Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery

A total of 213 patients with verified aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) were enrolled in a double-blind placebo-controlled trial to determine the effect of intravenous nimodipine on delayed ischemic deterioration and computerized tomography (CT)-visualized infarcts after SAH and surgery. The administration of the drug or matching placebo was started immediately after the radiological diagnosis of a ruptured aneurysm had been made. Of the 213 patients enrolled in the study, 58 were operated on early (within 72 hours after the bleed: Days 0 to 3), 69 were operated on subacutely (between Days 4 and 7), and 74 had late surgery (on Day 8 or later). Eleven patients died before surgery was undertaken and one was not operated on. A follow-up examination with CT scanning, performed 1 to 3 years after the SAH (mean 1.4 years), revealed no significant differences in the overall outcome between the groups. However, nimodipine treatment was associated with a significantly lower incidence of deaths caused by delayed cerebral ischemia (p = 0.01) and significantly lower occurrence of cerebral infarcts visualized by CT scanning in the whole population (p = 0.05), especially in patients without an associated intracerebral hemorrhage on admission CT scan (p = 0.03).     

Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study

A total of 216 patients with a ruptured aneurysm of the anterior part of the circle of Willis were enrolled into this prospective randomized study of timing of the operation after aneurysmal subarachnoid hemorrhage (SAH). Only patients in clinical Grades I to III (according to the classification of Hunt and Hess) who were admitted and randomly assigned to a treatment group within 72 hours after the SAH were included in the trial. The patients were randomly assigned to one of three operation groups: acute surgery (AS: 0 to 3 days after the SAH; day of SAH = Day 0), intermediate surgery (IS: 4 to 7 days after the SAH), or late surgery (LS: 8 days to an indefinite time after the SAH). Three patients (4.3%) in the IS group and six patients (8.6%) in the LS group died before surgery was undertaken. At 3 months post-SAH, 65 patients (91.5%) from the AS group were classified as independent compared to 55 (78.6%) from the IS group and 56 (80.0%) from the LS group. The management mortality rate in the AS group was 5.6% compared to 12.9% in the LS group. Of the 216 patients enrolled in the timing study, 159 were randomly assigned to an independent double-blind placebo-controlled trial of nimodipine in Grade I to III patients. A total of 79 patients received nimodipine and 80 placebo. When the nimodipine group and the no-nimodipine group (the 80 placebo-treated patients plus the 52 patients who were not entered into the nimodipine trial) were analyzed separately, a significant difference was seen in the outcome of the no-nimodipine group (dependent AS vs. dependent IS, p = 0.01). Nimodipine treatment was associated with a significant reduction of delayed ischemic deterioration (all operation group combined, nimodipine vs. no nimodipine p = 0.01; LS with nimodipine vs. LS with no nimodipine, p = 0.03).     

Risks factors for cerebral infarction in good-grade patients after aneurysmal subarachnoid hemorrhage and surgery: a prospective study

A prospective series of 265 patients with aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) upon admission were evaluated as to neurological outcome and computerized tomography (CT) findings 1 to 3 years (mean 1.4 years) after the SAH and surgery. A total of 73 patients underwent acute surgery (within 72 hours after the bleed: Days 0 to 3), 86 were operated on subacutely (between Days 4 and 7), and 91 had late surgery (on Day 8 or later). Fifteen patients died before surgery was undertaken and another 20 patients died during the follow-up period. A total of 104 patients received nimodipine and the rest of the patients received either placebo (109 patients) or no medication (52 patients). A logistical regression analysis revealed the following prognostic factors for cerebral infarction, in order of importance: the amount of blood on the primary CT scan; postoperative angiographic vasospasm; the timing of the operation; and a history of hypertension. The use of nimodipine was associated with a significant reduction of cerebral infarcts visualized by CT scanning in patients who received intermediate or late surgery. In patients who underwent acute surgery no significant difference between the incidence of cerebral infarcts was observed.     

