, two further studies were conducted to test the safety and efficacy of higher doses of tirilazad mesylate (15 mg/kg/
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day) in women experiencing aneurysmal subarachnoid hemorrhage.41,42 This second study conducted in Europe, Australia, New Zealand, and South Africa, showed a decreased rate of symptomatic cerebral vasospasm but did not result in better patient outcomes. In the North American trial, no beneficial effect was observed in the overall group. However, sequential analysis revealed a reduction in mortality rates among patients with neurologic grades IV and V at admission. The different responses of tirilazad in patients with various degrees of neurologic impairment could not be explained by the studies’ authors. In a recent meta-analysis of trials of tirilazad mesylate, NW Dorsch (invited lecture at the 7th International Conference on Cerebral Vasospasm, June 18–21, 2000) confirmed that patients presenting in WFNS grade IV and V had a better outcome if high-dose tirilazad treatment (men 6 mg/kg/day and women 15 mg/kg/day) was started within 24 hours from subarachnoid hemorrhage. A constant result among these trials was the safety of tirilazad mesylate administration. No major side effects were observed. Despite experimental evidence favoring a beneficial effect of tirilazad and the discrepancies of the results of the clinical trials, and in the absence of an overall benefit in patient outcome, tirilazad mesylate cannot be recommended for routine clinical use in patients with aneurysmal SAH.
Transluminal Balloon Angioplasty Development of endovascular techniques since 1984 has allowed transluminal balloon angioplasty43 to be performed in cerebral vessels affected by vasospasm with or without selective injection of papaverine into the involved territories.44,45 Despite small anecdotal series46–58 of angiographically confirmed reversal of cerebral vasospasm and high rates of clinical improvement, no controlled investigation of the efficacy of this procedure has been conducted. As opposed to intra-arterial administration of papaverine hydrochloride alone,44,45 balloon angioplasty demonstrates excellent angiographic results that are, in most cases, permanent. In most of the small series, clinical improvement has been observed in approximately 60% of patients treated with angioplasty.47,51,52,58 In a recent study, Polin et al.59 analyzed 38 patients enrolled in the North America trial of tirilazad42 who had angioplasty for cerebral vasospasm; the authors failed to demonstrate a benefit of angioplasty over medical treatment in patients presenting with symptomatic cerebral vasospasm. In summary, the ability of transluminal balloon angioplasty to reverse angiographic cerebral vasospasm is unquestioned. Its clinical role, however, is not proven. Future studies have to clearly define the indications for its use. First, the clinical efficacy and not only angiographic improvement must be confirmed. Second, the anatomic types of cerebral vasospasm (proximal versus distal) amenable to angioplasty must be studied. Third, the timing of the procedure with regard to symptom onset and computed tomography (CT) findings must be defined. Balloon angioplasty has gained an important role in the algorithm of vasospasm management and it can be recommended as an adjunct to triple-H therapy, but not as a replacement for careful medical management of subarachnoid hemorrhage patients in the intensive care unit. Intra-arterial papaverine injection without balloon angioplasty cannot be recommended.60
70 Clinical Trials in Neurologic Practice OTHER TREATMENTS FOR VASOSPASM One of the most important and critical aspects of SAH-induced cerebral vasospasm is its failure to consistently respond to treatment. A large number of pharmacologic interventions have been tried in experimental models and clinical trials with only partial success. The purpose here is not to review all of the experimental data. Some selected clinical data are presented in the next paragraph. The efficacy of these treatment forms has not been confirmed with large randomized controlled trials; therefore, none of the treatments described in this paragraph can be advocated in clinical practice.
Intracisternal Fibrinolytic Treatment Fibrinolytic substances, such as recombinant tissue plasminogen activator (rt-PA) or urokinase, can facilitate the normal clearing of blood from the subarachnoid space and, in this manner, may prevent delayed arterial spasm after SAH. Two forms of administration of rt-PA were developed and tested: (1) single intraoperative intracisternal bolus injection61 and (2) repetitive postoperative intracisternal bolus injection via a cisternal catheter.62–64 In a randomized controlled trial, 100 patients with ruptured intracranial saccular aneurysms causing severe SAH were treated with a single 10-ml intraoperative injection of vehicle buffer solution or rt-PA into the opened basal subarachnoid cisterns immediately after aneurysm clipping.61 The rates for no or mild, moderate, and severe angiographic vasospasm were 69%, 16%, and 15% respectively, in the rt-PA–treated group versus 42%, 35%, and 23%, respectively, in the placebo group. There was a trend toward lesser degrees of cerebral vasospasm in the rt-PA–treated group, but this was not statistically significant ( p = .07). Overall, bleeding complication rates did not differ between the two groups. The study concluded that efficacy in preventing clinical vasospasm and its ischemic complications was not demonstrated, despite a trend toward less severe cerebral vasospasm and improved outcome. In a prospective study examining 105 patients, postoperative rt-PA was used until all of the cerebral cisterns exhibited low-density on CT scan (mean, 4–7 days).62 Patients showing diffuse thick subarachnoid blood clots on CT with greater than 75 Hounsfield units were included in the rt-PA therapy group; those with less than 75 Hounsfield units comprised the control group. Follow-up angiography showed that 26 cases (87%) in the rt-PA group had no cerebral vasospasm, three (10%) had moderate vasospasm, and one (3%) had severe vasospasm. In contrast, there were 11 patients (15%) with delayed ischemic neurologic deficits in the control group. Three complications in the rt-PA group were reported: One case of SAH caused by catheter removal, one small epidural hematoma, and one subgaleal fluid accumulation. All of these complications were treated conservatively with favorable results. Usui and colleagues64 retrospectively compared three groups of patients. The first was comprised of patients who had simple, spontaneous cisternal drainage through a catheter left at surgery until CT scanning showed basal cisternal clot clearance (n = 29). The second group had continuous irrigation between two cisternal catheters using a urokinase solution, 120 IU/ml at 21 ml per hour, started
