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Edward H. Oldfield, Johanna J. Loomba, Stephen J. Monteith, R. Webster Crowley, Ricky Medel, Daryl R. Gress, Neal F. Kassell, Aaron S. Dumont, and Craig Sherman

Object

Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion.

Methods

In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter.

Results

In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14.

Conclusions

Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm. Clinical trial registration no.: NCT00873015 (ClinicalTrials.gov).

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R. Webster Crowley, Hian K. Yeoh, George J. Stukenborg, Adina A. Ionescu, Neal F. Kassell, and Aaron S. Dumont

Object

Several studies have indicated that short-term mortality risk is higher among patients who are admitted on the weekends. This “weekend effect” has been observed among patients admitted with a variety of diagnoses, including myocardial infarction, pulmonary embolism, ruptured abdominal aortic aneurysm, and stroke. This study examines the relationship between short-term mortality risk and weekend admission among patients hospitalized following subarachnoid hemorrhage (SAH).

Methods

This retrospective cohort study examines mortality outcomes among patients included in the Nationwide Inpatient Sample (NIS) for 2004. Patients included in the cohort were identified using the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code for SAH. Multivariable logistic regression analyses and Cox proportional hazard regression analyses are used to measure the association of weekend admission on mortality for patients with SAH, adjusted for differences in patient characteristics that also contribute to mortality risk.

Results

Weekend admissions occurred among 27.5% of the 5667 patients with SAH in the NIS database. Weekend admission was not a statistically significant independent predictor of death in the SAH study population at 7 days (OR 1.07, 95% CI 0.91–1.25), 14 days (OR 1.01, 95% CI 0.87–1.17), or 30 days (OR 1.03, 95% CI 0.89–1.19).

Conclusions

Weekend admission is not associated with significantly increased short-term mortality risk among patients hospitalized with SAH.

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Roberto C. Heros

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Chih-Lung Lin, Aaron S. Dumont, Yu-Feng Su, Yee-Jean Tsai, Jih-Hui Huang, Kao-Ping Chang, Shen-Long Howng, Aij-Lie Kwan, Neal F. Kassell, and Cheng-Hsing Kao

Object

Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17β-estradiol (E2) attenuates experimental SAH–induced cerebral vasospasm. Moreover, E2 has been shown to reduce neuronal apoptosis and secondary injury following cerebral ischemia. Adenosine A1 receptor (AR-A1) expression is increased following ischemia and may represent an endogenous neuroprotective effect. This study was designed to evaluate the efficacy of E2 in preventing cerebral vasospasm and reducing secondary injury, as evidenced by DNA fragmentation and AR-A1 expression, following SAH.

Methods

A double-hemorrhage model of SAH in rats was used, and the degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after the first SAH. A cell death assay was used to detect apoptosis. Changes in the protein expression of AR-A1 in the cerebral cortex, hippocampus, and dentate gyrus were compared with levels in normal controls and E2-treated groups (subcutaneous E2, 0.3 mg/ml).

Results

The administration of E2 prevented vasospasm (p < 0.05). Seven days after the first SAH, DNA fragmentation and protein levels of AR-A1 were significantly increased in the dentate gyrus. The E2 treatment decreased DNA fragmentation and prevented the increase in AR-A1 expression in the dentate gyrus. There were no significant changes in DNA fragmentation and the expression of AR-A1 after SAH in the cerebral cortex and hippocampus in the animals in the control and E2-treated groups.

Conclusions

The E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis in the dentate gyrus, and reducing the expression of AR-A1 in the dentate gyrus after SAH. Interestingly, E2 appears to effectively prevent cerebral vasospasm subsequent to SAH as well as attenuate secondary injury by reducing both apoptosis and a compensatory increase in AR-A1 expression in the dentate gyrus.

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Andreas H. Kramer, Michael Hehir, Bart Nathan, Darryl Gress, Aaron S. Dumont, Neal F. Kassell, and Thomas P. Bleck

Object

Delayed cerebral ischemia is a major cause of morbidity and death following aneurysmal subarachnoid hemorrhage and requires timely intervention for a successful outcome to be achieved. In this study the investigators compared the commonly used Fisher scale with 2 newer radiographic scales for the prediction of vasospasm, delayed infarction, and poor outcome.

Methods

This was a single-center, retrospective cohort study involving 271 consecutive patients with a ruptured cerebral aneurysm. Without knowledge of subsequent events, admission CT scans were each assigned scores by using 3 different grading schemes: the Fisher, modified Fisher, and Claassen scales. For each of the scales, the relationship between an increasing score and the risk of later complications was assessed in univariate and multiple logistic regression analyses.

