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Giuseppe Lanzino, Neal F. Kassell, Teresa P. Germanson, Gail L. Kongable, Laura L. Truskowski, James C. Torner, John A. Jane, and Participants

✓ Advanced age is a recognized prognostic indicator of poor outcome after subarachnoid hemorrhage (SAH). The relationship of age to other prognostic factors and outcome was evaluated using data from the multicenter randomized trial of nicardipine in SAH conducted in 21 neurosurgical centers in North America. Among the 906 patients who were studied, five different age groups were considered: 40 years or less, 41 to 50, 51 to 60, 61 to 70, and more than 71 years. Twenty-three percent of the individuals enrolled were older than 60 years of age. Women outnumbered men in all age groups.

Level of consciousness (p = 0.0002) and World Federation of Neurological Surgeons grade (p = 0.0001) at admission worsened with advancing age. Age was also related to the presence of a thick subarachnoid clot (p = 0.0001), intraventricular hemorrhage (p = 0.0003), and hydrocephalus (p = 0.0001) on an admission computerized tomography scan. The rebleeding rate increased from 4.5% in the youngest age group to 16.4% in patients more than 70 years of age (p = 0.002). As expected, preexisting medical conditions, such as diabetes (p = 0.028), hypertension (p = 0.0001), and pulmonary (p = 0.0084), myocardial (p = 0.0001), and cerebrovascular diseases (p = 0.0001), were positively associated with age. There were no age-related differences in the day of admission following SAH, timing of the surgery and/or location, and size (small vs. large) of the ruptured aneurysm.

During the treatment period, the incidence of severe complications (that is, those complications considered life threatening by the reporting investigator) increased with advancing age, occurring in 28%, 33%, 36%, 40%, and 46% of the patients in each advancing age group, respectively (p = 0.0002). No differences were observed in the reported frequency of surgical complications. No age-related differences were found in the overall incidence of angiographic vasospasm; however, symptomatic vasospasm was more frequently reported in the older age groups (p = 0.01). Overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, was poorer with advancing age (p < 0.001). Multivariate analysis of overall outcome, adjusting for the different prognostic factors, did not remove the age effect, which suggests that the aging brain has a less optimal response to the initial bleeding. Age as a risk factor is a continuum; however, there seems to be a significant increased risk of poor outcome after the age of 60 years.

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Gail L. Kongable, Giuseppe Lanzino, Teresa P. Germanson, Laura L. Truskowski, Wayne M. Alves, James C. Torner, Neal F. Kassell, and the Participants

✓ Female gender is a recognized risk factor for the occurrence of aneurysmal subarachnoid hemorrhage. In the present study the authors analyzed differences in admission characteristics and outcome between 578 women (64%) and 328 men (36%) who were enrolled in a recently completed clinical trial. The female-to-male ratio was nearly 2:1. The women in the study were older than the men (mean age 51.4 years vs. 47.3 years, respectively, p < 0.001). Female patients harbored aneurysms of the internal carotid artery more frequently than male patients (36.8% vs. 18.0%, p < 0.001) and more often had multiple aneurysms (32.4% vs. 17.6%, p < 0.001). On the other hand, anterior cerebral artery aneurysms were more commonly encountered in men (46.1% in men vs. 26.6% in women, p < 0.001). Other baseline prognostic factors were balanced between the gender groups. Surgery was performed equally in both sexes (98%), although the time to operation was shorter for women (mean 3.6 days for women vs. 5.3 days for men, p = 0.0002). In the placebo group, the occurrence of vasospasm was not statistically different between the two groups. Primary causes of death and disability were the same, and favorable outcome rates at 3 months were not statistically different between the genders (69.7% for women vs. 73.4% for men, p = 0.243). The odds of a favorable outcome in women versus one in men were not statistically significant either before or after adjustment for age. These observations lead the authors to suggest that although women are older and harbor more aneurysms, the 3-month outcome for women and men who experience aneurysmal subarachnoid hemorrhage is the same.

