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.     

Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage

OBJECTIVE: Serum brain natriuretic peptide (BNP) is elevated after subarachnoid hemorrhage (SAH), causes diuresis and natriuresis (cerebral salt wasting), and may exacerbate delayed ischemic neurological deficits. We examined the temporal relationship between serum BNP elevation, hyponatremia, and the onset of delayed ischemic neurological deficits and determined whether serum BNP levels correlated with the 2-week outcome after SAH. METHODS: Serum BNP and sodium were measured prospectively every 12 hours for 14 days in 40 consecutive patients admitted with SAH. All patients remained euvolemic, underwent transcranial Doppler assessment every 48 hours, and underwent angiography at the onset of delayed neurological deficits. New-onset neurological deficits were attributed to vasospasm only in the absence of other causes and when supported by transcranial Doppler or cerebral angiography. RESULTS: Sixteen patients (40%) experienced symptomatic cerebral vasospasm after SAH. A more than threefold increase in admission serum BNP was associated with the onset of hyponatremia (P < 0.05). Mean BNP levels were similar between vasospasm and nonvasospasm patients fewer than 3 days after SAH (126 +/- 39 pg/ml versus 154 +/- 40 pg/ml; P = 0.61) but were elevated in the vasospasm cohort 4 to 6 days after SAH (285 +/- 67 pg/ml versus 116 +/- 30 pg/ml; P < 0.01), 7 to 9 days after SAH (278 +/- 72 pg/ml versus 166 +/- 45 pg/ml; P < 0.01), and 9 to 12 days after SAH (297 +/- 83 pg/ml versus 106 +/- 30 pg/ml; P < 0.01). BNP level remained independently associated with vasospasm adjusting for Fisher grade and Hunt and Hess grade (odds ratio, 1.28; 95% confidence interval, 1.1-1.6). In patients in whom vasospasm developed, mean serum BNP increased 5.4-fold within 24 hours after vasospasm onset and 11.2-fold the first 3 days after vasospasm onset. Patients with increasing BNP levels from admission demonstrated no change (0 +/- 3) in Glasgow Coma Scale score 2 weeks after SAH versus a 3.0 +/- 2 (P < 0.05) improvement in Glasgow Coma Scale score in patients without increasing serum BNP levels. CONCLUSION: Increasing serum BNP levels independently were associated with hyponatremia, significantly increased the first 24 hours after onset of delayed ischemic neurological deficits, and predicted the 2-week Glasgow Coma Scale score.     

Efficacy and safety of fasudil in patients with subarachnoid hemorrhage: final results of a randomized trial of fasudil versus nimodipine

Fasudil is believed to be at least equally effective as nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for subarachnoid hemorrhage (SAH). We report the final results of a randomized, open trial to compare the efficacy and safety of fasudil with nimodipine. A total of 63 patients undergoing surgery for SAH received fasudil and 66 received nimodipine between 1998 and 2004. Symptomatic vasospasm, low density areas on computed tomography (CT), clinical outcomes, and adverse events were all recorded, and the results were compared between the fasudil and nimodipine groups. Absence of symptomatic vasospasm, occurrence of low density areas associated with vasospasm on CT, and occurrence of adverse events were similar between the two groups. The clinical outcomes were more favorable in the fasudil group than in the nimodipine group (p = 0.040). The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group. There were no serious adverse events reported in the fasudil group. The present results suggest that fasudil is equally or more effective than nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for SAH.     

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.     

