Effect of the aminosteroid U74006F after cardiopulmonary arrest in dogs.
The oxygen free radical-induced lipid peroxidative reactions that occur during resuscitation from normothermic cardiac arrest may contribute to the degree of neurologic dysfunction sustained. A blinded, randomized experimental trial was performed to determine whether U74006F, a potent inhibitor of lipid peroxidation, reduces morbidity and 24-hour mortality after 10 minutes of normothermic cardiopulmonary arrest; ventricular fibrillation was induced by electrical stimulation in 24 open-chest, halothane-anesthetized dogs, and circulation was reestablished by direct cardiac compressions, administration of a standardized drug regime, and internal countershocks. When spontaneous circulation was restored, a bolus injection of 1.5 mg/kg U74006F (n = 12) or 25 mM citrate vehicle (n = 12) was infused intravenously in 15 minutes and an infusion was continued at 0.125 mg/kg/hr for the next 12 hours. In the drug-treated group, plasma U74006F concentration averaged 0.13 microgram/ml between 3 and 12 hours after cardiac arrest. By 24 hours after arrest, 10 of 12 (83%) vehicle-treated dogs had died but only four of 12 (33%) U74006F-treated dogs had died (p = 0.017). U74006F-treated dogs survived significantly longer (mean +/- SEM 22 +/- 1 hr) than vehicle-treated dogs (18 +/- 1 hr), with significantly better neurologic function 1, 2, and 24 hours after arrest. Plasma fatty acid hydroperoxide concentrations 12 hours after arrest were 88 +/- 81 pmol/ml in U74006F-treated and 241 +/- 49 pmol/ml in vehicle-treated dogs (p less than 0.05). Vitamin E concentrations were significantly higher in the plasma of U74006F-treated dogs 2, 3, and 6 hours after arrest compared with vehicle-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Natale
J E
JE
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109.
Schott
R J
RJ
Hall
E D
ED
Braughler
J M
JM
D'Alecy
L G
LG
D000818:Animals; D004285:Dogs; D006323:Heart Arrest / Q000150:complications*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000628:therapy; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology; D009994:Osmolar Concentration; D011281:Pregnatrienes / Q000097:blood / Q000627:therapeutic use*; D012151:Resuscitation; D013997:Time Factors; D014810:Vitamin E / Q000097:blood
D008054:Lipid Peroxides; D011281:Pregnatrienes; D014810:Vitamin E; C053355:tirilazad