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Biomedical subjects

N F Kassell

Publications and source records attributed to N F Kassell.

At least 19 recordsLinked to original sources
PubMed1999

Posterior inferior cerebellar artery aneurysms associated with posterior fossa arteriovenous malformation: report of five cases and literature review.

BACKGROUND: The association of posterior inferior cerebellar artery (PICA) aneurysms with posterior fossa arteriovenous malformation (AVM) is uncommon. Over the past 3 years, five patients with this condition were treated at this institution. A review of the clinical history of these and other reported cases has illuminated common threads in the presentation, treatment, and outcome of these lesions. METHODS: The findings of 27 patients (5 from our institution and 22 from the medical literature) with PICA aneurysms associated with AVMs were reviewed. RESULTS: Eighty-four percent of individuals presented with sub-arachnoid hemorrhage (SAH); 89% of these episodes resulted from aneurysm rupture documented by either intraoperative inspection or autopsy. All aneurysms were located on a feeding artery to the AVM, and 81% originated from distal portions of PICA. The majority of patients presented with Hunt & Hess grade I SAH; all patients who presented with hemorrhage were treated surgically. Surgical strategy was directed both to secure the aneurysm and to resect the AVM during the course of a single procedure. Although four individuals either died on admission or in the perioperative period, overall outcome was excellent or good in 82% of patients. CONCLUSIONS: PICA aneurysms associated with AVMs most often involve the distal segments of the artery. Patients usually present with SAH secondary to aneurysmal rupture. Surgical clipping of the aneurysm and excision of the AVM is possible in a single procedure with minimal morbidity. Overall prognosis is favorable in 80% of the cases.

Adult↗
PubMed1999

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.

Dose-Response Relationship, Drug↗
PubMed1999

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.

Dose-Response Relationship, Drug↗
PubMed1998

Risk classification after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Prediction of patient outcome is an important aspect of the management and study of aneurysmal subarachnoid hemorrhage (SAH). In the present study, we evaluated the prognostic value of two multivariate approaches to risk classification, Classification and Regression Trees (CART) and multiple logistic regression, and compared them with the best single predictor of outcome, level of consciousness. METHODS: Data prospectively collected in the first Cooperative Aneurysm Study of intravenous nicardipine after aneurysmal SAH (NICSAH I, n = 885) were used to develop the prediction models. Low-, medium-, and high-risk groups for unfavorable outcome were devised using CART and a stepwise logistic regression analysis. Admission factors incorporated into both classification schemes were: level of consciousness, age, location of aneurysm (basilar versus other), and the Glasgow Coma Score. The CART prediction tree also branched on a dichotomy of admission glucose level. The two multivariate classifications were then compared with a prediction scheme based on the single best performing prognostic factor, level of consciousness in an independent series, NICSAH II (n = 353), and also in the original training dataset. RESULTS: A similar discrimination of risk was achieved by the three classification systems in the testing sample (NICSAH II). The 8%, 19%, and 52% rates of unfavorable outcome obtained from low-, medium-, and high-risk groups defined by LOC approximated those obtained using the more complex multivariate systems. CONCLUSION: Although multivariate classification systems are useful to characterize the relationship of multiple risk factors to outcome, the simple clinical measure LOC is favored as a concise and practical classification for predicting the probability of unfavorable outcome after aneurysmal SAH.

Calcium Channel Blockers↗
PubMed1998

Attenuation of experimental subarachnoid hemorrhage-induced cerebral vasospasm by CGS 26303, an endothelin-converting enzyme inhibitor.

The effect of CGS 26303, an endothelin-converting enzyme inhibitor, on the prevention and reversal of cerebral vasospasm was investigated in a rabbit model of subarachnoid hemorrhage (SAH). In the prevention study, rabbits were injected with 3 ml of autologous blood in the cisterna magna and treatment with CGS 26303 i.v. was initiated 1 h later. The compound was subsequently administered at 12, 24, and 36 h post SAH and animals were sacrificed at 48 h post SAH. Treatment with CGS 26303 at 3, 10, and 30 mg/kg resulted in dose-dependent increases in the concentrations of the compound in cerebrospinal fluid samples, and the arterial narrowing after SAH was significantly attenuated in all three groups. Morphologically, corrugation of the internal elastic lamina of vessels was often observed in the vehicle-treated group, but it was not prominent in the CGS 26303-treated groups and the healthy controls. In the reversal study, treatment with CGS 26303 was initiated 24 h post SAH and a second injection was given 12 h later. Arterial narrowing was significantly attenuated in rabbits treated with CGS 26303 at 30 mg/kg. These results demonstrate that CGS 26303 may be an effective agent in prevention and reversal of cerebral vasospasm after aneurysmal SAH.