Computerized tomography and prognosis in early aneurysm surgery

A study of computerized tomography (CT) scans was performed in a consecutive series of 100 patients with ruptured saccular cerebral aneurysms who were admitted, diagnosed, and operated on within 72 hours after subarachnoid hemorrhage (SAH) and treated with calcium antagonists. The aneurysms were in the anterior portion of the circle of Willis in 95% of patients and in the posterior portion in 5%; 12% had multiple aneurysms. Preoperative neurological grades according to Hunt and Hess were I to III in 74% of patients and IV or V in 26%. Subarachnoid hemorrhage as determined by CT scanning was minor in 20%, moderate in 43%, and severe in 37% of patients. All patients received intraoperative and postoperative administration of the calcium antagonist nimodipine. Three days postoperatively, SAH (as measured by CT) was significantly reduced in the majority of patients but was still moderate in 18%. In the postoperative course, 2% of patients developed delayed ischemic neurological symptoms due to vasospasm. In two additional patients, ischemic symptoms were transient and fully reversible. At the 6-month follow-up interval, a significant prognostic difference was found between two patient groups with different CT scan findings. Among the patients with SAH only, the rate of good outcome (no or minimal deficit) was 93% when the preoperative neurological Grade was I or II; but even with a Grade of III to V, there was a good outcome in 84% of patients. By contrast, in patients with additional intracerebral and/or intraventricular hemorrhage, the good-outcome rate was only 44%. From these data it is concluded that morphological preoperative CT findings are of prognostic value and may even be superior to clinical grading in predicting outcome.     

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).     

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.     

Contribution of endovascular therapy to the management of poor-grade aneurysmal subarachnoid hemorrhage: Clinical and angiographic outcomes

OBJECT: Treatment of patients presenting with poor-grade (Hunt and Hess Grade IV or V) subarachnoid hemorrhage (SAH) is controversial. Endovascular coil embolization has been considered a valuable therapeutic alternative to surgical clip placement for this kind of patient. The aim of the present study was to evaluate immediate and long-term angiographic and clinical outcomes in patients with poor-grade SAH treated by endovascular embolization. METHODS: One hundred eleven patients with Hunt and Hess Grade IV or V SAH were treated with endovascular embolization at the University of California at Los Angeles Medical Center between October 1990 and December 2004. Eighty patients harbored Grade IV hemorrhages and 31 patients had Grade V ones. Immediate and long-term anatomical and clinical outcomes were evaluated in all patients. Long-term clinical outcome assessments were based on follow-up data obtained over an average of 32 months posttherapy. Technical complications occurred in 15 patients (13.5%). Immediate complete aneurysm occlusion was observed in 51.4% of aneurysms. Angiographic, long-term follow-up review revealed aneurysm recanalization in 16.2% of cases. Thirty-nine patients (35.1%) demonstrated a favorable long-term clinical outcome. The overall mortality rate in this patient series was 32.4%. The mortality rate associated with vasospasm was significantly higher in patients with Grade IV SAHs than in those with Grade V hemorrhages. CONCLUSIONS: The results of this study demonstrate a valuable contribution of endovascular therapy of ruptured intracranial aneurysms in patients with Hunt and Hess Grade IV or V SAH. This technique was successful in decreasing repeated aneurysm rupture and in enabling aggressive medical management during the acute phase of SAH. This is particularly important in patients with Grade IV SAH because of their potential for obtaining higher physical and functional recoveries.     

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.     

Traitement pharmacologique du vasospasme de l'hémorragie sous-arachnoïdienne

Pharmacological treatment of vasospasm in subarachnoid haemorrhage (SAH) is founded on prevention and treatment of arterial narrowing and delayed ischaemic deficits. Safety and efficacy of different agents have been studied and trials classified according to the level of evidence proposed by the “Stroke Council” of the American Heart Association. Early intracisternal fibrinolysis can prevent vasospasm (level III to V of evidence, grade C). Pharmacological treatment is based on few drugs. Nimodipine reduces poor outcome related to vasospasm, but does not affect angiographic vessel caliber (level of evidence I and II, grade A). Its use is strongly recommended. Nicardipine decreases symptomatic and angiographic vasospasm, but does not affect outcome (level of evidence I to V, grade B). Tirilazad associated with nimodipine prevents delayed ischaemic deficits due to vasospasm and improves outcome in male patients. Intra-arterial infusion of papaverine associated with transluminal angioplasty can improve symptomatic vasospasm, resistant to conventional therapy (level of evidence IV to V, grade C). Pharmacological treatment of vasospasm associated with specific management founded on pathophysiology of SAH has improved patients outcome.     

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.     

Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH. A preliminary report

Nimodipine was given as an intracarotid slow bolus injection in six patients with subarachnoid hemorrhage (SAH) due to rupture of a cerebral aneurysm, with angiographically demonstrated vasospasm. The patients were followed by serial angiograms for demonstration of the effect of nimodipine on vasospasm. After angiography, all patients were treated with a constant venous infusion of this new calcium antagonist. Although the therapeutic regimen was started only a few hours after onset of vasospasm, there was no change in cerebral vessel caliber detectable on angiograms following the intracarotid injection. Three patients died, two patients finally recovered with neurological deficits due to cerebral ischemia, and one patient with asymptomatic vasospasm remained symptom-free. Although nimodipine may act to prevent cerebral vasospasm after SAH, the authors believe that the intracarotid application is not effective after vasospasm has occurred.     

Evaluation of cerebral vasospasm in patients with subarachnoid hemorrhage using single photon emission computed tomography

Cerebral vasospasm (CVS) occurs as a result of the breakdown in cerebral autoregulation mechanisms. Because cerebral vasospasm can occur after subrachnoid hemorrhage (SAH), it is important to evaluate borderline perfusion. Evaluation of borderline vascular insufficiency is important to reduce ischemic complications. In this study 25 patients with SAH were investigated by somatosensory evoked potentials (SEP), computed tomography (CT), digital subtraction angiography (DSA) and single photon emission computed tomography (SPECT) in order to predict borderline ischemic areas. Clinical grades were also correlated with these investigations. Thirteen patients had symptomatic vasospasm and 15 patients had angiographic vasospasm. SPECT showed hypoperfusion in 22 out of 25 patients. CT predicted CVS in 8 of these 22 patients. Our study shows that brain perfusion SPECT is a non-traumatic, non-invasive, non-allergic, inexpensive method for the prediction of cerebral vasospasm. We conclude that brain SPECT with Tc-99m HM-PAO is an accessible technique that can demonstrate varying degrees of regional tissue hypoperfusion in patients with delayed ischemic deficits due to CVS following SAH.     

Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings.

Thirty patients admitted after suffering closed head injuries, with Glasgow Coma Scale scores ranging from 3 to 15, were evaluated with transcranial Doppler ultrasound monitoring. Blood flow velocity was determined in the middle cerebral artery (MCA) and the intracranial portion of the internal carotid artery (ICA) in all patients. Because proximal flow in the extracranial ICA declines in velocity when arterial narrowing becomes hemodynamically significant, the extracranial ICA velocity was concurrently monitored in 19 patients. To assess cerebral perfusion, cerebral blood flow (CBF) measurements obtained with the intravenous 133Xe technique were completed in 16 patients. Vasospasm, designated as MCA velocity exceeding 120 cm/sec, was found in eight patients (26.7%). Severe vasospasm, defined as MCA velocity greater than 200 cm/sec, occurred in three patients, and was confirmed by angiography in all three. Subarachnoid hemorrhage (SAH) was documented by computerized tomography in five (62.5%) of the eight patients with vasospasm. All cases of severe vasospasm were associated with subarachnoid blood. The time course of vasospasm in patients with traumatic SAH was similar to that found in patients with aneurysmal SAH; in contrast, arterial spasm not associated with SAH demonstrated an uncharacteristically short duration (mean 1.25 days), suggesting that this may be a different type of spasm. A significant correlation (p less than 0.05) was identified between the lowest CBF and highest MCA velocity in patients during the period of vasospasm, indicating that arterial narrowing can lead to impaired CBF. Ischemic brain damage was found in one patient who had evidence of cerebral infarction in the territories supplied by the arteries affected by spasm. These findings demonstrate that delayed cerebral arterial spasm is a frequent complication of closed head injury and that the severity of spasm is, in some cases, comparable to that seen in aneurysmal SAH. This experience suggests that vasospasm is an important secondary posttraumatic insult that is potentially treatable.     

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.     

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.