Results

With the Fisher scale, the risk of complications was relatively high when the score was 3, but not for other scores. In contrast, using the other scales, there was a more linear relationship between a rising score and the frequency of complications. This was particularly true for the modified Fisher scale, in which each stepwise increase was associated with an escalating risk of vasospasm, delayed infarction, and poor prognosis. Kappa scores measuring interobserver variability among 4 CT readers were also slightly better with the newer scales.

Conclusions

Although the modified Fisher and Claassen scales have yet to be prospectively validated, the authors' findings suggest that the clinical performance of these systems is superior to that of the Fisher scale.

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Paul T. Boulos, Neal F. Kassell, Nasser Razack, Charles A. Sansur, Mary E. Jensen, and Aaron S. Dumont

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Chih-Lung Lin, Huei-Chuan Shih, Ann-Shung Lieu, Kung-Shing Lee, Aaron S. Dumont, Neal F. Kassell, Shen-Long Howng, and Aij-Lie Kwan

Object

Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5′-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm.

Methods

Experimental SAH was induced in Sprague–Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated.

Prior to perfusion–fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment.

Conclusions

This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.

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Chih-Lung Lin, Aij-Lie Kwan, Aaron S. Dumont, Yu-Feng Su, Neal F. Kassell, Chih-Jen Wang, Shu-Chuan Wu, Ching-Ling Kuo, Ching-Shan Huang, Arco Y. Jeng, and Chin-San Liu

Object

Adhesion molecules, including intercellular adhesion molecule–1 (ICAM-1), vascular cell adhesion molecule–1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model.

Methods

New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion–fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured.

Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303–treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH.

Conclusions

These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.

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D. Kojo Hamilton, Neal F. Kassell, Mary E. Jensen, and Aaron S. Dumont

✓This 34-year-old man with a 10-year history of HIV infection presented with an acute onset of severe headache, fever, nausea, vomiting, and left-sided weakness. Computed tomography (CT) scanning demonstrated diffuse subarachnoid hemorrhage (SAH), and subsequent CT angiography revealed multiple large and giant intracranial aneurysms with diffuse vasculopathy. The patient's CD4-positive cell count was low, although he had been receiving combination antiret-roviral therapy and his viral load was undetectable.

The preponderance of the literature on HIV-infected patients with intracranial vascular involvement has concerned children in whom there is a high viral load. In such children, appropriate antiretroviral therapy may result in the complete resolution of these vascular abnormalities. In the present study, the authors report on the unique case of an HIV-infected adult patient who presented with SAH, diffuse intracranial vasculopathy, and multiple giant and fusiform aneurysms, despite having received adequate antiretroviral treatment and demonstrating an undetectable viral load. Intracranial vascular involvement in these patients may become increasingly common as the management of HIV infection continues to improve and afflicted patients survive for longer periods.

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Chih-Lung Lin, Huei-Chuan Shih, Aaron S. Dumont, Neal F. Kassell, Ann-Shung Lieu, Yu-Feng Su, Shen-Long Hwong, and Chin Hsu

Object

Sex differences in the outcome of aneurysmal subarachnoid hemorrhage (SAH) are controversial, and the potential influence of estradiol on vasodilation is unclear. In the present study the authors evaluate the effect and possible mechanism of 17β-estradiol (E2) on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH.

Methods

A 30-mm Silastic tube filled with E2 in corn oil (0.3 mg/ml) was subcutaneously implanted in male rats. Serum levels of E2 were measured on Days 0, 1, 2, 3, 4, and 7 postimplantation. The degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery (BA) 7 days after the first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) in the BA were also evaluated.

Serum levels of E2 in the E2-treated rats were at physiological levels (56–92 pg/ml) and were significantly higher than those in the control and vehicle-treated groups. Treatment with E2 significantly (p < 0.01) attenuated SAH-induced vasospasm. Induction of iNOS messenger (m)RNA and protein in the BA by SAH was significantly diminished by the E2 treatment but not by vehicle treatment. The SAH-induced suppression of eNOS mRNA and protein was relieved by E2 treatment.

Conclusions

These results suggest that continuous treatment with E2 at physiological levels prevents cerebral vasospasm following SAH. The beneficial effect of E2 may be in part related to the prevention of augmentation of iNOS expression and the preservation of normal eNOS expression after SAH. Treatment with E2 holds therapeutic promise in the treatment of cerebral vasospasm following SAH and merits further investigation.