Acetaminophen (APAP) poisoning is a disorder caused by excessive intake of APAP and is manifested by jaundice, nausea, vomiting, abdominal discomfort, and potential death from hepatic necrosis if not treated appropriately.

Paracetamol poisoning

• APAP is one of the most widely prescribed antipyretics and analgesics in the U.S. Potentially toxic ingestions, both intentional and unintentional, exceed 100,000 cases annually in the U.S.
• APAP is the most commonly potential toxic pharmaceutical reported to U.S. Poison Control Centers.
• APAP is available in more than 100 over-the-counter combination formulations, such as DayQuil/NyQuil Cold and Flu, Excedrin, and Robitussin Cold and Flu.
• APAP toxicity is the number one cause of liver transplant in the U.S. Death rate is approximately 1 in 1000 persons. Nearly 50% of exposures occur in children ≤6 yr.
• Hepatic necrosis is most likely to occur in people who (1) are chronically malnourished, (2) have alcohol use disorder, (3) have chronic liver disease, and (4) use other potentially hepatotoxic medications.
• Combination opioid and acetaminophen medications are an important source of APAP toxicity.

• The physical examination may vary depending on the amount of time since ingestion.
• Phase I (0-24 hr): Initial symptoms may be mild or absent and may consist of anorexia, diaphoresis, malaise, nausea, vomiting, lethargy, and a subclinical rise in transaminase levels. In a massive APAP ingestion, altered mental status and lactic acidosis can occur in phase I.
• Phase II (24-72 hr): Right upper quadrant pain, vomiting, somnolence, tachycardia, jaundice, hypotension, and continued increase in transaminases.
• Phase III (72-96 hr): Hepatic necrosis with abdominal pain, jaundice, hepatic encephalopathy, coagulopathy, hypoglycemia, renal failure, fatality from multiorgan failure.
• Phase IV (4 days to 2 wk): Complete resolution of symptoms and resolution of organ failure.
• Table E1 summarizes the four phases/stages of acetaminophen poisoning.

TABLE E1 Four Stages of Acetaminophen Poisoning

ALT, Alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio.

From Adams J (ed), Barton E et al (associate eds): Emergency medicine: clinical essentials, ed 2, Philadelphia, 2013, Saunders.

• The amount of APAP necessary for hepatic toxicity varies with the patient’s body size and hepatic function. APAP hepatotoxicity occurs when its typical metabolism pathway is overwhelmed, resulting in glutathione depletion and accumulation of the toxic metabolite, NAPQI.
• When prescribing APAP, it is recommended that APAP intake should not exceed 3 to 4 g for adults and 90 mg/kg in children within a 24-hr period. A potentially toxic single ingestion of APAP is 7.5 g for adults or 150 mg/kg in a child.
• There is no standard accepted definition, but a massive APAP ingestion is characterized by a single ingestion of >30 g to >50 g or an APAP concentration of greater than 250 mcg/ml to 300 mcg/ml in 4 h.
• A standardized nomogram (Fig. 1 ) is used to determine potential hepatic toxicity by knowing the APAP plasma level and the number of hr after ingestion. See the APAP ingestion algorithm.

• Liver disease from alcohol use disorder
• Viral hepatitis
• Ingestion of other hepatotoxic substances
• Bacterial/viral gastroenteritis
• Pancreatitis

Initial workup is aimed at confirming APAP overdose with plasma APAP level and assessment of hepatic damage. A careful history should elicit the time of APAP ingestion, amount, preparation (e.g., extended release), and possible coingestants (see “Laboratory Tests”).

• Initial laboratory evaluation should include an initial plasma APAP level with a second level drawn approximately 4 hr after the initial ingestion. Subsequent levels can be obtained every 2 to 4 hr until the levels stabilize or decline. Levels starting from 4 hr post-ingestion should be plotted on the Rumack-Matthew nomogram (see acetaminophen ingestion algorithm to calculate potential hepatic toxicity). The nomogram cannot be used with patients who present >24 hr after ingestion, took extended-release preparations, had chronic ingestions, or when the time of ingestion is unknown.
• Transaminases (aminotransferase [AST], alanine aminotransferase [ALT]), serum glucose, bilirubin level, lipase level, prothrombin time (INR), blood urea nitrogen, creatinine, ECG, and urinalysis should be initially obtained on all patients.
• Serum and urine toxicology screens for other potential toxic substances (e.g., salicylate level, ethanol level, urine drugs of abuse screening) are also recommended on admission. Screening for infectious hepatitis should also be considered.
• Urine for β-hCG should be obtained from all women of childbearing age.