Time course of blood velocity changes related to vasospasm in the circle of Willis measured by transcranial Doppler ultrasound

Fifty patients with ruptured aneurysms were operated on within 72 hours after the first subarachnoid hemorrhage (SAH). To prevent symptomatic vasospasm, the patients were given the calcium channel blocker, nimodipine, intravenously (2 mg/hr) for 14 days and orally (60 mg four times daily) for another 7 days. At short intervals (at least every 3rd day) the blood flow velocity in the different segments of the circle of Willis was measured with a noninvasive transcranial Doppler ultrasonography method. Within the first 72 hours after SAH, the velocity was normal in the large branches of the circle of Willis and angiography revealed no signs of vasospasm. The Doppler frequency changes that relate to blood flow accelerated between Days 3 and 10, and maximum blood flow velocities were recorded between Days 11 and 20, with normalization occurring within the following 4 weeks. The changes showed a significant relationship to the source of SAH, the side of the operative approach, and the method of nimodipine administration. A comparison between the angiographically proven diameter of spastic arteries and the Doppler-measured blood flow velocity showed an inverse relationship in flow of the middle cerebral artery and the internal carotid artery that was statistically highly significant (p less than 0.001) while this correlation was only slightly significant in the A1 segment of the anterior cerebral artery (p = 0.054). Seven patients (14%) developed delayed ischemic deficits (DID's), which were all functionally reversible. One patient (2%) died as a result of decompensated vasospasm. Based on the information provided by Doppler measurement of the individual blood flow velocity changes due to vasospasm, preventive hypertensive treatment was introduced to improve the perfusion pressure while patients were still in an asymptomatic stage. Among the last 40 patients who were treated according to this regimen, reversible DID's were observed in only three patients (7.5%) and postoperative angiography to detect vasospasm was not necessary.     

Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms

The therapeutic efficacy of intravenous nimodipine to treat the syndrome of delayed ischemic deterioration or vasospasm after subarachnoid hemorrhage caused by a ruptured aneurysm was investigated in a randomized, double-blind, placebo-controlled multicenter study. A total of 188 patients (nimodipine (N) = 102, placebo (P) = 86) were enrolled in the study, both pre- and postoperatively, within 24 hours of clinical deterioration connected with vasospasm or within 24 hours of arteriography that identified vasospasm. After 61 patients were excluded for not meeting study criteria or for protocol violation, the results were supported by 127 validated case reports: 73 patients received intravenous treatment with nimodipine, and 54 were given placebo. Analysis of the main criterion of efficacy, the number of deaths and of patients with severe deficit related to vasospasm alone, showed a significant statistical difference (N = 8 (19%), P = 17 (49%), P = 0.01). The risk of death or disability was reduced by 66% in the treated group. Analysis of this criterion by type of inclusion (clinical or angiographic) also showed a significant reduction in the clinical group (P = 0.05), but there was no difference in the angiographic group. The risk of mortality connected with vasospasm was reduced by 82%, but analysis by group showed that there was no significant difference for those patients included on clinical criteria, whereas mortality was reduced to a much greater extent in the angiographic group. These results demonstrate the therapeutic efficacy of nimodipine in reducing secondary ischemic brain damage in patients already suffering from angiographic vasospasm or delayed ischemic deterioration.     

Evaluation of the calcium-antagonist nimodipine for the prevention of vasospasm after aneurysmal subarachnoid haemorrhage

Summary 70 consecutive patients admitted within four days after the first aneurysmal subarachnoid haemorrhage (SAH) were evaluated by daily transcranial Doppler ultrasound (TCD) measurement of the blood flow velocities (BFVs) of both middle cerebral arteries (MCAs) and by daily recordings of their clinical grade (Hunt and Hess). Patients with no or only little subarachnoid blood in the first CT after admission were classified as low-risk for the development of symptomatic vasospasm (VSP), and patients with big subarachnoid clots or thick layers of subarachnoid blood were graded as high-risk patients for symptomatic VSP. The first series of 33 patients received no nimodipine whereas the second series of 37 patients were treated with nimodipine 2 mg/h intravenously, starting within 24 hours after the SAH in the majority of patients. 7–14 days postoperatively, the intravenous dose was changed to oral nimodipine 60 mg/q4h for one week and then discontinued. A mean BFV curve of the side with the higher flow velocities correlated with the mean clinical status (Hunt and Hess) was calculated by computer analysis for the patients treated without nimodipine and for those receiving nimodipine in each risk group. The mean BFV curves of the same risk groups were compared in order to evaluate the effect of nimodipine for the prevention of vasospasm following SAH. The delayed neurological deficits (DIND) and the functional outcome six months after the SAH were recorded in each group and compared.Nimodipine given within four days after the SAH did not prevent vasospasm evaluated by TCD, but it significantly reduced the severity of the vasoconstriction, especially in high-risk patients. It reduced significantly the incidence of DIND in high-risk patients and improved their functional outcome. Although nimodipine may have a reduced efficacy in preventing vasospasm after early operation of high-risk patients, it probably protects the brain by increasing its tolerance to focal ischaemia.     