Animals↗
PubMed1998

Systemic administration of the potassium channel activator cromakalim attenuates cerebral vasospasm after experimental subarachnoid hemorrhage.

OBJECTIVE: Cerebral vasospasm is a primary complication after aneurysmal subarachnoid hemorrhage (SAH). Recent evidence indicates that the activation of potassium (K+) channels may be of benefit in relieving spastic constriction. The present study examined the effects of systemic administration of a K+ channel activator, cromakalim, on cerebral vasospasm after experimental SAH. METHODS: Experimental SAH was performed in rabbits by injecting autologous blood into the cisterna magna. Intravenous injections of cromakalim or vehicle were administered twice daily with the first injection administered 1 hour after induction of SAH. Animals were killed by perfusion-fixation 48 hours after SAH. Basilar arteries were removed and sectioned, and the luminal cross-sectional areas were measured. RESULTS: Experimental SAH induced cerebral vasospasm in untreated and vehicle-treated animals. Cromakalim attenuated cerebral vasospasm in a dose-dependent manner. This effect achieved statistical significance at doses of 0.1 and 0.3 mg/kg. CONCLUSION: These results support the concept that targeting vascular K+ channels can be of benefit in preventing the development of cerebral vasospasm. The findings also indicate that cromakalim represents a potential therapeutic agent for the treatment of cerebrovascular pathophysiology after SAH.

Animals↗
PubMed1998

Intra-arterially administered papaverine for the treatment of symptomatic cerebral vasospasm.

OBJECTIVE: We examined the therapeutic benefits of intra-arterially administered papaverine for treatment of symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH). Recent advances in microcatheter technology have facilitated endovascular approaches to vessels experiencing vasospasm after SAH. However, despite numerous encouraging anecdotal reports, no rigorous examination of the efficacy of these procedures has been published. Intra-arterial infusion of papaverine has become part of the standard management of vasospasm at some centers. METHODS: We examined a series of 31 patients undergoing papaverine infusion for the treatment of symptomatic vasospasm after SAH. The patients were a subgroup of the series enrolled in the North American Trial of Tirilizad for Aneurysmal Subarachnoid Hemorrhage. These individuals were matched with patients from the same trial who exhibited similar clinical characteristics (including the degree of vasospasm and the modified Glasgow Coma Scale scores measured at the time of admission and on the day of papaverine infusion) but received medical management alone for vasospasm. RESULTS: Logistic regression analysis comparing these two groups showed no statistical difference in the 3-month Glasgow Outcome Scale scores between patients receiving papaverine and control subjects (58% favorable outcomes for control subjects versus 45% for patients receiving papaverine). CONCLUSION: Although isolated series documenting clinical successes have prompted the increased use of papaverine as a treatment for vasospasm after SAH, this series suggests that, as it is currently being used, the drug does not provide added benefits, compared with medical treatment of vasospasm alone. This result does not preclude the possibility that alterations in the timing of or indications for drug treatment might produce beneficial effects.

Adult↗
PubMed1998

Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits.

BACKGROUND AND PURPOSE: Inflammatory responses have been implicated in the elaboration of several forms of central nervous system injury, including cerebral vasospasm after subarachnoid hemorrhage (SAH). A critical event participating in such responses is the recruitment of circulating leukocytes into the inflammatory site. Two of the key adhesion molecules responsible for the attachment of leukocytes to endothelial cells are intercellular adhesion molecule-1 (ICAM-1) and the common beta chain of the integrin superfamily (CD18). This study examined the effects of monoclonal antibodies on ICAM-1 and the effects of CD18 on cerebral vasospasm after SAH. METHODS: A rabbit model of SAH was utilized to test the influence of intracisternally administered antibodies to ICAM-1 and CD18 on cerebral vasospasm. Antibodies were administered alone or in combination, and the cross-sectional area of basilar arteries was assessed histologically on day 2 post-SAH. RESULTS: Treatment with antibodies to ICAM-1 or CD18 inhibited vasospasm by 22% and 27%, respectively. When administered together, the attenuation of vasospasm increased to 56%. All of these effects achieved statistical significance. CONCLUSIONS: These findings provide the first evidence that the severity of cerebral vasospasm can be attenuated using monoclonal antibodies against ICAM-1 and CD18. The results reinforce the concept that cell-mediated inflammation plays an important role in cerebral vasospasm after SAH and suggest that therapeutic targeting of cellular adhesion molecules can be of benefit in treating cerebral vasospasm.

