PEDIATRICS Vol. 62 No. 5s November 1978, pp. 880-889
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Pathophysiology of Acetam inophen Overdosage Toxicity: Implications for Management

Elliot Piperno M.S., D.V.M.1, A. Harris Mosher V.M.D., Ph.D.1, Daniel A. Berssenbruegge 1, James D. Winkler 1, and Roger B. Smith Ph.D.1

1 Toxicology Research Unit and the Pathology Section, McNeil Laboratories, Inc., Fort Washington, Pennsyluania

Acute acetaminophen intoxication was studied in the dog to characterize pathogenesis and in the mouse as a model for antidotal research. In the dog, overt toxicity was manifested principally by cyanosis, facial and paw edema, gastrointestinal disturbance, and coma. Typical laboratory findings were metheinoglobinemia, hemoconcentration, leukocytosis, and hepatic centrolobular necrosis. In the mouse, physical signs of acetaminophen overdose appeared to be central in origin; sequelae included anemia, leukopenia, thrombocvtopenia, and hepatic centrolobular necrosis.

The antidotal profile of acetylcysteine in mice was characterized. When acetylcysteine therapy was instituted early (one hour after acetaminophen overdose), it conferred doserelated protection from lethality coupled with hepatoprotection, as judged from transaminase activity. When acetylcysteine therapy was instituted relatively late (4frac12 hours after acetaminophen overdose), its beneficial effect on survival persisted but was unaccompanied by distinct hepatoprotection, indicating that SGPT activity was an unreliable prognostic indicator. Acetylcysteine was well tolerated in mice even when administered in the presence of preexisting acetaminophen-induced liver damage.