Nimodipine and chronic vasospasm in monkeys: Part 1. Clinical and radiological findings

The efficacy of the calcium channel blocker nimodipine in the prevention of chronic cerebral vasospasm (VSP) and delayed ischemia after subarachnoid hemorrhage (SAH) in monkeys was examined in a blind, randomized, placebo-controlled trial. The primate model developed in this laboratory reliably induces chronic cerebral vasospasm and can induce pathologically proven delayed ischemic neurological deficits (DINDs). With standard microsurgical procedures, an average 6.4-ml autologous hematoma was placed directly against the major anterior cerebral vessels in the right basal subarachnoid spaces of 24 monkeys. The monkeys were randomized to one of four groups and were treated orally q8h for 7 days with nimodipine (3, 6, or 12mg/kg)or placebo. An additional 2 monkeys underwent the surgical procedure without clot placement. Drug administration began between 14 and 20 hours after clot placement. Indices monitored before and after SAH included neurological status, angiographic cerebral vessel caliber, and cerebral blood flow. Significant VSP (25 to 100% reduction in vessel caliber) was present on Day 7 on the clot side in 83% of the animals (P less than or equal to 0.001). There was no significant difference (P greater than 0.05) in the incidence of VSP among the four groups. Similarly, there was no significant difference (P greater than 0.05) in the mean vessel caliber reduction after SAH among the four treatment groups. There was no VSP present on Day 7 in the sham-operated animals. One animal receiving high dose nimodipine (12 mg/kg p.o. q8h) developed a DIND on Day 5 after SAH. A second animal in the 12-mg/kg group developed a transient neurological deficit between Days 4 and 7.     

Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration

OBJECT: The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). Although most randomized studies have been focused on the effect of the peroral administration of nimodipine, intravenous infusion is an alternative and the preferred mode of treatment in many centers. It is unknown whether the route of administration is of any importance for the clinical efficacy of the drug. METHODS: One hundred six patients with acute aneurysmal SAH were randomized to receive either peroral or intravenous nimodipine treatment. The patients were monitored for at least 10 days after bleeding in terms of delayed ischemic neurological deficits (DINDs) and with daily measurements of blood flow velocities in the middle cerebral arteries by using transcranial Doppler ultrasonography. Three months after SAH, clinical outcome and new cerebral infarctions according to MR imaging studies were recorded. RESULTS: Baseline characteristics (age, sex distribution, clinical status on admission, radiological findings, and aneurysm treatment) did not differ between the treatment groups. There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging. CONCLUSIONS: The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.     

Significance of "ultra-early" rebleeding in subarachnoid hemorrhage

Knowledge of the local incidence of aneurysm rupture permits the conclusion that almost every patient in the population of 933,800 persons served by the authors' institution who was stricken by this catastrophe and survived long enough to be transported was treated at this center (121 patients during 34 months). Of these, 9.1% were admitted late (greater than 72 hours after subarachnoid hemorrhage (SAH]; of the remaining cases, 94.5% were seen within 24 hours and 50% within 6 hours post-SAH. Of the 121 patients, 10% were neurologically devastated on arrival, a late operation was planned for 19%, and the earliest possible surgery and nimodipine administration was selected for 71%. In this latter group, 50% of the operations were begun within 24 hours and 76% within 48 hours post-SAH. Sixty percent of all mortality and morbidity could be linked to the initial aneurysm bleed. The remaining 40% could be ascribed to potentially avoidable causes of unfavorable outcome. No less than 9.6% of all patients admitted within 24 hours after SAH suffered from "ultra-early" rebleeding during transportation or preparation for operation. The mortality rate from such rebleeding was 7.4%, compared with the 9.1% combined mortality rate from complications and late ischemia.     