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after postoperative angiography confirmed complete aneurysm ablation and continued for 5–7 days (n = 60). The third group received six hourly, intermittent injections of rt-PA via a single cisternal catheter that, after clamping for several hours, was left open to drain. The patients were not randomly allocated to treatment groups, and by design, the first group had less severe SAHs. The authors concluded that postoperative fibrinolytic treatment reduced cerebral vasospasm and that rt-PA injections were easier to administer and more effective than urokinase irrigation. The most important trial with intrathecal urokinase investigated 217 consecutive patients classified as Fisher CT Group 3.65 After clipping the aneurysm, irrigation tubes were placed in the Sylvian fissure (inlet) unilaterally or bilaterally and in the prepontine or chiasmal cistern (outlet). Lactated Ringer’s solution with urokinase (120 IU/ml) and ascorbic acid (4 mg/ml) was infused at a rate of 30 ml/ hour/side for approximately 10 days. Symptomatic cerebral vasospasm was observed in six cases (2.8%), and two of these six cases (0.9%) demonstrated sequelae. Complications occurred in eight patients during irrigation therapy: Two patients experienced seizures, two patients developed meningitis, and four patients had an intracranial hemorrhage. All recovered without neurologic deficits. Confirmation or denial of significant clinical cerebral vasospasm prevention, with less ischemic infarction and improved overall outcome, requires a larger randomized trial, as does any meaningful comparison of fibrinolytic treatment methods. Fibrinolytic treatment appears to bear acceptable bleeding risk, providing surgery is uncomplicated and aneurysm clipping complete. However, the studies have confirmed the extreme danger of fibrinolytic treatment when the aneurysm is incompletely secured.
Intravenous Thromboxane Synthetase Inhibitor In a large, randomized, and double-blind trial at 48 neurosurgical services in Japan, the thromboxane synthetase inhibitor OKY-046 was investigated in two different doses and compared with placebo.66 In subjects with severe cerebral vasospasm, the incidence of delayed ischemic deficit was significantly lower, with better functional prognosis, in the low dosage (80 mg per day) of thromboxane synthetase inhibitor group than in the placebo group. Additionally, in subjects with severe grades on the Glasgow Coma Scale, Japan Coma Scale, or High Density Score, the functional prognosis at 1 month after aneurysmal rupture was significantly better although no significant differences were seen in the overall investigation. Combinations of thromboxane synthetase inhibitors and serine protease inhibitors67 or calcium antagonists68 were investigated without random allocation. Further randomized controlled trials, including groups with combination therapies should be performed to confirm the efficacy of thromboxane synthetase inhibitors before definitive recommendations can be formulated.
Endothelin Receptor Antagonists and Natrium Nitroprusside Numerous metabolic pathways that regulate vascular tone are present in both the smooth muscle and endothelial cells.69 An imbalance between vasoconstriction and vasodilation may play a major role in cerebral vasospasm development. The
72 Clinical Trials in Neurologic Practice endothelial cell produces both endothelium-derived relaxing factors, most notably nitric oxide, and endothelium-derived constricting factors, most notably endothelin. The fine equilibrium between vasoconstriction and vasodilation can be modified by several conditions. Endothelium-dependent relaxation has been shown to be impaired after SAH. 69 Similarly, increased endothelin content in cerebrospinal fluid has been reported after SAH.69 Oral or intravenous endothelin receptor antagonists70,71 and intrathecal nitric oxide donors, such as sodium nitroprusside,72 are promising drugs against cerebral vasospasm. The efficacy of these agents needs to be investigated in large clinical trials.
CONCLUSION Intensive care of a patient with aneurysmal subarachnoid hemorrhage should focus on treatment and prevention of the most frequent and deleterious complications of the disease: rebleeding and cerebral vasospasm. Several recent randomized trials have been conducted or are ongoing to try to improve management of patients with ruptured aneurysms. Continuous development and technical advancement in microsurgery and endovascular surgery have opened new avenues in aneurysm treatment. The ISAT study is comparing the results of aneurysm patients treated with surgical clipping or with endovascular coiling. The results of this large study will eventually help to define the indications and limitations of each treatment option in regard to aneurysm type and location. Acute cerebral vasospasm is still characterized by high morbidity and mortality. Thus, it is clear that more basic research and clinical studies are needed to further elucidate the underlying mechanisms and to improve outcome of SAHinduced cerebral vasospasm.
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Neurosurgery 1998;42:759–767; discussion 767–768. 33. Solenski NJ, Haley EC Jr, Kassell NF, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 1995;23:1007–1017. 34. Levy ML, Rabb CH, Zelman V, et al. Cardiac performance enhancement from dobutamine in patients refractory to hypervolemic therapy for cerebral vasospasm. J Neurosurg 1993;79:494–499. 35. Miller JA, Dacey RG Jr, Diringer MN. Safety of hypertensive hypervolemic therapy with phenylephrine in the treatment of delayed ischemic deficits after subarachnoid hemorrhage. Stroke 1995;26:2260–2266. 36. Solomon RA, Fink ME, Pile-Spellman J. Surgical management of unruptured intracranial aneurysms. J Neurosurg 1994;80:440–446. 37. Zuccarello M, Marsch JT, Schmitt G, et al. Effect of the 21-aminosteroid U74006F on cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg 1989;71:98–104. 38. Steinke DE, Weir BK, Findlay JM, et al. A trial of the 21-aminosteroid U74006F in primate model of chronic cerebral vasospasm. Neurosurgery 1989;24:179–186.