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E. Clarke Haley Jr., Neal F. Kassell, James C. Torner, Laura L. Truskowski, Teresa P. Germanson, and the Participants

✓ High-dose intravenous nicardipine has been shown to reduce the incidence of angiographic and symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH), but treatment may be complicated by side effects, including hypotension or pulmonary edema/azotemia. From August, 1989, to January, 1991, 365 patients at 21 neurosurgical centers were entered into a randomized double-blind trial comparing high-dose (0.15 mg/kg/hr) nicardipine with a 50% lower dose (0.075 mg/kg/hr) administered by continuous intravenous infusion for up to 14 days following SAH. Patients in all neurological grades were eligible for the study.

During the study period, 184 patients were randomly assigned to receive high-dose nicardipine and 181 to receive the low dose. There were no significant differences in patient age, admission neurological condition, or amount and distribution of blood clot on initial computerized tomography scan. Patients in the high-dose group received a significantly smaller proportion of the planned dose than those in the low-dose group (80% ± 0.2% vs. 86% ± 0.2%, p < 0.05), largely because of premature treatment termination after adverse medical events. The incidence of symptomatic vasospasm was 31% in both groups, and the overall 3-month outcomes were nearly identical. These data suggest that, from a clinical standpoint, the results of high-dose and low-dose nicardipine treatment are virtually equivalent, but administration of low-dose nicardipine is attended by fewer side effects.

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E. Clarke Haley Jr., Neal F. Kassell, James C. Torner, and Participants

✓ Because of their action as cerebral vasodilators, dihydropyridine calcium antagonists have received intense scrutiny for their potential benefit in ameliorating the devastating consequences of delayed cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). From October, 1987, to September, 1989, 41 North American neurosurgical centers in the Cooperative Aneurysm Study accrued 906 patients with recent (Days 0 to 7) aneurysmal SAH into a prospective randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine to test whether treatment with this agent improved overall outcome. Eligible patients received 0.15 mg/kg/hr of either nicardipine or placebo by continuous infusion for up to 14 days following hemorrhage. The 449 patients randomly assigned to the nicardipine-treated group and the 457 patients assigned to the placebo-treated group were balanced with regard to prognostic factors for ischemic deficits from vasospasm and for overall outcome. Other medical and surgical interventions were used with similar frequency in both groups, except that antihypertensive agents were used less frequently in the nicardipine-treated patients (26% of the nicardipine-treated group vs. 43% of the placebo-treated group, p < 0.001), and more patients in the placebo-treated group had intentional hypervolemia, induced hypertension, and/or hemodilution administered therapeutically for symptomatic vasospasm (38% of the placebo-treated group vs. 25% of the nicardipine-treated group, p < 0.001). The incidence of symptomatic vasospasm during the treatment period was higher in the placebo-treated group (46%) than in the nicardipine-treated group (32%) (p < 0.001). Despite the reduction in symptomatic vasospasm in the nicardipine-treated group, overall outcome at 3 months was similar between the two groups. Fifty-five percent of nicardipine-treated patients were rated as having a good recovery according to the Glasgow Outcome Scale at follow-up review and 17% were dead, compared to 56% and 18%, respectively, in the placebo-treated group (not statistically significant).

These data suggest that high-dose intravenous nicardipine treatment is associated with a reduced incidence of symptomatic vasospasm in patients with recent aneurysmal SAH, but not with an improvement in overall outcome at 3 months when compared to standard management in North America. It is postulated that, while nicardipine prevents vasospasm, hypertensive/hypervolemic therapy may be effective in reversing ischemic deficits from vasospasm once they occur.

