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Nitrite Infusions to Prevent Delayed Cerebral Vasospasm in a Primate Model of Subarachnoid Hemorrhage
Ryszard M. Pluta, MD, PhD;
Andre Dejam, MD, PhD;
George Grimes, PhD;
Mark T. Gladwin, MD;
Edward H. Oldfield, MD
JAMA. 2005;293:1477-1484.
Context Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.
Objective To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.
Design, Setting, and Subjects A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004.
Interventions A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.
Main Outcome Measures Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.
Results In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) µmol/L to 0.4 (0.1) µmol/L at day 7 and to 0.4 (0.4) µmol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity.
Conclusion Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.
Author Affiliations: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (Drs Pluta and Oldfield), Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases (Dr Dejam), Pharmacy Department, Clinical Center (Dr Grimes), Vascular Therapeutics Section, Cardiovascular Branch, National Heart, Lung, and Blood Institute (Dr Gladwin), and Critical Care Medicine Department (Dr Gladwin), National Institutes of Health, Bethesda, Md.
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