74 Clinical Trials in Neurologic Practice 39. Kassell NF, Haley EC Jr, Apperson-Hansen C, Alves WM. Randomized, double-blind, vehiclecontrolled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996;84:221–228. 40. Haley EC Jr, Kassell NF, Apperson-Hansen C, et al. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 1997;86:467–474. 41. Lanzino G, Kassell NF. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 1999;90:1018–1024. 42. Lanzino G, Kassell NF, Dorsch NW, et al. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg 1999;90:1011–1017. 43. Zubkov YN, Nikiforov BM, Shustin VA. Balloon catheter technique for dilatation of constricted cerebral arteries after aneurysmal SAH. Acta Neurochir 1984;70:65–79. 44. Elliott JP, Newell DW, Lam DJ, et al. Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 1998;88:277–284. 45. Polin RS, Hansen CA, German P, et al. Intra-arterially administered papaverine for the treatment of symptomatic cerebral vasospasm. Neurosurgery 1998;42:1256–1264; discussion 1264–1267. 46. Barnwell SL, Higashida RT, Halbach VV, et al. Transluminal angioplasty of intracerebral vessels for cerebral arterial spasm: reversal of neurological deficits after delayed treatment. Neurosurgery 1989;25:424–429. 47. Bejjani GK, Bank WO, Olan WJ, Sekhar LN. The efficacy and safety of angioplasty for cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 1998;42:979–986; discussion 986–987. 48. Brothers MF, Holgate RC. Intracranial angioplasty for treatment of vasospasm after subarachnoid hemorrhage: technique and modifications to improve branch access. AJNR Am J Neuroradiol 1990;11:239–247. 49. Coyne TJ, Montanera WJ, Macdonald RL, Wallace MC. Percutaneous transluminal angioplasty for cerebral vasospasm after subarachnoid hemorrhage. Can J Surg 1994;37:391–396. 50. Dion JE, Duckwiler GR, Vinuela F, et al. Pre-operative micro-angioplasty of refractory vasospasm secondary to subarachnoid hemorrhage. Neuroradiology 1990;32:232–236. 51. Eskridge JM, McAuliffe W, Song JK, et al. Balloon angioplasty for the treatment of vasospasm: results of first 50 cases. Neurosurgery 1998;42:510–516; discussion 516–517. 52. Fujii Y, Takahashi A, Yoshimoto T. Effect of balloon angioplasty on high grade symptomatic vasospasm after subarachnoid hemorrhage. Neurosurg Rev 1995;18:7–13. 53. Higashida RT, Halbach VV, Dowd CF, et al. Intravascular balloon dilatation therapy for intracranial arterial vasospasm: patient selection, technique, and clinical results. Neurosurg Rev 1992;15:89–95. 54. Konishi Y, Maemura E, Shiota M, et al. Treatment of vasospasm by balloon angioplasty: experimental studies and clinical experiences. Neurol Res 1992;14:273–281. 55. Livingston K, Guterman LR, Hopkins LN. Intraarterial papaverine as an adjunct to transluminal angioplasty for vasospasm induced by subarachnoid hemorrhage [published erratum in AJNR Am J Neuroradiol 1993;14(4):1025]. AJNR Am J Neuroradiol 1993;14:346–347. 56. Newell DW, Eskridge J, Mayberg M, et al. Endovascular treatment of intracranial aneurysms and cerebral vasospasm. Clin Neurosurg 1992;39:348–360. 57. Rosenwasser RH, Armonda RA, Thomas JE, et al. Therapeutic modalities for the management of cerebral vasospasm: timing of endovascular options. Neurosurgery 1999;44:975–979;discussion 979–980. 58. Terada T, Kinoshita Y, Yokote H, et al. The effect of endovascular therapy for cerebral arterial spasm, its limitation and pitfalls. Acta Neurochir 1997;139:227–234. 59. Polin RS, Coenen VA, Hansen CA, et al. Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 2000;92:284–290. 60. Polin RS, Hansen CA, German P, et al. Intra-arterially administered papaverine for the treatment of symptomatic cerebral vasospasm. Neurosurg 1998;42:1256–1264. 61. Findlay JM, Kassell NF, Weir BK, et al. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 1995;37:168–176; discussion 177– 178. 62. Mizoi K, Yoshimoto T, Takahashi A, et al. Prospective study on the prevention of cerebral vasospasm by intrathecal fibrinolytic therapy with tissue-type plasminogen activator. J Neurosurg 1993;78:430–437. 63. Sasaki T, Ohta T, Kikuchi H, et al. A phase II clinical trial of recombinant human tissue-type plasminogen activator against cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 1994;35:597–604; discussion 604–605.