OBJECT: Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH. METHODS: To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated because no differences in the incidence of untoward medical events were noted between the two groups. Medical and surgical interventions were no different in the two treatment groups except for hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution), which was more often used in the placebo-treated group to counteract symptomatic vasospasm (24% of patients given placebo compared with 18% of patients given tirilazad, p = 0.02). Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients given tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal significant differences in outcome, although a trend toward a lower mortality rate favoring the study drug was present in patients with neurological Grade IV and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in 33.7% of the placebo-treated patients as opposed to 24.8% of the patients who were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also attenuated by administration of the study drug (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 6% of patients in the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the tirilazad-treated group (p < 0.04). CONCLUSIONS: The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. The use of other potentially effective rescue therapies (that is, hypervolemia, hemodilution, and induced hypertension) to counteract vasospasm may have been responsible for these contrasting observations between the two groups.     

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.

OBJECT: To test the safety and efficacy of high-dose (15 mg/kg/day) tirilazad mesylate in women suffering from aneurysmal subarachnoid hemorrhage (SAH), a prospective randomized, double-blind, vehicle-controlled trial (parallel to the one conducted in Europe, Australia, New Zealand, and South Africa) was performed at 65 North American neurosurgical centers. METHODS: Of the 832 patients who were randomized, 823 received at least one dose of tirilazad (410 patients) or placebo vehicle containing citrate (413 patients). The two groups were similar with respect to their prognostic factors for overall outcome and delayed cerebral ischemia. There were no differences in medical and surgical interventions including hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution) between the two treatment groups. In contrast to the accompanying study, the protocol for the North American study was formally amended, in that a sequential analysis of the primary efficacy end point, mortality rate at 91 days postdosing, was performed. This analysis revealed a statistically significant difference in mortality rates, favoring the study drug, among patients who were neurological Grade IV or V at admission (24.6% compared with 43.4% in the placebo-treated group, p = 0.016). No significant differences, however. were found when the entire patient population was considered (15.6% in the placebo-treated group and 13% in the tirilazad-treated group). Other major and secondary end points, which included rate of favorable outcome (74% in the placebo-treated group and 71% in the tirilazad-treated group); symptomatic vasospasm (38% in the placebo-treated group and 35% in the tirilazad-treated group); and vasospasm severity (severe symptomatic vasospasm in 14% of patients in both groups), were also not significantly different between the two groups. In patients with neurological Grades I through III, rates of favorable outcome advantageous to the vehicle-treated group were observed (83.3% compared with 76.7%, p = 0.04). CONCLUSIONS: High-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Sequential analysis revealed a significant reduction in mortality rates among patients with neurological Grades IV and V, favoring the study drug and confirming the same effect observed in male patients in previous large studies. No beneficial effect was observed in patients who were in a good neurological grade at admission.     

Management morbidity and mortality of poor-grade aneurysm patients

Preliminary experience with the occasional good survival of patients in Hunt and Hess Grade IV or V with aneurysmal subarachnoid hemorrhage (SAH) led to a prospective management protocol employed during a 2 1/2-year period. The protocol utilized computerized tomography (CT) scanning to diagnose SAH and to obtain evidence for irreversible brain destruction, consisting of massive cerebral infarction with midline shift or dominant basal ganglia or brain-stem hematoma. These patients, along with those who exhibited poor or absent intracranial filling on CT or angiography, were excluded from active treatment and given supportive care only. All other patients had immediate ventriculostomy placement and, if intracranial pressure (ICP) was controllable (less than or equal to 30 cm H2O without an intracranial clot or less than or equal to 50 cm H2O in the presence of a clot), went on to have craniotomy for aneurysm clipping. Aggressive postoperative hypertensive, hypervolemic, hemodilutional therapy was subsequently employed. Of 54 patients with poor-grade aneurysms, ventriculostomy was placed in 47 (87.0%) and yielded high ICP's in the overwhelming majority, with the mean ICP being 40.2 cm H2O. Nineteen poor-grade aneurysm patients received no surgical treatment and survived a mean of 31.8 hours with 100% mortality. Thirty-five patients underwent placement of a ventriculostomy, craniotomy for aneurysm clipping and intracranial clot evacuation, and postoperative hypertensive, hypervolemic, hemodilutional therapy. The outcome at 3 months of the 35 patients who were selected for active treatment was good in 19 (54.3%), fair in four (11.4%), poor in four (11.4%), and death in eight (22.9%). It is concluded that poor-grade aneurysm patients usually present with intracranial hypertension, even those without an intracranial clot. Based on radiographic rather than neurological criteria, a portion of these patients can be selected for active and successful treatment. Increased ICP can be present without ventriculomegaly, and immediate ventriculostomy should be performed. As long as ICP is controllable, craniotomy and postoperative intensive care can effect a favorable outcome in a significant percentage of these patients.     

Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage

OBJECT: Ischemia due to vasospasm is a feared complication in patients following aneurysmal subarachnoid hemorrhage (SAH). Cerebral online microdialysis monitoring may detect the metabolic changes in the extracellular fluid associated with ischemia. The aims of the present study were to correlate clinical course, microdialysis-recorded data, transcranial Doppler (TCD) ultrasonography findings, and angiographic findings in patients with SAH. METHODS: In 60 patients a microdialysis catheter was inserted into the brain parenchyma that is most likely to be affected by vasospasm directly after aneurysm clipping. Hourly analyses of glucose, pyruvate, lactate, and glutamate levels were performed using a bedside device. Blood-flow velocities were obtained using serial TCD measurements. Cerebral angiography was routinely performed on Day 7 after aneurysm clipping or earlier in cases of clinical deterioration (30 patients). In all patients the results of microdialysis monitoring, TCD ultrasonography, and angiography were correlated. The mean duration of monitoring was 7.3+/-2.5 days. In patients with acute ischemic neurological deficits (18 patients) immediate microdialysis-recorded alterations were observed if the probe was placed close to the malperfused region. In 13 of 15 patients with symptomatic vasospasm (delayed ischemic neurological deficit [DIND]), the microdialysis-recorded values revealed secondary deterioration. In terms of confirming DIND, microdialysis had the highest specificity (0.89, 95% confidence interval [CI] 0.78-1) compared with TCD ultrasonography (0.63, 95% CI 0.46-0.8) and angiography (0.53, 95% CI 0.35-0.7). For microdialysis, the positive likelihood ratio was 7.8, whereas this was significantly lower for TCD ultrasonography (1.7) and angiography (2.1). CONCLUSIONS: Although angiography also demonstrates vessel narrowing in asymptomatic patients, online microdialysis reveals characteristic metabolic changes that occur during vasospasm. Thus, online microdialysis may be used to confirm the diagnosis of vasospasm.     

Cerebral hemodynamic impairment after aneurysmal subarachnoid hemorrhage as evaluated using transcranial doppler ultrasonography: relationship to delayed cerebral ischemia and clinical outcome

OBJECT: In this study the authors evaluated the relative role of cerebral hemodynamic impairment (HDI) in the pathogenesis of delayed cerebral ischemia and poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Cerebral hemodynamics were assessed daily with transcranial Doppler (TCD) ultrasonography in 55 consecutive patients with verified SAH. Hemodynamic impairment was defined as blood flow velocity (BFV) values consistent with vasospasm in conjunction with impaired autoregulatory vasodilation as evaluated using the transient hyperemic response tests in the middle cerebral arteries. A total of 1344 TCD examinations were performed, in which the evaluation of HDI was feasible during 80.9% and HDI was registered during 12% of the examinations. It was found that HDI occurred in 60% of patients and was frequently recorded in conjunction with severe vasospasm (p < 0.05) and a rapid increase of BFV values (p < 0.05). Detection of HDI was closely associated with the development of delayed ischemic brain damage after SAH (p < 0.05). Furthermore, because delayed ischemia was never observed in cases in which vasospasm had not led to the development of HDI, its occurrence increased significantly the likelihood of subsequent cerebral ischemia among the patients with vasospasm (p < 0.05). Detection of HDI was independently related to unfavorable clinical outcome according to Glasgow Outcome Scale at 6 months after SAH (p < 0.05). CONCLUSIONS: The results showed that HDI is common after SAH and can be evaluated with TCD ultrasonography in routine clinical practice. Detection of HDI could be useful for identifying patients at high or low risk for delayed ischemic complications and unfavorable clinical outcome after SAH.