Acetaminophen overdose

Acetaminophen overdose may occur after an acute single ingestion of a large amount of acetaminophen or acetaminophen-containing drug formulations, or repeated ingestion of an amount exceeding recommended dosage.

Though acetaminophen is generally safe when taken at recommended doses, overdose can lead to hepatotoxicity and hepatic failure. Acetaminophen is responsible for over half of all cases of acute liver failure in the US and is the second most common cause of liver transplant worldwide.

Patients are often asymptomatic or have only mild gastrointestinal symptoms at initial presentation. Untreated acetaminophen poisoning may cause varying degrees of liver injury over the 1 to 4 days following ingestion, including fulminant hepatic failure.

Rarely, massive overdose may initially present with coma and severe metabolic acidosis. Presentation with coma may also occur if a combination formulation of acetaminophen and an opioid is taken in overdose, or after an overdose of multiple drugs.

Hepatotoxicity is extremely rare in patients treated with acetylcysteine within 8 hours of an acute acetaminophen overdose. The efficacy of acetylcysteine decreases subsequent to the first 8 hours following an acute acetaminophen overdose, with a corresponding stepwise increase in hepatotoxicity with increasing treatment delays beyond 8 hours.

The most common presentation of acetaminophen overdose is acute ingestion of an excessive amount.[1]Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 http://www.ncbi.nlm.nih.gov/pubmed/37552484?tool=bestpractice.com The patient’s history is important to determine whether or not acetylcysteine therapy is indicated, though determining the accuracy of a patient’s history can be challenging. Most clinical guidelines recommend the use of the Rumack-Matthew nomogram to determine whether acetylcysteine is indicated for the treatment of acute acetaminophen ingestion; however, sources differ on the definition of what constitutes an acute ingestion. The original studies defined acute ingestion as, “known or suspected acute ingestion of ≥7.5 g of acetaminophen within 24 hours of admission”; however, a 2023 US and Canadian consensus guideline defined acute ingestion as one that occurred over a period of less than 24 hours, regardless of ingestion pattern.[1]Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 http://www.ncbi.nlm.nih.gov/pubmed/37552484?tool=bestpractice.com [2]Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975 Jun;55(6):871-6. http://www.ncbi.nlm.nih.gov/pubmed/1134886?tool=bestpractice.com [3]Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981 Feb 23;141(3 spec no):380-5. http://www.ncbi.nlm.nih.gov/pubmed/7469629?tool=bestpractice.com [4]Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62. http://www.ncbi.nlm.nih.gov/pubmed/3059186?tool=bestpractice.com

In contrast, repeated supratherapeutic ingestions, sometimes referred to as therapeutic excess of acetaminophen, denotes ingestions occurring over a period greater than 24 hours.[1]Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 http://www.ncbi.nlm.nih.gov/pubmed/37552484?tool=bestpractice.com

Often these ingestions are accidental in an attempt to treat pain or fever, but they may be due to intentional attempts at self-harm, or due to an attempt to misuse or abuse drugs contained in combination drug formulations, such as opioids.[1]Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 http://www.ncbi.nlm.nih.gov/pubmed/37552484?tool=bestpractice.com

In adults, hepatotoxicity may occur following ingestion of ≥10 g of acetaminophen in 24 hours. Children are at risk for hepatotoxicity with acetaminophen ingestions ≥150 mg/kg in 24 hours.[1]Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062 http://www.ncbi.nlm.nih.gov/pubmed/37552484?tool=bestpractice.com

The definition of hepatotoxicity after acetaminophen overdose is a serum aspartate aminotransferase or alanine aminotransferase of 1000 international units/L or greater.[5]Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2023 Mar 1;77(3):1036-65. https://pmc.ncbi.nlm.nih.gov/articles/PMC9936988 http://www.ncbi.nlm.nih.gov/pubmed/35899384?tool=bestpractice.com ​​

Acetaminophen is known as paracetamol outside of the US, or N-acetyl-para-aminophenol (APAP).