Aneurysmal Subarachnoid Hemorrhage Trials 75 64. Usui M, Saito N, Hoya K, Todo T. Vasospasm prevention with postoperative intrathecal thrombolytic therapy: a retrospective comparison of urokinase, tissue plasminogen activator, and cisternal drainage alone. Neurosurgery 1994;34:235–244; discussion 244–245. 65. 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;53:110–117. 66. Suzuki S, Sano K, Handa H, et al. Clinical study of OKY-046, a thromboxane synthetase inhibitor, in prevention of cerebral vasospasms and delayed cerebral ischaemic symptoms after subarachnoid haemorrhage due to aneurysmal rupture: a randomized double-blind study. Neurol Res 1989;11:79–88. 67. Kaminogo M, Yonekura M, Onizuka M, et al. Combination of serine protease inhibitor FUT-175 and thromboxane synthetase inhibitor OKY-046 decreases cerebral vasospasm in patients with subarachnoid hemorrhage. Neurol Med Chir 1998;38:704–708; discussion 708–709. 68. Nakashima S, Tabuchi K, Shimokawa S, et al. Combination therapy of fasudil hydrochloride and ozagrel sodium for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurol Med Chir 1998;38:805–810; discussion 810–811. 69. Dietrich HH, Dacey RG. Molecular keys to the problems of cerebral vasospasm. Neurosurgery 2000;46:517–530. 70. Roux S, Breu V, Ertel SI, Clozel M. Endothelin antagonism with bosentan: a review of potential applications. J Mol Med 1999;77:364–376. 71. Roux S, Breu V, Giller T, et al. Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 1997;283:1110–1118. 72. 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;30:1409–1416.
Subarachnoid hemorrhage (SAH) continues to be a common cause of worldwide morbidity and mortality among young adults of both genders. Intracranial aneurysm rupture is the most common identifiable cause of nontraumatic SAH. Although the case-fatality rates from SAH have progressively declined,1 the incidence of SAH, unlike other types of stroke, has not declined over time.2 The outcome of patients remains poor, despite rapidly evolving research regarding diagnosis, causes, and treatment of SAH. The overall mortality rate is estimated to be 25%. Approximately 50% of patients who survive the aneurysmal rupture will have significant morbidity,3 for approximately 30% of which secondary ischemia is responsible.4,5 Cerebral vasospasm after aneurysmal SAH is a major cause of disability and death. Therefore, because little can be done to ameliorate the immediate deleterious effect of aneurysm rupture, rebleeding and vasospasm are the major problems for which clinical trials have been designed. Large, multicenter prospective cohort analyses and multicenter prospective randomized trials have influenced considerably the treatment protocols for SAH patients. Nevertheless, many currently accepted treatment options are not supported by rigorous clinical scientific evidence. Some specific treatments for SAH are not amenable to testing by randomized, prospective trials because of practical or ethical considerations. In 1994, the Stroke Council of the American Heart Association published practice guidelines for the management of aneurysmal SAH to precisely address these issues.6 The reading of these guidelines is strongly recommended, as it is not the purpose of this chapter to repeat them. They can also be found on the website of the American Heart Association (www.americanheart.org). Despite these guidelines, controversies around treatment protocols for patients with SAH are ongoing. The beneficial role of calcium antagonists, the role of prophylactic treatment with hypervolemia, and the role of transluminal balloon angioplasty are just some of the controversial issues. Recent multicenter prospective randomized trials have addressed the efficacy of antioxidant and
63
64 Clinical Trials in Neurologic Practice anti-inflammatory agents, mainly tirilazad mesylate. The technical development and advancement of interventional endovascular surgery has opened new avenues in aneurysm and cerebral vasospasm treatment. An international multicenter prospective randomized trial comparing treatment of ruptured aneurysm with surgical clipping versus endovascular coiling began in 1999 and is ongoing.
PREVENTION OF REBLEEDING Treatment of Ruptured Aneurysms The most extensive data on the results of modern management of ruptured aneurysms have been provided by the International Cooperative Study on Timing of Aneurysm Surgery, in which more than 3,000 patients were entered in a prospective observational study from 1980 to 1983.4,7 Surgical repair is today the firstline treatment option for ruptured aneurysms. Endovascular techniques for the treatment of intracranial aneurysms have been evolving since 1973. 8 The Guglielmi detachable coil device has been in use in North America since 1991 and in Europe since 1992.9 Significant improvement in coiling has an increased occlusion rate and a reduced complication rate. This has fueled the belief that aneurysm coiling could become the first-line treatment. The International Subarachnoid Aneurysm Trial (ISAT) compared surgery and endovascular coil treatment of ruptured aneurysms and is the largest ever randomized clinical trial in SAH management.10 The study had randomized more than 1,300 patients by mid-2000 and has planned to recruit more than 2,500 patients. The results of the ISAT study will answer two main questions. First, is aneurysm coiling as effective as clipping to protect against rebleeding? Second, is patient outcome improved with endovascular treatment? The results of this large, multicenter prospective randomized trial will have an impact on the management strategies in patients with aneurysmal subarachnoid hemorrhage.