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E. Clarke Haley Jr., Neal F. Kassell, James C. Torner, and Participants

✓ Calcium antagonist drugs were proposed for use in patients with recent aneurysmal subarachnoid hemorrhage (SAH) because of their ability to block the effects of a wide variety of vasoconstrictor substances on cerebral arteries in vitro. It was suggested that these agents might, therefore, be useful in ameliorating cerebral vasospasm and its ischemic consequences which frequently complicate SAH. This hypothesis was tested in an arm of a randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine in patients with recently ruptured aneurysms. Participating investigators were required to send selected copies of all admission and follow-up angiograms obtained between Days 7 and 11 following hemorrhage (the peak period of risk for vasospasm) to the Central Registry of the Cooperative Aneurysm Study for blinded interpretation and review for the presence and severity of angiographic vasospasm. In centers with transcranial Doppler ultrasound (TCD) capabilities, middle cerebral artery (MCA) mean flow velocities were measured and recorded.

Angiograms obtained between Days 7 and 11 were available for 103 (23%) of 449 patients receiving nicardipine and 121 (26%) of 457 receiving placebo. There was a balance of prognostic factors for vasospasm between the groups. Fifty-one percent of placebo-treated patients had moderate or severe vasospasm on “Day 7–11 angiograms” compared to 33% of nicardipine-treated patients. This difference is statistically significant (p < 0.01). Sixty-seven (49%) of 137 placebo-treated patients examined with TCD between Days 7 and 11 had mean MCA flow velocities exceeding 120 cm/sec compared to 26 (23%) of 112 nicardipine-treated patients (significant difference, p < 0.001). These data suggest that high-dose intravenous nicardipine reduces the incidence and severity of delayed cerebral arterial narrowing in patients following aneurysmal SAH.

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Neal F. Kassell, James C. Torner, John A. Jane, E. Clarke Haley Jr., Harold P. Adams, and participants

✓ A prospective, observational clinical trial was conducted by the International Cooperative Study on the Timing of Aneurysm Surgery to determine the best time in relation to the hemorrhage for surgical treatment of ruptured intracranial aneurysms. Sixty-eight centers contributed 3521 patients in a 2½-year period beginning in December, 1980. Analysis by a prespecified “planned” surgery interval demonstrated that there was no difference in early (0 to 3 days after the bleed) or late surgery (11 to 14 days). Outcome was worse if surgery was performed in the 7 to 10-day post-bleed interval. Surgical results were better for patients operated on after 10 days. Patients alert on admission fared best; however, alert patients had a mortality rate of 10% to 12% when undergoing surgery prior to Day 11 compared with 3% to 5% when surgery was performed after Day 10. Patients drowsy on admission had a 21% to 25% mortality rate when operated on up to Day 11 and 7% to 10% with surgery thereafter. Overall, early surgery was neither more hazardous nor beneficial than delayed surgery. The postoperative risk following early surgery is equivalent to the risk of rebleeding and vasospasm in patients waiting for delayed surgery.

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Neal F. Kassell, James C. Torner, E. Clarke Haley Jr., John A. Jane, Harold P. Adams, Gail L. Kongable, and Participants

✓ The International Cooperative Study on the Timing of Aneurysm Surgery evaluated the results of surgical and medical management in 3521 patients between December, 1980, and July, 1983. At admission, 75% of patients were in good neurological condition and surgery was performed in 83%. At the 6-month evaluation, 26% of the patients had died and 58% exhibited a complete recovery. Vasospasm and rebleeding were the leading causes of morbidity and mortality in addition to the initial bleed. Predictors for mortality included the patient's decreased level of consciousness and increased age, thickness of the subarachnoid hemorrhage clot on computerized tomography, elevated blood pressure, preexisting medical illnesses, and basilar aneurysms. The results presented here document the status of management in the 1980's.

