ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose
While individual practitioners may differ, this is the position of the American College of Medical Toxicology (ACMT) at the time written, after a review of the issue and pertinent literature. Acetylcysteine (previously called N acetylcysteine (NAC) the abbreviation NAC is used throughout to avoid confusion with activated charcoal) for the treatment of potentially toxic acetaminophen (APAP) ingestion is available in oral and intravenous (IV) formulations. The FDA approved a 72 h oral NAC regimen in 1985. However, evidence supports using shorter oral NAC courses provided that liver enzymes and synthetic function are normal or improving, and plasma APAP concentration is undetectable [1, 2] I n t r a v e n o u s NAC (Ac e t a d o t e(r) Cumbe r l a n d Pharmaceuticals) was approved by the FDA in 2004 and is indicated to prevent or lessen hepatic injury after potentially toxic APAP ingestion. The prescribing information for IV NAC recommends administering the drug within 8 h of APAP ingestion for maximal efficacy, and to administer as soon as possible for patients who present later than 8 h [3] The NAC treatment regimen described in the prescribing information was developed in the UK in the 1970s and delivers NAC 300 mg/kg, with half given as a loading dose, and the remainder infused over 20 h. The primary mechanism of action involves enhanced detoxification of N acetyl p benzoquinone imine, a hepatotoxic APAPmetabolite. Later investigations demonstrated improved mortality in APAP induced liver failure, presumably via other mechanisms, even when IV NAC was administered after APAP had been eliminated from the blood [4, 5] Since approval of IV NAC in the USA, several reported cases have documented rising hepatic aminotransferase concentrations or persistent serum APAP concentrations despite 21 h of treatment [6 8] With a short elimination half life after therapeutic dosing, APAP is typically eliminated within 21 h after an acute overdose. However, hepatic injury can slow acetaminophen metabolism and prolong its apparent half life [9] In addition, altered absorption following massive ingestion [6] or coingestants that slow gastrointestinal motility [7] can result in persistently elevated acetaminophen concentrations. In APAP poisoning, elevations in aminotransferases (AST or ALT equal or greater than 1000 U/L) precede laboratory markers of hepatic dysfunction. In APAP poisoning, many predictors of poor prognosis have been described. In practice, decreased pH, increases in phosphate, increased lactate, increases in prothrombin time/INR, and increases in serum creatinine are the most readily available predictors of poor prognosis [8, 10, 11] Treatment with 21 h of IV NAC is highly effective at preventing hepatotoxicity in most patients following acute APAP overdose and in reducing mortality in those with established hepatotoxicity [12] The administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg/h infusion may be appropriate in certain clinical scenarios [13 16] Treatment beyond 21 h is indicated when patients have evidence of hepatotoxicity evidenced by elevations in aminotransferases, abnormalities in predictors of poor prognosis, or persistent J. Med. Toxicol. (2017) 13:126 127 DOI 10.1007/s13181 016 0542 z
Journal of Medical Toxicology