Animals↗
PubMed1998

Enhanced endogenous antioxidant activity and inhibition of cerebral vasospasm in rabbits by pretreatment with a nontoxic endotoxin analog, monophosphoryl lipid A.

OBJECT: Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595. Monophosphoryl lipid A is relatively nontoxic and can stimulate the natural defense or immune system. Diphosphoryl lipid is relatively toxic; however, at higher concentrations, it can also stimulate an immune response. The purpose of the present study was to determine the effects of these endotoxin analogs on cerebral vasospasm after the onset of subarachnoid hemorrhage (SAH) in rabbits. METHODS: Intrathecal administration of MPL or DPL (5 microg/kg) was performed immediately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were killed by perfusion fixation for morphometric analyses of vessels or perfused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours later for assessment of SOD activity; no SAH was induced in these animals. Experimental SAH elicited spasm of the basilar arteries in each group. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals treated with DPL. A substantial reduction in SOD activity in the basilar artery accompanied the vasospasm; this loss of activity was significantly blocked by treatment with MPL, but not DPL. In animals that were not subjected to experimental SAH, MPL elicited a significant increase in SOD activity over basal levels, whereas DPL was ineffective. CONCLUSIONS: These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) responsible for the protective effect of MPL remains to be verified, an enhancement of basal antioxidant activity and an inhibition of SAH-induced loss of this activity are attractive candidates. An MPL-based therapy could represent a useful addition to current therapies for SAH-induced cerebral injury.

Adjuvants, Immunologic↗
PubMed1998

Cigarette smoking as a cause of aneurysmal subarachnoid hemorrhage and risk for vasospasm: a report of the Cooperative Aneurysm Study.

OBJECT: Cigarette smoking is associated with aneurysmal subarachnoid hemorrhage (SAH) and subsequent vasospasm. The purpose of this study was to quantify this association. METHODS: Nearly 3500 patients with SAH from North America and Europe have been enrolled in five different multicenter, controlled studies coordinated at the Neuroclinical Trials Center of the Virginia Neurological Institute at the University of Virginia. Among the prospective data gathered were whether the patient smoked at the time of their most recent SAH and the evolution of angiographic vasospasm. The rate of smoking in the patients enrolled in the studies was compared with the expected rate by using a chi-square statistic adjusted for age and gender, in the general population in the United States (U.S.) and Europe. In virtually all age and gender subgroups, and for the combined populations in the five clinical trials, patients with SAH reported current smoking rates 2.5 times higher than expected based on U.S. and European national surveys (p < 0.0001). Cigarette smoking was also associated with younger age at onset of SAH (5-10 years, p < 0.0001) and increased incidence of clinically confirmed vasospasm (p < 0.005). CONCLUSIONS: The findings of a significantly increased representation of current cigarette smokers in the study populations and significant association with younger age at the time of SAH and increased incidence of vasospasm concur with recent reports of smoking as a significant risk factor for ruptured aneurysms and subsequent vasospasm.

Adolescent↗
PubMed1998

Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage.