Antifibrinolytics Early clipping or coiling of the ruptured aneurysm is the most efficacious prevention of rebleeding and is becoming increasingly common in neurosurgical centers. In patients with delayed surgery the use of antifibrinolytic treatment has been recommended.11 Systematic reviews have shown that antifibrinolytics reduce the rebleeding rate by approximately 45% but do not affect overall outcome because of an increase in the rate of delayed cerebral ischemia due to cerebral vasospasm.6 The trials on antifibrinolytic therapy date from over 10 years, when triple-H therapy (hypervolemia, hypertension, hemodilution) and nimodipine were not used routinely to decrease the incidence of symptomatic vasospasm. Members of the STAR study group recently conducted a prospective double-blind, placebo-controlled multicenter clinical trial12 to investigate whether antifibrinolytics, in combination with treatment to prevent cerebral ischemia, improve outcome in patients with subarachnoid hemorrhage and delayed (longer than 48 hours) occlusion of the aneurysm. The overall results of
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this study show no beneficial effect on outcome despite reduction in rebleeding rate. Actually, in patients with impaired level of consciousness on admission (World Federation of Neurological Surgeons [WFNS] grade IV or V), antifibrinolytics adversely affected outcome. In patients with normal level of consciousness (WFNS grade I–III) there was a clear trend toward beneficial effect of this treatment. However, patients with normal levels of consciousness are ideal candidates for early surgery or coiling to prevent rebleeding. Antifibrinolytic treatment needs no consideration for SAH patients, even if combined with treatment to prevent cerebral ischemia.
PREVENTION AND TREATMENT OF SYMPTOMATIC VASOSPASM Calcium Antagonists in Aneurysmal Subarachnoid Hemorrhage Several controlled randomized clinical trials have studied calcium antagonists, mainly nimodipine, in patients with aneurysmal SAH and were published between 1983 and 1993.13–23 In two trials not using nimodipine, one used AT877,23 and the other nicardipine.19 According to the AHA guidelines, these trials can be summarized as follows: (1) Oral nimodipine consistently reduced poor outcome due to vasospasm in all grades of patients; (2) the incidence of symptomatic vasospasm was not affected by nimodipine; (3) angiographic vasospasm was not affected by nimodipine; and (4) complications and side effects of the drug were minimal. Despite these recommendations supported by level I and II evidence from the individual trials, some recent reports have called the use of calcium antagonists into question,24 and controversy about their beneficial effect exists. To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH and whether these drugs reduce the frequency of secondary cerebral ischemia, structured reviews have been published in which the authors performed a meta-analysis of all the controlled clinical trials.25–27 In their meta-analysis including seven trials and 1,202 patients, Barker and Ogilvy28 demonstrated that prophylactic nimodipine is effective in increasing the odds of good outcome after aneurysmal SAH. Efficacy was both statistically significant ( p = .004) and clinically significant in magnitude, with one additional good outcome expected for every seventh patient treated. The meta-analysis also showed that nimodipine significantly increased the odds of good or fair outcome and reduced the odds of radiographically detectable infarction and permanent deficit and death from secondary ischemia. A slight decrease in overall mortality or rebleeding-related death or deficit with nimodipine was demonstrated but was not statistically significant. Due to limitation of the data in the original trials, they declined to perform a meta-analysis of the potential effect of nimodipine on arteriographic vasospasm. They failed to show significant differences in other subgroup analyses comparing oral versus intravenous administration, and low dose versus high dose. They also analyzed the potential sources of bias in such observational studies.28 The meta-analysis was not weakened by publication bias or the undue influence of any single trial. As the trials included in the metaanalysis did not specify the use of prophylactic hypervolemic-hypertensive ther-
66 Clinical Trials in Neurologic Practice apy, the efficacy of nimodipine in such a setting cannot be analyzed. Barker and Ogilvy28 concluded that the efficacy of prophylactic nimodipine in improving outcome after SAH is demonstrated by meta-analysis and that isolated retrospective trials24 that fail to show efficacy under specific conditions should not weigh heavily in decisions regarding its use. Similarly, Feigin et al.27 demonstrate in their meta-analysis, including 10 controlled trials with 2,756 patients, significant reduction of poor outcome after SAH with nimodipine treatment (27% relative risk reduction; 95% confidence interval, 13–39%), as well as secondary ischemia (33% relative risk reduction; 95% confidence interval, 25–41%). Again, there was no significant difference between route or dosage of nimodipine administration. The clinical trials and their meta-analysis demonstrate that nimodipine improves overall outcome after aneurysmal SAH. Oral administration of nimodipine 60 mg every 4 hours can be advocated.
Triple-H Therapy (Hypervolemia, Hypertension, Hemodilution) A popular concept of cerebral vasospasm prevention, as well as of cerebral vasospasm treatment in patients experiencing SAH, is the induction of a hypervolemic, hemodiluted, and hypertensive/hyperdynamic state (triple-H therapy). Triple-H therapy can be used in prevention of cerebral vasospasm or as a treatment of symptomatic vasospasm and is based on the hypothesis that an increase in arterial pressure and cardiac output and a decrease of blood viscosity optimize cerebral blood flow, thereby decreasing the incidence of symptomatic vasospasm. However, it is not clear in the literature which component of triple-H therapy impacts prevention or treatment of cerebral vasospasm. Similarly, it is not well established how to define an induced hypertensive, hypervolemic, and hemodiluted state.
