Acetaminophen (paracetamol) is a widely used drug found in many over-the-counter and prescription analgesics and cold remedies. When it is combined or coingested with another drug, such as diphenhydramine, codeine, hydrocodone, oxycodone, dextromethorphan, or propoxyphene, the more dramatic acute symptoms caused by the other drug may mask the mild and nonspecific symptoms of early acetaminophen toxicity, resulting in a missed diagnosis or delayed antidotal treatment.

1. Hepatic injury. Metabolism of acetaminophen by cytochrome P450 (CYP) mixed-function oxidase enzymes produces the highly toxic and reactive metabolite NAPQI. Normally NAPQI is detoxified rapidly by glutathione in liver cells. However, in overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver injury.
2. Renal damage can occur by the same mechanism, owing to renal CYP metabolism.
3. Overdose during pregnancy has been associated with fetal death and spontaneous abortion.
4. Very high levels of acetaminophen can cause acidosis and altered mental status, probably due to mitochondrial dysfunction, lactate production, or the accumulation of pyroglutamic acid (5-oxoproline).
5. Pharmacokinetics. Acetaminophen is rapidly absorbed, with peak levels usually reached within 30-120 minutes. (Note: Absorption may be delayed after ingestion of sustained-release products or with co-ingestion of opioids or anticholinergics.) Volume of distribution (Vd) is 0.8-1 L/kg. Elimination is mainly by liver conjugation (90%) to nontoxic glucuronides or sulfates; mixed-function oxidase (CYP2E1, CYP1A2) accounts for only about 3-8% but produces a toxic intermediate (see Item A above). The elimination half-life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.

1. Acute ingestion of more than 200 mg/kg in children or 6-7 g in adults is potentially hepatotoxic.
   1. The margin of safety may be lower in patients with induced CYP microsomal enzymes because more of the toxic metabolite may be produced. High-risk patients include alcoholics and patients taking inducers of CYP2E1, such as isoniazid. Fasting and malnutrition may also increase the risk for hepatotoxicity, presumably by lowering cellular glutathione stores.
   2. Acute massive ingestion of acetaminophen (>30 grams) is associated with an increased risk of hepatotoxicity, as well as acidosis, hypotension and altered mental status.
2. Chronic toxicity has been reported after consumption of repeated supratherapeutic doses. A consensus guideline from the American Association of Poison Control Centers (AAPCC) recommends medical evaluation if more than 150 mg/kg/d (or 6 g/d) has been ingested for 2 days or longer. One study reported elevated transaminases in more than one-third of healthy volunteers given doses of 4 g/d for several days.
   1. Children have developed toxicity after receiving as little as 100-150 mg/kg/d for 2-8 days. The AAPCC guideline recommends medical evaluation for doses of more than 150 mg/kg/d for 2 days or 100 mg/kg/d for 3 days or more. There is a single case report of hepatotoxicity in an infant receiving 72 mg/kg/d for 10 days.
   2. As with acute overdose, the risk for injury from chronic use may be greater in patients who are alcoholic or malnourished, and those taking isoniazid and other drugs that induce CYP2E1.
3. Intravenous acetaminophen (10 mg/mL) is now available and 10-fold dosing errors have occurred. An acute overdose of more than 150 mg/kg is considered potentially toxic. (One report of hepatotoxicity after 75 mg/kg IV acetaminophen was probably due to other complications leading to ischemic liver injury.)

Clinical manifestations depend on the time after ingestion.

1. Early after acute acetaminophen overdose, there are usually no symptoms other than anorexia, nausea, or vomiting. Rarely, a massive overdose may cause altered mental status, hypotension, and metabolic acidosis in the absence of any laboratory evidence of liver damage. Transient prolongation of the prothrombin time/international normalized ratio (PT/INR) in the absence of hepatitis has been noted in the first 24 hours; some, but not all, of these patients go on to develop liver injury.
2. After 24-48 hours, when aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise, hepatic necrosis becomes evident. If acute fulminant hepatic failure occurs, death may ensue. Encephalopathy, metabolic acidosis, and a continuing rise in PT/INR indicate a poor prognosis. Acute renal failure occasionally occurs, with or without concomitant liver failure.
3. Chronic excessive use of acetaminophen.
   1. Patients often have nausea and vomiting, and may already show evidence of hepatic injury by the time they seek medical care.
   2. Glutathione depletion associated with chronic acetaminophen ingestion has also been associated with anion gap metabolic acidosis due to the accumulation of 5-oxoproline.

Prompt diagnosis is possible only if the ingestion is suspected and a serum acetaminophen level is obtained. However, patients may fail to provide the history of acetaminophen ingestion because they are unable (eg, comatose from another ingestion), unwilling, or unaware of its importance. Therefore, many clinicians routinely order acetaminophen levels in all overdose patients regardless of the history of substances ingested.

