06. Acetaminophen Overdose

Mechanism and Pharmacokinetics

Acetaminophen is absorbed by the duodenum; metabolized by the liver. Normally safely metabolized by glucuronidation and sulfonation (>90%); even at appropriate doses a small fraction will be metabolized to a highly toxic reactive intermediate (NAPQI), which is normally detoxified by conjugation with glutathione for renal excretion. Overdose will lead to excess NAPQI, which depletes glutathione supply, and reactive intermediates damage hepatocytes. N-acetylcysteine (NAC, Mucomyst®) works by repleting glutathione, enhancing sulfate conjugation, and may directly bind to NAPQI.

  • Serum acetaminophen peaks at 4 hours.
  • Toxicity is likely in adults after single, acute ingestion of >250mg/kg or >12g per 24h; blood level >150 mg/L after 4 hours is toxic and will require treatment.
  • Toxicity is worsened by starvation (low glutathione) and chronic alcohol use (induces P450 enzymes which creates more toxic metabolites). Kidneys also have P450 enzymes and can sustain damage from toxic intermediates.
  • Acetaminophen is found in combination with opioids (e.g. Percocet) and as part of many over the counter cold medications (e.g. Sudafed); can lead to accidental overdose.

Signs and Symptoms

  • Stage I – 0-24 hours: anorexia, nausea, vomiting, diaphoresis, lethargy, malaise, pallor; may also be asymptomatic, especially early. Massive ingestions (e.g., serum levels >500 mg/L) can cause acute CNS depression, AGMA, and hypotension. Serum aminotransferases are often normal, but can rise as early as 8-12h after massive ingestion.
  • Stage II – 24-72 hours: stage I symptoms may improve, but laboratory values will worsen, with elevated hepatic aminotransferases (usually AST first, then ALT) by 36 hours. Will develop RUQ pain, tenderness, and liver enlargement. Abnormalities in renal function and coagulopathy may also begin to appear.
  • Stage III – 72-96 hours: same symptoms as in stage I return, along with jaundice, hepatic encephalopathy, drastic LFT rise, elevated ammonia, and coagulopathy. Patients with severe hepatotoxicity will have transaminases >10K, increased INR, hypoglycemia, lactic acidosis, total bilirubin >4. May also have acute renal failure. If death occurs, it is in this stage, usually from multiorgan failure.
  • Stage IV – 96 hours-2 weeks: recovery phase. Usually is complete by 7 days post-ingestion, but can be prolonged in very ill patients. Resolution of symptoms and labs may take longer.

Evaluation

  • If possible, determine dose, single ingestion or recurrent, time since ingestion, intentional vs accidental, baseline liver disease or risk factors.
  • Obtain serum acetaminophen concentration immediately and at 4 hours from ingestion (if known) or presentation (if not known).
  • Obtain BMP, LFTs, coagulation factors, urinalysis, urine toxicology; consider other causes of acute liver failure.
  • Evaluate 4-hour serum concentration on Rumack-Matthew nomogram: if value is above the treatment line, NAC should be administered.
    • Note that the nomogram is only validated for a single ingestion with a known time of ingestion, and is not accurate in cases of repeat or chronic ingestion. It assumes rapid absorption, so may be unreliable when absorption is delayed by sustained-release formulation, co-ingestion of opioids, or anticholinergic drugs.
  • Note that very elevated bilirubin or creatinine can cause false positive acetaminophen level; if any doubt, treat as true positive.

Initial Management

  • Activated charcoal: single dose activated charcoal at 1g/kg (or 50g) PO or via NG tube to all patients within 4 hours of ingestion. May be helpful >4h if co-ingestion is present.
  • N-acetylcysteine (NAC): low threshold to treat, given low toxicity and cost. Best if given within 8 hours of ingestion and before ALT rise. Can give with charcoal.
    • Oral dosing: 140mg/kg loading dose, followed by 17 doses of 70mg/kg q4h (72 hours). If patient vomits within 1 hour of administration, immediately give full dose again.
    • IV dosing: can give IV if unable to tolerate PO/NG. If no evidence of liver failure, 20-hour IV protocol (150mg/kg IV loading dose in the first hour). If evidence of liver failure (INR>2), 20-hour IV protocol + continuous infusion until INR<2. Watch for allergic or anaphylactic reaction (in up to 20%!).
    • When to give NAC:
      • Serum APAP concentration for indicated hour post-ingestion above treatment line on nomogram.
      • Serum APAP concentration is unable to be obtained and suspected ingestion of >150mg/kg or >7.5g regardless of weight.
      • Serum APAP >10mcg/mL for unknown time of ingestion.
      • APAP ingestion with any evidence of liver injury.
      • When in doubt, treat!
  • Antiemetics: ondansetron, metoclopramide; especially important to give with PO NAC.
  • Call Poison Control (800-222-1222) for further guidance.

Monitoring

  • Check LFTs and INR q12h; if ALT>1000, also check BMP q12h to monitor for renal failure. Severe illness may require more frequent lab monitoring.
  • Check serial APAP levels if concerned for delayed absorption; can continue NAC until APAP levels undetectable and LFTs and coagulopathy improving.
  • Normal transaminases 24 hours after ingestion indicate very low risk of hepatotoxicity (assuming APAP now undetectable).
  • Evaluate potential need for liver transplant: consult GI early for severe transaminitis with rising INR and bilirubin. Calculate Kings College criteria for liver transplant, which include pH <7.3, creatinine >3.4, INR >6.5, and grade III or IV hepatic encephalopathy.

Key Points

  • Amount of ingestion and time to treatment are most prognostic of subsequent hepatotoxicity.
  • Low threshold to initiate treatment with N-acetylcysteine, with greatest benefit of intervention within 8 hours of ingestion.

 

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