Triple-H Therapy as Prevention Clinically relevant reduction of cerebral vasospasm was reported in observational studies using preventive triple-H therapy compared with observational studies not using preventive therapy.29 Only small randomized, controlled studies were conducted of triple-H therapy as a preventive treatment analyzing clinically relevant end points, such as symptomatic cerebral vasospasm, neurologic disability, and mortality.30–32 Rosenwasser et al.31 compared preoperative hypervolemia (n = 15) (administering blood [aim: hematocrit 45%], albumin, and crystalloid) with preoperative normovolemia (n = 15) in patients scheduled for late surgical aneurysm treatment. Their results showed that the incidence of symptomatic cerebral vasospasm was significantly decreased in the group treated with preventive hypervolemia. Mayer et al.32 compared the outcome of 19 hypervolemic patients with 19 normovolemic patients using central venous pressure measurements to evaluate the state of intravascular volemia. Hypervolemia was defined as a central venous pressure greater than 8 mm Hg, and normovolemia was defined as a central venous pressure greater than 5 mm Hg. Patients in both groups received 0.9% saline solution
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1,920 ml per day, as a baseline; hypervolemia was achieved by additional 5% albumin administration to increase central venous pressure as needed. Five of 19 patients in the hypervolemic group and seven of 24 patients in the normovolemic group developed symptomatic cerebral vasospasm with delayed cerebral ischemia (29% versus 26%; no significant difference). Pulmonary edema requiring treatment was observed in one patient in the hypervolemic group. The same research group published a more recent trial, using the same methodological design, randomizing 41 patients into the hypervolemic and 41 patients into the normovolemic groups.30 The incidence of symptomatic vasospasm was 20% in both groups, and no side effects were reported from induction of hypervolemia. Solenski et al.33 reported, however, in a large prospective observational study, that 104 of 457 (23%) treated with triple-H therapy experienced pulmonary edema. A confounding factor in the judgment of the potential complications induced by triple-H therapy may be the frequent presence of neurogenic pulmonary edema associated with SAH. In fact, Solenski et al.33 observed an increased incidence of pulmonary edema among patients presenting in high clinical grades (WFNS IV and V), which may support the hypothesis that other factors besides induction of hypervolemia could play a role in the development of pulmonary edema. The lack of randomized controlled trials enrolling a significant number of patients (as estimated by power analysis) implies that the efficacy and safety of triple-H therapy are not well established. Guidelines, recommendations, and clinical implementation of triple-H therapy as a preventive treatment of cerebral vasospasm can therefore not be based on evidence.
Triple-H Therapy as Treatment Triple-H therapy as a treatment of symptomatic cerebral vasospasm consists of a more aggressive implementation of triple-H therapy in patients with established symptomatic cerebral vasospasm. A step-by-step concept of triple-H therapy (progressive from prevention to treatment) was proposed by Levy et al.34: First, in all patients with SAH, a hypervolemic state is induced. Second, in patients manifesting neurologic compromise, additional infusions of colloids are started to achieve a pulmonary artery wedge pressure of 14 mm Hg. Third, in patients without improvement of neurologic status over the next few hours, cardiac output (cardiac index greater than or equal to 3.5) and arterial pressure (20– 30%) are increased with intravenous infusion of dobutamine, a beta-1-adrenergic receptor agonist. In a prospective observational study applying this protocol, a reversal of the delayed ischemic symptoms was obtained in 18 of 23 patients (78%). Whereas Levy et al.34 support a hyperdynamic model to decrease delayed ischemic deficits (i.e., increase of cardiac output to increase cerebral blood flow), other authors support a hypertensive model (i.e., an increase of systemic arterial pressure). Miller et al.35 administered phenylephrine, a selective alpha1-adrenergic receptor agonist, to increase mean arterial pressure by 20–25% above the patient’s baseline and even up to 35% above the patient’s baseline, if the neurological deficit is not reversed. With such a regimen, these authors observed neurologic improvement in 21 out of 24 patients (88%). However, dobutamine and phenylephrine both increase cardiac oxygen consumption and may, therefore, induce cardiac ischemia or infarction, contributing to the increased
68 Clinical Trials in Neurologic Practice risk of lung edema.33 None of the catecholamines has proven advantageous over the others in vasospasm treatment. Safety of triple-H therapy as treatment in patients with symptomatic cerebral vasospasm after SAH is reported rarely in the literature and is never investigated systematically.36 As already mentioned under Triple-H Therapy as Prevention, there is a lack of randomized controlled trials analyzing efficacy and safety of triple-H therapy as treatment of delayed ischemia. Furthermore, there is a lack of consensus in defining the intermediate aims of triple H-treatment (blood pressure versus cardiac output), the type and amount of fluid to administer, and the type and dose of vasoactive drugs to use. Guidelines, recommendations, and clinical implementation of triple H-treatment cannot be based on evidence. Clinicians have to base their decisions on clinical experience and local protocols until randomized controlled trials with sufficient group sizes are available. Triple-H therapy can, however, be recommended for prevention and treatment of delayed ischemic deficits, based on the step-by-step concept of triple-H therapy as proposed by Levy et al.34 Patients receiving triple-H therapy must be monitored closely in an intensive care setting for hemodynamic function and electrolyte balance.
