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Satoshi Suzuki, Katsunobu Takenaka, Neal F. Kassell, and Kevin S. Lee

✓ The roles of hemoglobin (Hb) in the pathogenesis of cerebral vasospasm remain a matter of discussion. Hemoglobin is known to be released from extravasated red blood cells in a variety of pathological conditions, including subarachnoid hemorrhage. These conditions are often accompanied by infiltration of inflammatory cells and an associated release of multiple cytokines. Certain of these cytokines, including interleukin-1β (IL-1β), are capable of increasing nitric oxide (NO) production via the inducible form of nitric oxide synthase (NOS), and excessive NO production under these conditions may contribute to cellular dysfunction. This study further examines these questions by investigating the effects of Hb on the induction of NOS by IL-1β.

The effects of Hb on IL-1β-induced NO production were examined in cultured smooth-muscle cells of rat aorta (RA-SMC's). Production of NO was estimated from the accumulation of nitrite, an oxidative product of NO, in the culture medium. The synthesis of NO was induced by IL-1β in a concentration-dependent manner. This activation of NO production was inhibited by: 1) a general inhibitor of NOS (Nω-nitro-L-arginine); 2) a protein synthesis inhibitor (cycloheximide); and 3) two selective inhibitors of the inducible form of NOS (hydrocortisone and aminoguanidine). These results suggest that IL-1β promotes the expression of the inducible form of NOS in RA-SMC's. The effects of Hb on NO production were tested by adding purified human Hb to the culture medium of the cells in both the presence and absence of IL-1β. Nitrite accumulation was slightly but significantly increased by Hb in the absence of IL-1β. In contrast, Hb markedly augmented nitrite accumulation induced by IL-1β. This augmentation persisted even after the removal of Hb from the culture medium. The number of cells was not affected by Hb or IL-1β.

The findings demonstrate that Hb can modify cytokine-induced production of NO in RA-SMC's by increasing the inducible form of NOS. These observations suggest that Hb can also modify the action of inflammatory cells by facilitating NO production in target cells.

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Yongcheng Jin, Oren Sagher, Quoc-Anh Thai, Neal F. Kassell, and Kevin S. Lee

✓ Papaverine (PPV) is a nonspecific vasodilator with widespread clinical uses in the treatment of arterial spasm. It has also been utilized in an attempt to reverse cerebral vasospasm. Recent angiographic results have demonstrated significant reversal of vasospasm in large vessels after selective intra-arterial application of PPV; however, these impressive results lacked good clinical correlation. In this study, phorbol dibutyrate was used to stimulate protein kinase C in an in vitro model of cerebral microvessels. Papaverine was found to elicit a dose-dependent exacerbation of phorbol dibutyrate-induced microvascular constriction in this model system. Because protein kinase C is thought to play a key role in the development of cerebral vasospasm, PPV-induced vasoconstriction represents a potentially important deleterious effect that may not be apparent on angiography. Such a constrictor response may compromise the beneficial vasodilatory effect seen with intra-arterial injection of PPV.

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Toshiki Aoki, Katsunobu Takenaka, Satoshi Suzuki, Neal F. Kassell, Oren Sagher, and Kevin S. Lee

✓ The importance of factors within hemolysate in modulating oxyhemoglobin (oxyHb)-induced contraction was examined in an in vitro model of rabbit basilar arteries. When the basilar arteries were exposed to purified oxyHb alone, the contractile response observed was significantly weaker than that seen in arteries exposed to hemolysate containing an equal concentration of oxyHb. In order to delineate the nature of the factors within hemolysate that facilitate contraction, hemolysate was fractionated, and various components were tested individually for their ability to elicit this effect. A low-molecular-weight fraction of hemolysate, ranging from 0.5 to 2.0 kD, elicited only a mild contraction. However, when this fraction was combined with purified oxyHb, the contractile response was comparable in magnitude to that of unfractionated hemolysate. These studies confirm that purified oxyHb is capable of inducing contraction in vitro. The data also demonstrate that oxyHb elicits a significantly weaker contraction than does hemolysate. In addition, the results suggest that low-molecular-weight components in hemolysate (in the 0.5- to 2.0-kD range), while incapable of inducing a potent contraction alone, may act in concert with oxyHb to elicit the vasoconstriction seen following subarachnoid hemorrhage.