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Tadayoshi Nakagomi, Kazuhiro Hongo, Neal F. Kassell, Tomio Sasaki, R. Michael Lehman, Hisayuki Ogawa, Dennis G. Vollmer, and James C. Torner

✓ Endothelium-dependent relaxation was induced by acetylcholine (ACh), adenosine triphosphate (ATP), and thrombin in isolated cerebral and extracerebral arteries obtained from rabbits and dogs. Using an isometric tension-recording method, the authors then examined the difference in the extent of relaxation between the cerebral and extracerebral arteries. In rabbits, the dose-response curve of the basilar artery for ACh was significantly different (p < 0.05) from curves of the femoral and common carotid arteries. The IC50 value (the concentration inducing a one-half inhibition of the initial contractile tone) for the basilar artery in ACh-induced relaxation was significantly higher (p < 0.05) than for the common carotid artery, although the mean maximum relaxation of the basilar artery to ACh was not significantly different from that seen in extracerebral arteries. The relaxing effect of ACh in dogs was much less in the middle cerebral and basilar arteries than in the common carotid, vertebral, and femoral arteries. On the other hand, both ATP (in rabbits and dogs) and thrombin (in dogs) induced significantly more (p < 0.05) relaxation in the cerebral arteries than in the extracerebral arteries.

Endothelium-dependent relaxation induced by ACh or ATP has been demonstrated in a wide range of arteries from a variety of animals. The present results suggest that ATP has a more important role than ACh in the regulation of the vascular tone of the major cerebral arteries in these two species.

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Tadayoshi Nakagomi, Neal F. Kassell, Tomio Sasaki, R. Michael Lehman, James C. Torner, Kazuhiro Hongo, and Joung H. Lee

✓ The effect of endothelium removal on the contractile responses to KCl, hemoglobin, serotonin (5-HT), norepinephrine (NE), prostaglandin (PG)F2α, PGD2, and PGE2 was investigated in canine and rabbit basilar arteries by an isometric tension-recording method. In canine basilar arteries, endothelium removal elevated the dose-response curves to 5-HT, PGF2α, and PGD2, and PGE2, but not to KCl, hemoglobin, or NE. In rabbit basilar arteries, on the other hand, removal of the endothelium elevated the dose-response curves to 5-HT, NE, PGF2α, and PGD2, but not to KCl or hemoglobin. Neither contractile nor inhibitory response was elicited by PGE2 in rabbit basilar arteries. Contraction induced by 5-HT and NE following endothelium removal had a much more pronounced effect in rabbit basilar arteries than in canine basilar arteries.

These results suggest that, following endothelium removal, abolition of the spontaneous release of endothelium-derived relaxing factor is the most probable mechanism of the enhanced vasocontraction. Since endothelial damage results from subarachnoid hemorrhage, the aforementioned mechanism of vasocontractile enhancement may play a role in the pathogenesis of cerebral vasospasm.

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Tadayoshi Nakagomi, Neal F. Kassell, Tomio Sasaki, Shigeru Fujiwara, R. Michael Lehman, Hiroo Johshita, and James C. Torner

✓ The purpose of this experiment was to evaluate the effect of hypoxia on the in vitro contractile responses of canine basilar artery to KCl, prostaglandin (PG) F2α, and hemoglobin. Hypoxia was induced by changing the bubbling gas mixture in the chamber from 95% O2/5% CO2 to 95% N2/5% CO2. Hypoxia augmented the contractile response developed at 95% O2 to 25 mM and 50 mM KCl, 3 × 10−7 M and 10−5 M PGF2α, and 10−6 M hemoglobin. No significant alteration of the hypoxic augmentation in any preparation exposed to 25 mM KCl, 3 × 10−7 M PGF2α, or 10−6 M hemoglobin was observed with guanethidine (10−5 M), prazosin (10−5 M), methysergide (10−5 M), or diphenhydramine (10−5 M).

Endothelial denudation did not affect hypoxic augmentation. Hypoxia did not cause any alteration of the contractile response to 10−6 M PGF2α in Ca++-free media. Pretreatment with a calcium channel blocker, nicardipine, significantly inhibited the hypoxic potentiation of the contractile response to 25 mM KCl, 3 × 10−7 M PGF2α, and 10−6 M hemoglobin.

These results suggest that hypoxia augments the contractile response to these agonists by a direct action on the smooth-muscle cells, facilitating the transmembrane influx of extracellular calcium. Hypoxia of smooth-muscle cells in the major cerebral arteries might be involved in the pathogenesis of vasospasm.