1. Specific levels. Note: 1 mg/L = 1 mcg/mL = 6.6 mcmol/L.
   1. After an acute oral or intravenous overdose, obtain a serum acetaminophen level 4 hours after the overdose and use the nomogram (Figure II-1) to predict the likelihood of toxicity. Do not attempt to interpret a level drawn before 4 hours, unless it is “nondetectable.” Obtain a second level at 8 hours if the 4-hour value is borderline or if delayed absorption is anticipated.
   2. The nomogram should not be used to assess chronic or repeated ingestions.
   3. Falsely elevated acetaminophen levels may occur in the presence of high levels of salicylate and other interferents by certain older laboratory methods (see Table I-32). This problem is rare with currently used analytic methods. High concentrations of bilirubin (>10 mg/dL) and lipids can cause a false-positive result.
2. Other useful laboratory studies include electrolytes (presence of an anion gap), arterial or venous blood gas, glucose, BUN, creatinine, liver aminotransferases, bilirubin, and PT/INR.

1. Emergency and supportive measures
   1. Spontaneous vomiting may delay the oral administration of antidote or charcoal (see below) and can be treated with metoclopramide or a serotonin (5-HT3) receptor antagonist such as ondansetron.
   2. Provide general supportive care for hepatic or renal failure if it occurs. Emergency liver transplant may be necessary for fulminant hepatic failure. Encephalopathy, metabolic acidosis, hypoglycemia, and a progressive rise in the prothrombin time are indications of severe liver injury.
2. Specific drugs and antidotes
   1. Acute single ingestion or intravenous overdose
      1. If the serum level falls above the treatment line on the nomogram or if stat serum levels are not immediately available, initiate antidotal therapy with N-acetylcysteine (NAC). The effectiveness of NAC depends on early treatment, before the toxic metabolite accumulates; it is of maximal benefit if started within 8-10 hours and of diminishing value after 12-16 hours; however, treatment should not be withheld even if the delay is 24 hours or more. If vomiting interferes with or threatens to delay oral acetylcysteine administration, give the NAC IV.
      2. If the serum level falls below but near the nomogram line, consider giving NAC if the patient is at increased risk for toxicity—for example, if the patient is alcoholic, is taking a drug that induces CYP2E1 activity (eg, isoniazid [INH]), or has taken multiple or subacute overdoses—or if the time of ingestion is uncertain or unreliable.
      3. If the serum level falls well below the nomogram line, few clinicians would treat with NAC unless the time of ingestion is very uncertain or the patient is considered to be at particularly high risk.
      4. Note: After ingestion of extended-release tablets, which are designed for prolonged absorption, there may be a delay before the peak acetaminophen level is reached. This can also occur after co-ingestion of drugs that delay gastric emptying, such as opioids or anticholinergics. In such circumstances, repeat the serum acetaminophen level at 8 hours and possibly 12 hours. In such cases, it may be prudent to initiate NAC therapy before 8 hours while waiting for subsequent levels.
      5. Duration of NAC treatment. The conventional US protocol for the treatment of acetaminophen poisoning calls for 17 doses of oral NAC given over approximately 72 hours. However, for decades successful protocols in the United States, Canada, the United Kingdom, and Europe have used IV NAC for only 20 hours. In uncomplicated cases, give NAC (orally or IV) for 20 hours (or until acetaminophen levels are no longer detectable) and follow hepatic transaminase levels and the PT/INR; if evidence of liver injury develops, continue NAC until liver function tests are improving.
      6. Massive ingestion. Use a higher dose of NAC to treat very large overdoses (reported ingestions of >30 grams or if the measured serum acetaminophen level is greater than twice the nomogram line). See NAC, for detailed recommendations. Fomepizole (see), a potent inhibitor of cytochrome 2E1, may provide benefit as an adjunctive treatment by reducing the formation of NAPQI. Also consider early hemodialysis (see enhanced elimination below).
   2. Chronic or repeated acetaminophen ingestions: Patients may give a history of several doses taken over 24 hours or more, in which case the nomogram cannot accurately estimate the risk for hepatotoxicity. In such cases, we advise NAC treatment if the amount ingested was more than 200 mg/kg within a 24-hour period, 150 mg/kg/d for 2 days, or 100 mg/kg/d for 3 days or more and liver enzymes are elevated; or if there is detectable acetaminophen in the serum; or if the patient falls within a high-risk group (see above). Treatment may be stopped when acetaminophen is no longer detectable and the liver enzymes and PT/INR are normal or improving.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
   1. Although activated charcoal adsorbs some of the orally administered antidote NAC, this effect is not considered clinically important.
   2. Do not administer charcoal if more than 1-2 hours has passed since ingestion unless delayed absorption is suspected (eg, as with extended release products or co-ingestants containing opioids or anticholinergic agents).
4. Enhanced elimination. Hemodialysis effectively removes acetaminophen from the blood but is not generally indicated because antidotal therapy is so effective. Dialysis should be considered for massive ingestions with very high levels (eg, over 900-1,000 mg/L) complicated by severe acidosis, coma, and/or hypotension.

FIGURE II-1. Nomogram for Prediction of Acetaminophen Hepatotoxicity Following Acute Overdosage

Nomogram for prediction of acetaminophen hepatotoxicity following acute overdosage. Patients with serum levels above the line after acute overdose should receive antidotal treatment. (Reproduced with permission from Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA; Panel of Australian and New Zealand clinical toxicologists. Guidelines for the management of paracetamol poisoning in Australia and New Zealand-explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust. 2008;188(5):296-301. doi:10.5694/j.1326-5377.2008.tb01625.x)