Outcome in 60 consecutive patients treated with early aneurysm operation and intravenous nimodipine

Sixty consecutive patients with a ruptured supratentorial aneurysm underwent operation during the acute stage, 56 of them within 72 hours after the first bleed, one on the 4th day, and three on the 5th day. Six patients were classified preoperatively in Hunt and Hess neurological Grade I, 39 in Grade II, 11 in Grade III, and four in Grade IV or V. Nine patients had severe intracerebral hematomas, and one patient had a subdural hematoma. After the aneurysm was clipped, nimodipine was applied to the exposed arterial segments in a 2.5 X 10(-5)M solution for 10 minutes. Subsequently, all patients received a continuous intravenous nimodipine infusion (2 mg/hr) for 7 to 12 days, followed by oral treatment (270 mg/day). Forty-six patients (77%) made a good neurological recovery; the morbidity rate was 22%, and mortality rate 1.5%. Of the 45 patients in good condition (Grades I to II) preoperatively, 38 (84%) made a good neurological recovery. Two patients (3% of the total series) developed a typical picture of cerebral ischemic dysfunction of delayed onset with subsequent fixed neurological deficits. The results favor the opinion that early operative intervention is beneficial in patients in good condition rather than delaying surgery, and indicate that nimodipine provides an additional anti-ischemic effect. The appearance and severity of late angiographic vasospasm did not seem to be affected by nimodipine.     

Acute operation and preventive nimodipine improve outcome in patients with ruptured cerebral aneurysms

Sixty-five patients with ruptured aneurysms were operated upon within 48 to 72 hours after subarachnoid hemorrhage (SAH) and were treated with a regimen of intra- and postoperative nimodipine for the prevention of symptomatic vasospasm. The clinical grading (Hunt and Hess) was I to III in 49 patients and IV or V in 16. The SAH was mild in 15 patients, moderate in 27, and severe in 23; 12 patients harbored an intracerebral hematoma, and 6 had intraventricular bleeding. Acute hydrocephalus was observed on preoperative computed tomography (CT) in 19 patients. On CT 3 days postoperatively (i.e., Day 3-4 after SAH), 30 of 65 patients still had subarachnoid blood; however, severe symptomatic vasospasm as the deciding threatening event during the delayed postoperative period was not encountered in this series. Transient symptoms of ischemia were noted in 2 patients (3%) and were accompanied by angiographic spasm in 1. Irreversible neurological deficit occurred in 2 patients (3%); in 1 of these, it was a complication of postoperative control angiography. Of the patients preoperatively graded I or II, 96% had an excellent to fair outcome 6 months postoperatively, and 1 patient (4%) had died because of a surgical complication. Among patients preoperatively graded III or IV, 86% had an excellent to fair outcome, and the remaining 14% had a poor outcome. Shunt-dependent hydrocephalus developed in 7% of the patients. Acute surgical repair of ruptured cerebral aneurysms and preventive topical and intravenous administration of nimodipine reduce management complications and improve outcome; above all, ischemic lesions from symptomatic vasospasm are reduced to a minimum.     

Morbidity and mortality after early aneurysm surgery — a prospective study with nimodipine prevention