Tirilazad in Prevention of Vasospasm The use of tirilazad mesylate, a 21-aminosteroid free-radical scavenger, in animal models of subarachnoid hemorrhage and focal cerebral ischemia has shown a reduction of cerebral vasospasm and cerebral infarct.37,38 Several powerful randomized controlled clinical trials with a multicenter design, including more than 3,500 patients, were conducted to test efficacy and safety of this drug.39–42 The results of these large trials have been difficult to interpret, mainly because of differences in drug effectiveness within the studies. Despite a very similar trial design, tirilazad mesylate was more effective in the cooperative study in Europe, Australia, New Zealand, and South Africa39 than in North America.40 In the former study, tirilazad mesylate at a dose of 6 mg/kg per day improved overall outcome and reduced mortality at 3 months, particularly in men with admission grades IV and V. These results are at odds with the cooperative study conducted in North America that showed no statistical benefit on mortality rate, functional outcome, or ischemic symptoms. The reasons for the differing results are unclear but could include differences in epidemiologic characteristics or standard care of patients. In the North American trials, there were more patients with a history of arterial hypertension (40% and 44% versus 25% and 27%), with triple-H therapy as prevention (75% and 74% versus 45% and 60%), and with triple-H therapy as treatment (30% and 34% versus 18% and 24%). Similarly, nimodipine was more often administered per os in the North American trial compared to the European, Australian, New Zealand and South African trial. Differences were also observed in the results of the control groups. Mortality among men in North America, for example, was half that among men in the European, Australian, New Zealand, and South African trial. Alternatively, the authors suggested the possibility of lower blood levels of the study drug in the North American patients as compared to the other trial, due to broader use of antiepileptic medications as well as gender difference. For these reasons, two further studies were conducted to test the safety and efficacy of higher doses of tirilazad mesylate (15 mg/kg/
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day) in women experiencing aneurysmal subarachnoid hemorrhage.41,42 This second study conducted in Europe, Australia, New Zealand, and South Africa, showed a decreased rate of symptomatic cerebral vasospasm but did not result in better patient outcomes. In the North American trial, no beneficial effect was observed in the overall group. However, sequential analysis revealed a reduction in mortality rates among patients with neurologic grades IV and V at admission. The different responses of tirilazad in patients with various degrees of neurologic impairment could not be explained by the studies’ authors. In a recent meta-analysis of trials of tirilazad mesylate, NW Dorsch (invited lecture at the 7th International Conference on Cerebral Vasospasm, June 18–21, 2000) confirmed that patients presenting in WFNS grade IV and V had a better outcome if high-dose tirilazad treatment (men 6 mg/kg/day and women 15 mg/kg/day) was started within 24 hours from subarachnoid hemorrhage. A constant result among these trials was the safety of tirilazad mesylate administration. No major side effects were observed. Despite experimental evidence favoring a beneficial effect of tirilazad and the discrepancies of the results of the clinical trials, and in the absence of an overall benefit in patient outcome, tirilazad mesylate cannot be recommended for routine clinical use in patients with aneurysmal SAH.
Transluminal Balloon Angioplasty Development of endovascular techniques since 1984 has allowed transluminal balloon angioplasty43 to be performed in cerebral vessels affected by vasospasm with or without selective injection of papaverine into the involved territories.44,45 Despite small anecdotal series46–58 of angiographically confirmed reversal of cerebral vasospasm and high rates of clinical improvement, no controlled investigation of the efficacy of this procedure has been conducted. As opposed to intra-arterial administration of papaverine hydrochloride alone,44,45 balloon angioplasty demonstrates excellent angiographic results that are, in most cases, permanent. In most of the small series, clinical improvement has been observed in approximately 60% of patients treated with angioplasty.47,51,52,58 In a recent study, Polin et al.59 analyzed 38 patients enrolled in the North America trial of tirilazad42 who had angioplasty for cerebral vasospasm; the authors failed to demonstrate a benefit of angioplasty over medical treatment in patients presenting with symptomatic cerebral vasospasm. In summary, the ability of transluminal balloon angioplasty to reverse angiographic cerebral vasospasm is unquestioned. Its clinical role, however, is not proven. Future studies have to clearly define the indications for its use. First, the clinical efficacy and not only angiographic improvement must be confirmed. Second, the anatomic types of cerebral vasospasm (proximal versus distal) amenable to angioplasty must be studied. Third, the timing of the procedure with regard to symptom onset and computed tomography (CT) findings must be defined. Balloon angioplasty has gained an important role in the algorithm of vasospasm management and it can be recommended as an adjunct to triple-H therapy, but not as a replacement for careful medical management of subarachnoid hemorrhage patients in the intensive care unit. Intra-arterial papaverine injection without balloon angioplasty cannot be recommended.60
70 Clinical Trials in Neurologic Practice OTHER TREATMENTS FOR VASOSPASM One of the most important and critical aspects of SAH-induced cerebral vasospasm is its failure to consistently respond to treatment. A large number of pharmacologic interventions have been tried in experimental models and clinical trials with only partial success. The purpose here is not to review all of the experimental data. Some selected clinical data are presented in the next paragraph. The efficacy of these treatment forms has not been confirmed with large randomized controlled trials; therefore, none of the treatments described in this paragraph can be advocated in clinical practice.