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Patricia L. Foley, Katsunobu Takenaka, Neal F. Kassell, and Kevin S. Lee

✓ The release of intracellular products from lysed blood cells is believed to play a critical role in the etiology of vascular pathology following intracerebral hemorrhage. The present studies investigated the effects of a mixture of blood and cerebrospinal fluid (CSF) on bovine intracranial endothelial cells maintained in culture. The incorporation of 3H-leucine into endothelial cells was used as an index of cellular viability. Cerebrospinal fluid alone did not alter the incorporation of 3H-leucine into the cells. In contrast, CSF preincubated with blood for 3 days or longer prior to treatment elicited significant reductions in leucine incorporation. Treatment with CSF preincubated with blood for 5 to 7 days resulted in the rapid deterioration of the culture, with large numbers of cells detaching almost immediately. Concentrations of hemoglobin were elevated profoundly in mixtures of blood and CSF preincubated for periods longer than 3 days. The increases in hemoglobin concentration were related temporally to increases in the cytotoxic impact of the bloody CSF.

These findings suggest that factors released during the breakdown of blood exert a deleterious effect on intracranial endothelial cells. The time course of this effect is closely related to the development of vasospasm in humans following subarachnoid hemorrhage. Taken together, these observations are consistent with the hypothesis that intracellular blood products, particularly hemoglobin, contribute to vasospasm by directly compromising endothelial function.

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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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Giuseppe Lanzino, Neal F. Kassell, Teresa Germanson, Laura Truskowski, and Wayne Alves

✓ Plasma glucose levels were studied in 616 patients admitted within 72 hours after subarachnoid hemorrhage (SAH). Glucose levels measured at admission showed a statistically significant association with Glasgow Coma Scale scores, Botterell grade, deposition of blood on computerized tomography (CT) scans, and level of consciousness at admission. Elevated glucose levels at admission predicted poor outcome. A good recovery, as assessed by the Glasgow Outcome Scale at 3 months, occurred in 70.2% of patients with normal glucose levels (≤ 120 mg/dl) and in 53.7% of patients with hyperglycemia (> 120 mg/dl) (p = 0.002). The death rates for these two groups were 6.7% and 19.9%, respectively (p = 0.001). The association was still maintained after adjusting for age (> or ≤ 50 years) and thickness of clot on CT scans (thin or thick) in the subset of patients who were alert/drowsy at admission. Increased mean glucose levels between Days 3 and 7 also predicted a worse outcome; good recovery was observed in 132 (73.7%) of 179 patients who had normal mean glucose levels (≤ 120 mg/dl) and 160 (49.7%) of 322 who had elevated mean glucose levels (> 120 mg/dl) (p < 0.0001). Death occurred in 6.7% and 20.8% of the two groups, respectively (p < 0.0001). It is concluded that admission plasma glucose levels can serve as an objective prognostic indicator after SAH. Elevated glucose levels during the 1st week after SAH also predict a poor outcome. However, a causal link between hyperglycemia and outcome after delayed cerebral ischemia, although suggested by experimental data, cannot be established on the basis of this study.

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Gregory A. Helm, Nathan E. Simmons, Charles G. diPierro, and Neal F. Kassell

✓ Several types of adjustable clamp have been widely utilized to gradually occlude the carotid artery for the treatment of various intracranial vascular lesions. A fairly large number of patients, many of whom have not been adequately followed, have these clamps still in place. The authors report two patients, initially treated with a Crutchfield clamp for an intracranial aneurysm, in whom carotid artery system revascularization occurred through the clamp many years later, leading to continued filling of the aneurysm. Recommendations are given on monitoring patients with Crutchfield clamps in order to minimize long-term complications.