OBJECT: The goal of this study was to explore whether the levels of soluble adhesion molecules were elevated in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH). This association was suggested by the known inflammatory response in vasospasm and the role of vascular adhesion molecules in regulating leukocytic adhesion to, and migration across, vascular endothelium. METHODS: A prospective analysis was performed on CSF samples obtained in 17 patients who had suffered a recent aneurysmal SAH and in 16 control patients by using quantitative enzyme-linked immunosorbent assays for E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and L-selectin. Levels of soluble forms of E-selectin (p=0.0013), ICAM-1 (p=0.0001), and VCAM-1 (p=0.048) were found to be elevated in the CSF of patients after SAH compared with levels in the CSF of norminal controls, patients with unruptured aneurysms, and patients tested months after SAH occurred. In addition, individual patients tested at the time of their initial ictus demonstrated a fall in adhesion molecule levels over time. Levels of E-selectin (p=0.044) were highest in patients who later developed moderate or severe vasospasm. CONCLUSIONS: Adhesion molecules are known to be involved in white cell adherence to the endothelium and subsequent diapedesis and migration in which a role in initiation of tissue damage is postulated. The authors have demonstrated the elevation of three adhesion molecules, with severely elevated levels of E-selectin seen in patients who later develop vasospasm. A correlation with a role of vascular adhesion molecules in the pathogenesis of cerebral vasospasm is suggested.

Adult↗
PubMed1998

Surgical treatment of the ruptured aneurysm. Timing.

Timing of surgery is one of the most important and controversial aspects in the management of the patient with a ruptured aneurysm. For each patient with a ruptured aneurysm, the treating physician is faced with a difficult decision: to operate acutely in order to avoid rebleeding despite the swollen brain, or to wait until the effects of the initial hemorrhage subside. The decision of whether or not to perform surgery acutely after subarachnoid hemorrhage (SAH) strongly affects the ability to prevent and treat some of the complications of SAH. Either approach, early or delayed surgery, has pros and cons. This article reviews the numerous factors that play a role in this delicate decision-making process.

Age Factors↗
PubMed1998

Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm.

OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.

Animals↗
PubMed1997

Induction of ischemic tolerance and antioxidant activity by brief focal ischemia.

Three forms of non-injurious ischemic preconditioning were tested for their effects on endogenous antioxidant activity and subsequent ischemic injury. Test ischemia alone, consisting of 1 h occlusion of both carotid arteries (BCAs) and one middle cerebral artery (MCA), elicited an average volume of cerebral infarction of 143.4 +/- 15.0 mm3 (mean +/- s.e.m.). Twenty minutes occlusion of the MCA only or MCA and BCAs (but not BCAs only) 24 h before test ischemia significantly increased the activity of the antioxidant enzyme superoxide dismutase and significantly reduced the cerebral infarction volume. These findings demonstrate that brief focal ischemia can attenuate the injurious impact of subsequent ischemia and that an upregulation of endogenous antioxidant activity may play a key role in this neuroprotective effect.

Analysis of Variance↗
PubMed1997

Inhibition of nitric oxide generation and lipid peroxidation attenuates hemolysate-induced injury to cerebrovascular endothelium.

The mechanisms of hemolysate-induced cerebral injury following subarachnoid hemorrhage are just beginning to be clarified. This study examined the injurious effects of hemolysate on endothelial cells derived from bovine middle cerebral arteries, and evaluated the roles of lipid peroxidation and nitric oxide production in this type of damage. Cultured endothelial cells were grown to confluency on gelatin-coated plates. The cells were characterized as endothelial cells on the basis of morphology. Factor VIII-related antigen staining, and low density lipoprotein (LDL) uptake. Additional cells were grown to confluency on collagen-coated well inserts, and were treated with hemolysate for 24 hours. Prior to hemolysate exposure, cells were treated with: a) an inhibitor of iron-dependent lipid peroxidation (tirilazad mesylate 100 microM), or b) an inhibitor of nitric oxide synthase (either N-nitro-L-arginine: NLA 300 microM, or aminoguanidine: AG at 1.5, 7.5, 15 or 150 microM). Permeability of the tracer, U-14C-sucrose, across the layer of endothelial cells was examined over a 24 hour period. Hemolysate induced a significant increase in the permeability across the endothelial cell layer. Pretreatment with tirilazad mesylate, NLA, or AG attenuated significantly hemolysate-induced changes in the endothelial cell barrier. These findings indicate that free radical generation and lipid peroxidation are critical participants in hemolysate-induced injury to the barrier function of the cerebrovascular endothelium. In addition, the results indicate that endothelial cells provide an adequate source of nitric oxide to damage their own cellular function. Finally, these findings strongly implicate free radical mechanisms in endothelial damage associated with subarachnoid hemorrhage.

Animals↗