Intracisternal Fibrinolytic Treatment Fibrinolytic substances, such as recombinant tissue plasminogen activator (rt-PA) or urokinase, can facilitate the normal clearing of blood from the subarachnoid space and, in this manner, may prevent delayed arterial spasm after SAH. Two forms of administration of rt-PA were developed and tested: (1) single intraoperative intracisternal bolus injection61 and (2) repetitive postoperative intracisternal bolus injection via a cisternal catheter.62–64 In a randomized controlled trial, 100 patients with ruptured intracranial saccular aneurysms causing severe SAH were treated with a single 10-ml intraoperative injection of vehicle buffer solution or rt-PA into the opened basal subarachnoid cisterns immediately after aneurysm clipping.61 The rates for no or mild, moderate, and severe angiographic vasospasm were 69%, 16%, and 15% respectively, in the rt-PA–treated group versus 42%, 35%, and 23%, respectively, in the placebo group. There was a trend toward lesser degrees of cerebral vasospasm in the rt-PA–treated group, but this was not statistically significant ( p = .07). Overall, bleeding complication rates did not differ between the two groups. The study concluded that efficacy in preventing clinical vasospasm and its ischemic complications was not demonstrated, despite a trend toward less severe cerebral vasospasm and improved outcome. In a prospective study examining 105 patients, postoperative rt-PA was used until all of the cerebral cisterns exhibited low-density on CT scan (mean, 4–7 days).62 Patients showing diffuse thick subarachnoid blood clots on CT with greater than 75 Hounsfield units were included in the rt-PA therapy group; those with less than 75 Hounsfield units comprised the control group. Follow-up angiography showed that 26 cases (87%) in the rt-PA group had no cerebral vasospasm, three (10%) had moderate vasospasm, and one (3%) had severe vasospasm. In contrast, there were 11 patients (15%) with delayed ischemic neurologic deficits in the control group. Three complications in the rt-PA group were reported: One case of SAH caused by catheter removal, one small epidural hematoma, and one subgaleal fluid accumulation. All of these complications were treated conservatively with favorable results. Usui and colleagues64 retrospectively compared three groups of patients. The first was comprised of patients who had simple, spontaneous cisternal drainage through a catheter left at surgery until CT scanning showed basal cisternal clot clearance (n = 29). The second group had continuous irrigation between two cisternal catheters using a urokinase solution, 120 IU/ml at 21 ml per hour, started
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after postoperative angiography confirmed complete aneurysm ablation and continued for 5–7 days (n = 60). The third group received six hourly, intermittent injections of rt-PA via a single cisternal catheter that, after clamping for several hours, was left open to drain. The patients were not randomly allocated to treatment groups, and by design, the first group had less severe SAHs. The authors concluded that postoperative fibrinolytic treatment reduced cerebral vasospasm and that rt-PA injections were easier to administer and more effective than urokinase irrigation. The most important trial with intrathecal urokinase investigated 217 consecutive patients classified as Fisher CT Group 3.65 After clipping the aneurysm, irrigation tubes were placed in the Sylvian fissure (inlet) unilaterally or bilaterally and in the prepontine or chiasmal cistern (outlet). Lactated Ringer’s solution with urokinase (120 IU/ml) and ascorbic acid (4 mg/ml) was infused at a rate of 30 ml/ hour/side for approximately 10 days. Symptomatic cerebral vasospasm was observed in six cases (2.8%), and two of these six cases (0.9%) demonstrated sequelae. Complications occurred in eight patients during irrigation therapy: Two patients experienced seizures, two patients developed meningitis, and four patients had an intracranial hemorrhage. All recovered without neurologic deficits. Confirmation or denial of significant clinical cerebral vasospasm prevention, with less ischemic infarction and improved overall outcome, requires a larger randomized trial, as does any meaningful comparison of fibrinolytic treatment methods. Fibrinolytic treatment appears to bear acceptable bleeding risk, providing surgery is uncomplicated and aneurysm clipping complete. However, the studies have confirmed the extreme danger of fibrinolytic treatment when the aneurysm is incompletely secured.
Intravenous Thromboxane Synthetase Inhibitor In a large, randomized, and double-blind trial at 48 neurosurgical services in Japan, the thromboxane synthetase inhibitor OKY-046 was investigated in two different doses and compared with placebo.66 In subjects with severe cerebral vasospasm, the incidence of delayed ischemic deficit was significantly lower, with better functional prognosis, in the low dosage (80 mg per day) of thromboxane synthetase inhibitor group than in the placebo group. Additionally, in subjects with severe grades on the Glasgow Coma Scale, Japan Coma Scale, or High Density Score, the functional prognosis at 1 month after aneurysmal rupture was significantly better although no significant differences were seen in the overall investigation. Combinations of thromboxane synthetase inhibitors and serine protease inhibitors67 or calcium antagonists68 were investigated without random allocation. Further randomized controlled trials, including groups with combination therapies should be performed to confirm the efficacy of thromboxane synthetase inhibitors before definitive recommendations can be formulated.
Endothelin Receptor Antagonists and Natrium Nitroprusside Numerous metabolic pathways that regulate vascular tone are present in both the smooth muscle and endothelial cells.69 An imbalance between vasoconstriction and vasodilation may play a major role in cerebral vasospasm development. The
72 Clinical Trials in Neurologic Practice endothelial cell produces both endothelium-derived relaxing factors, most notably nitric oxide, and endothelium-derived constricting factors, most notably endothelin. The fine equilibrium between vasoconstriction and vasodilation can be modified by several conditions. Endothelium-dependent relaxation has been shown to be impaired after SAH. 69 Similarly, increased endothelin content in cerebrospinal fluid has been reported after SAH.69 Oral or intravenous endothelin receptor antagonists70,71 and intrathecal nitric oxide donors, such as sodium nitroprusside,72 are promising drugs against cerebral vasospasm. The efficacy of these agents needs to be investigated in large clinical trials.
CONCLUSION Intensive care of a patient with aneurysmal subarachnoid hemorrhage should focus on treatment and prevention of the most frequent and deleterious complications of the disease: rebleeding and cerebral vasospasm. Several recent randomized trials have been conducted or are ongoing to try to improve management of patients with ruptured aneurysms. Continuous development and technical advancement in microsurgery and endovascular surgery have opened new avenues in aneurysm treatment. The ISAT study is comparing the results of aneurysm patients treated with surgical clipping or with endovascular coiling. The results of this large study will eventually help to define the indications and limitations of each treatment option in regard to aneurysm type and location. Acute cerebral vasospasm is still characterized by high morbidity and mortality. Thus, it is clear that more basic research and clinical studies are needed to further elucidate the underlying mechanisms and to improve outcome of SAHinduced cerebral vasospasm.
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