Summary Based on the outcome in 116 consecutive patients who were subjected to early aneurysm operation combined with additional nimodipine treatment, and who were controlled by transcranial Doppler (TCD) sonography, a morbidity and mortality analysis was performed. Of the 84 patients who preoperatively were in Hunt & Hess grades III, 79 patients (94%) were considered to show a favourable (good-fair) late recovery, while one patient (1%) had a poor outcome, and four patients (5%) died. Of the 32 poor condition patients (H & H IV–V), 17 (53%) showed a favourable recovery, while seven (22%) had a poor outcome, and eight patients (25%) died. Altogether, 20 patients (17%) had an unfavourable (poor-dead) outcome. Only two of these patients showed delayed ischaemic deterioration, one as a consequence of a secondary occlusion of perforating branches from the basilar artery and one with decompensated vasospasm after the evacuation of an epidural haematoma and a longlasting severe systemic hypotension; both these patients died. In another six of the patients with an unfavourable outcome, this was mainly related to a complicated surgery. The unfavourable outcome was related to primary brain damage produced by the subarachnoid haemorrhage (SAH) in ten patients and in two patients to internal medical complications. In addition to the two patients who died following delayed deterioration, secondary neurological dysfunction occurred in 11 patients. In 10 of these patients transient neurological dysfunction was attributed to vasospasm or to a combination of vasospasm with intraoperative or postoperative complications. One further case of delayed deterioration was attributed to secondary occlusion of the internal carotid artery after a complicated operation. From these data we conclude that following early aneurysm operation combined with intravenous nimodipine treatment, vasospasm alone is no more a major clinical problem. Morbidity and mortality are mainly related to primary effects of the SAH and/or complicated surgery.     

Therapeutic trial of cerebral vasospasm with the serine protease inhibitor, FUT-175, administered in the acute stage after subarachnoid hemorrhage.

The therapeutic effect of the synthetic serine protease inhibitor, FUT-175, on cerebral vasospasm after subarachnoid hemorrhage (SAH) was investigated. Twenty-three patients with severe SAH who were admitted between February and July 1990 and who underwent surgery within 48 hours of the initial aneurysmal rupture were treated with an intravenous administration of FUT-175 soon after the operation. The patients were divided randomly into three groups, each receiving a different dose of FUT-175 (Group A, 20 mg every 12 hours for 4 days; Group B, 20 mg every 6 hours for 4 days, Group C, 40 mg every 6 hours for 4 days). The results were compared with another group of twenty-two patients with severe SAH who were admitted before February 1990 and received equivalent treatment, except they were not treated with FUT-175. In 64% of all the patients treated with FUT-175 (Groups A, B, C), and in 85% of those treated with higher doses of FUT-175 (Groups B and C), there was no spasm or only mild vasospasm on the angiogram. The incidence of a delayed ischemic neurological deficit significantly decreased from 55% in the control group to 13% in all patients treated with FUT-175 and to 7% in the patients treated with higher doses (P less than 0.05). The incidence of cerebral infarction resulting from vasospasm significantly decreased from 43% in the control group to 9% in patients treated with FUT-175. In the patients treated with higher doses of FUT-175 (Groups B and C), none developed cerebral infarction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between the timing of aneurysm surgery and the development of delayed cerebral ischemia

A consecutive series of 145 patients with acute aneurysmal subarachnoid hemorrhage (SAH) were operated on within 7 days of SAH and were prospectively evaluated over a 4-year period to determine if the timing of aneurysm surgery influenced the development of delayed cerebral ischemia. All patients were managed with a standardized policy of urgent surgical clipping and treatment with aggressive prophylactic postoperative volume expansion. Patients with delayed ischemic symptoms were additionally treated with induced hypertension. Forty-nine patients underwent surgery on Day 0 or 1 (Group 1) post-SAH, 60 patients on Day 2 or 3 (Group 2), and 36 patients on Days 4 through 7 (Group 3). Postoperative delayed cerebral ischemia developed in 16% of (Group 1) patients, in 22% of Group 2 patients, and in 28% of Group 3 patients. Cerebral infarction resulting from delayed cerebral ischemia developed in only 4% of Group 1 patients, 10% of Group 2 patients, and 11% of Group 3 patients. A bad clinical outcome as a result of delayed cerebral ischemia occurred in one Group 1 patient (2%), two Group 2 patients (3%), and one Group 3 patient (3%). Preoperative grade was not significantly correlated with the incidence or severity of delayed cerebral ischemia at any time interval except that patients in modified Hunt and Hess Grade I or II who underwent surgery on Day 0 or 1 after SAH had no strokes or bad outcomes from delayed cerebral ischemia. This study demonstrates that there is no rationale for delaying aneurysm surgery based on the time interval between SAH and patient evaluation.     