Consultation with a Poison Control Center (1-800-222-1222 in the United States) is recommended for patients who have ingested a large amount of APAP and/or other toxic substances. In health care encounters where APAP will be prescribed or recommended, it is important for the health care team to educate patients on the potentially toxic effects of APAP if taken in excess.

• It is important to make the diagnosis and start treatment early, as later initiation of treatment can result in more severe hepatoxicity.
• Hepatotoxicity is defined as any increase in ALT or aspartate AST >1000 IU/L, and hepatic failure manifests as hepatotoxicity with hepatic encephalopathy. For those who cannot be risk stratified using the nomogram, the American College of Emergency Physicians recommends that N-acetylcysteine (NAC) be administered without delay to those >12 yr and >8 hr after ingestion at presentation. This would include anyone with an ingestion of APAP over many days with an APAP level <20 μg/ml (with or without ALT elevation) or anyone with undetectable APAP levels with an elevated ALT and a history of excessive APAP intake.
• Administer activated charcoal 1 g/kg PO if the patient is seen within 4 h of ingestion or the clinician suspects polysubstance ingestion that delays gastric emptying.
• Gastric lavage and whole-bowel irrigation are unnecessary and not helpful in APAP overdose as APAP is rapidly absorbed in the stomach and can delay administration of a very effective antidote if given timely, NAC.
• Determine serum acetaminophen levels 4 h after ingestion; if in the toxic range based on the Rumack-Matthew nomogram, start NAC either IV (Acetadote) or PO (Mucomyst). NAC IV loading dose is 150 mg/kg ×1 diluted in 200 ml D5W over 15 to 60 min. Maintenance dose is 50 mg/kg diluted in 500 ml D5W over 4 h, followed by 100 mg/kg diluted in 1000 ml D5W over 16 h. The dose does not require adjustment for renal or hepatic impairment or for dialysis. Total administration time is 21 h.
• Oral administration is 140 mg/kg PO as a loading dose, followed after 4 h by 70 mg/kg PO q4h for a total of 18 doses. NAC therapy should be started within 24 h of APAP overdose. Total administration time is 72 h.
• Advantages of IV administration include more reliable absorption, fewer doses, and shorter duration of treatment. Disadvantages include cost, lower hepatic concentrations from first-pass flow as compared to oral acetylcysteine, and potential for anaphylactoid reactions. Oral NAC commonly causes nausea, vomiting, diarrhea, or headache in 20% of patients.
• Monitor APAP level; use Rumack-Matthew nomogram to trend hepatic toxicity. Repeat AST/ALT and APAP levels after 12 to 14 h of IV acetylcysteine infusion and continue infusion longer than 16 h if transaminases are elevated, if APAP concentration is still measurable, or if coagulopathy exists (INR >1.5-2.0). Patients with severe, irreversible liver failure may need to continue NAC until liver transplantation is available.
• Provide adequate IV hydration (e.g., D₅½NS at 150 ml/h).
• Patients on IV N-acetylcysteine with liver failure require frequent monitoring of vital signs, oxygen saturation by pulse oximetry, and frequent blood draws. Frequent reassessment for hypoglycemia and infection is also essential.
• If APAP level is nontoxic, N-acetylcysteine therapy may be discontinued.
• Hemodialysis is recommended in APAP poisoning when:
  1. APAP is greater than 1000 and NAC is not administered
  2. Patient has altered mental status, metabolic acidosis, an elevated lactate, and APAP is >900 even if NAC is given
  3. Patient has altered mental status, metabolic acidosis, an elevated lactate, and APAP is >700 and NAC is not administered
• Continue NAC therapy during dialysis at an increased rate.

All patients with confirmed APAP poisoning will require admission, usually to an intensive care unit. Most patients (90%) will recover fully without persistent hepatic abnormalities. Hepatic failure is particularly unusual in children <6 yr.

Psychiatric referral is recommended after intentional ingestions.

Acetaminophen Overdose (Patient Information)