Being ubiquitous, acetaminophen is one of the most common pharmaceuticals taken in overdose, whether accidentally by young children or for self-harm by adolescents and adults. Despite the high incidence of overdose, a large margin of safety and a highly effective antidote ensure that death caused by acute acetaminophen ingestion is unheard of in young children.¹ Fatalities are vanishingly rare provided acetylcysteine treatment is started within 20 hours of acute overdose, and hepatic injury unlikely when started within 8 hours. Young children are frequently suspected of ingesting liquid acetaminophen preparations formulated for children. These are absorbed more rapidly than pills but in most instances not enough has been ingested (200 mg/kg)¹ to warrant concern once the volume and concentration present in the container are considered. Because these patients typically present asymptomatic shortly after the exposure, most of these unintentional exposures do not need empirical therapy with antidote, especially when a serum acetaminophen concentration can be readily measured. Dosing errors with the antidote are not infrequent, particularly in young children. Therefore, the indications and dosing calculations as well as total fluid volume administered should be verified meticulously. Adolescents often are not aware that acetaminophen ingestion can be lethal, or that many different products contain acetaminophen, and may unknowingly take a life-threatening amount as a suicidal gesture.²

Acetaminophen (APAP, or paracetamol) is a synthetic analgesic and antipyretic. The therapeutic dose in children is 10 to 15 mg/kg (maximum 650 mg) every 4 to 6 hours, with a maximum recommended total of five doses per day. Therapeutic serum concentrations are 10 to 20 μg/mL. Acetaminophen is well absorbed after an oral therapeutic dose, with peak levels generally occurring within 30 to 60 minutes. Even after overdose, absorption is only minimally delayed in most cases, with peak concentrations seen within 4 hours of acute ingestion.³ Coingested opioids and antimuscarinic agents, solids, and sustained-release formulations of acetaminophen have only a minor effect on this absorption. Absorption of liquid formulations is more rapid than that of tablets or caplets. Following gastrointestinal absorption, APAP is metabolized by the liver, which is the primary target organ of toxicity. The normal serum elimination half-life is 2 to 3 hours but becomes prolonged following massive overdose or liver injury. Indeed, a post-peak acetaminophen concentration that fails to fall at least tenfold over 12 hours (i.e., elimination half-life >4 hours) is one of the first manifestations of serious liver injury.

After a therapeutic dose, 90% of the drug is inactivated by conjugation with sulfate and glucuronide. In young children, the sulfate conjugate predominates. Less than 5% is excreted unchanged in the urine. The remainder is metabolized primarily by CYP2E1 to the toxic electrophile NAPQI. In the presence of adequate hepatic glutathione, NAPQI is rapidly inactivated. In overdose, the sulfate and glucuronide pathways become saturated, glutathione becomes depleted, and eventually NAPQI attacks cellular macromolecules, causing fulminant liver failure.

Acute ingestion of more than 200 mg/kg or 10 g (whichever is less) is potentially toxic and requires emergent evaluation. It is important to remember that acetaminophen is found in many combination products, and that many patients are unaware of the acetaminophen content of such products.

Patients are frequently asymptomatic shortly after acute acetaminophen ingestion, although vomiting may occur. Coingestants present in combination products such as codeine and antihistamines may provide early symptoms of overdose. Rarely, massive ingestion of acetaminophen (~1 g/kg) can by itself cause lethargy, coma, anion-gap metabolic acidosis, hypothermia, and hyperglycemia.⁴ Even in such cases, consideration should still be given to the possibility of coingestants.

As serum acetaminophen concentrations fall, and in the absence of treatment, the aspartate and alanine aminotransferases (AST and ALT) will begin to rise. Severe hepatic failure is demonstrated by encephalopathy, coagulopathy, jaundice, hypoglycemia, and markedly elevated aminotransferases (>1000 IU/L). While the degree of aminotransferase elevation may be impressive, at times exceeding 20,000 or 30,000 IU/L, the degree of elevation is not by itself prognostic. Patients with isolated rises in aminotransferases without other signs of liver dysfunction invariably recover. All patients who ultimately recover have a complete recovery with essentially normal hepatic function and architecture on histology several weeks later.

The presence of persistent metabolic acidosis despite fluid resuscitation, or the combination of progressive encephalopathy, worsening coagulopathy, and renal failure indicate a poor prognosis unless liver transplantation is performed. Deaths in children under the age of 6 years are generally due to repeated supratherapeutic dosing over days in the context of an intercurrent illness with minimal oral intake.⁵ There is no well-documented case of death in a child less than 6 years of age attributable to a single acute overdose of acetaminophen.¹