The haemodynamic effect of transcranial Doppler-guided high-dose nimodipine treatment in established vasospasm after subarachnoid haemorrhage

Summary Eleven patients (7 females) with aneurysmal subarachnoid haemorrhage (SAH) and transcranial Doppier (TCD) signs of vasospasm during prophylactic intravenous nimodipine treatment (2 mg/h) were treated with TCD-guided high-dose (4 mg/h) intravenous nimodipine. The patients were followed clinically and with serial TCD investigations. Increasing nimodipine to high-dose treatment led to a reduction of the abnormally elevated mean flow velocities (FV) in all patients. There was also a reversal of clinical signs of delayed ischaemia. In one patient, repeated computer tomographic (CT) investigations revealed a reversal of ischaemic changes. Reduction of nimodipine from 4 to 2 mg/hr resulted in a return to abnormally elevated mean FV as well as a return of clinical signs of cerebral ischaemia. The outcome was favourable in 82% of the patients and there was no mortality or vegetative survival. No patient deteriorated clinically due to vasospasm during treatment with high-dose nimodipine. The individual effect of nimodipine treatment can be monitored by the use of serial TCD investigations. TCD-guided high-dose nimodipine treatment appears to be an effective treatment in SAH patients developing vasospasm despite prophylactic standard dose treatment. The data give support for a direct vascular effect of nimodipine on cerebral vasospasm.     

Delayed ischemic optic neuropathy after surgery on skull base meningiomas successfully treated with nimodipine and rheological therapy: report of two cases

Two patients operated on because of skull base meningiomas experienced delayed ischemic optic neuropathy with loss of vision in one eye on days 6 and 12 after surgery. Treatment with nimodipine and rheological therapy was effective in restoring visual acuity. Possible pathophysiological mechanisms and treatment options are discussed.     

Delayed Ischemic Optic Neuropathy After Surgery on Skull Base Meningiomas Successfully Treated with Nimodipine and Rheological Therapy: Report of Two Cases

Two patients operated on because of skull base meningiomas experienced delayed ischemic optic neuropathy with loss of vision in one eye on days 6 and 12 after surgery. Treatment with nimodipine and rheological therapy was effective in restoring visual acuity. Possible pathophysiological mechanisms and treatment options are discussed.     

The significance of early operation in the management of ruptured intracranial aneurysms—An analysis of 251 cases hospitalized within 24 hours after subarachnoid haemorrhage

Summary An analysis of 251 patients who were hospitalized within 24 hours after rupture of supratentorial aneurysms and were not comatose during the very early stage was carried out. The patients were divided into three groups in relation to timing and methods of surgery. In 61 patients of Group A, the operation was planned to be delayed more than 10 days from subarachnoid haemorrhage (SAH). In 91 patients of Group B, clipping of aneurysms was performed within 48 hours of SAH and subarachnoid blood clots were simultaneously removed while approaching the aneurysms. In 99 patients of Group C, clipping of aneurysms was performed within 48 hours of SAH and radical and extensive removal of any subarachnoid blood clot identified on the computerized tomographic scan was tried at the same time. The outcome at 3 months after SAH was the most favourable in Group C patients and the least favourable in Group A patients.Early operation combined with radical removal of subarachnoid clots minimizes the overall mortality and morbidity in patients with ruptured intracranial aneurysms by preventing rebleeding and probably by avoiding vasospasm.     

Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group

OBJECT: Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients. METHODS: Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups. CONCLUSIONS: The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.     

Correlation of transcranial Doppler sonography findings with timing of aneurysm surgery

Thirty-six patients with a proven first subarachnoid hemorrhage (SAH) from a ruptured supratentorial aneurysm were subjected to repeated transcranial Doppler sonography assessments. Eighteen individuals (Group A) were operated on within 48 hours, while the other 18 (Group B) had surgery between 49 and 96 hours after SAH. The patients represented two clinically comparable groups. In the first 72 hours post-SAH, no increased flow velocities suggestive of arterial narrowing or vasospasm were recorded. There was no significant difference in preoperative flow velocities between the groups. Postoperative flow velocities were significantly lower in patients operated on within 48 hours (p less than 0.001). Two patients, who had surgery on Day 4 post-SAH and who showed the highest recorded postoperative flow velocities, died from cerebral vasospasm and infarction. The results favor a referral system which enables early surgical intervention not only to prevent rebleeds but also aimed at reducing delayed ischemic dysfunction.