Acetaminophen toxicity

Background

• Recommended maximum total daily dose:
  • Adults: 3gm
  • Peds: 75mg/kg
• Toxic dose
  • >10gm or >200mg/kg as single ingestion or over 24hr period OR
  • >6gm or >150mg/kg per 24hr period x2d
• Peak serum levels seen within 2hr

The 140 Rule

• Toxic dose is 140 mg/kg
• Give NAC if level is >140 mcg/mL four hours post-ingestion
• Initial loading dose of NAC is 140 mg/kg PO

Pathophysiology

• APAP toxic metabolite NAPQI usually quickly detoxified by glutathione
  • In overdose, glutathione runs out, NAPQI accumulates -> liver injury
• NAC increases availability of glutathione

Clinical Features

1. Stage 1 (first 24hr)
   1. Mild N/V/malaise
   2. Hypokalemia (a/w high 4-hr level)
2. Stage 2 (days 2-3)
   1. Improvement in symptoms
   2. RUQ abd pain
   3. Elevated transaminases
   4. Elevated bilirubin, PT (if severe)
3. Stage 3 (days 3-4)
   1. Recurrence of N/V
   2. Hepatic failure
   3. Jaundice
   4. Coagulopathy
   5. Encephalopathy (esp w/ massive ingestions)
   6. Renal failure (1-2%; usually after hepatic failure is evident)
   7. Pancreatitis (rare)
4. Stage 4 (after day 5)
   1. Clinical improvement and recovery (7-8d) OR
   2. Deterioration to multi-organ failure and death OR
   3. Continued deterioration

Diagnosis

1. APAP level
   1. Obtain 4hrs post-ingestion
   2. Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
2. Nomogram (see below)
   1. Only indicated for single, acute ingestion occurring <24hr prior to presentation

Work UP

1. APAP level
2. Chemistry
   1. Metabolic acidos seen w/ extremely large ingestion
3. LFT
4. PT/PTT/INR
5. Acetaminophen level: 4 hours post ingestion and repeat in 4 hours

Treatment

N-acetylcysteine

1. Background
   1. Almost 100% effective if given <8 hr post-ingestion; less effective if 16-24 hr post-ingestion
      1. May still be useful >24 hr post-ingestion, even with fulminant hepatic failure
   2. In pts who develop hepatic injury, give NAC until LFTs improve (not until APAP level is 0)
2. When to give:
   1. Wait for level before initiating therapy if level will return within 8hr post-ingestion
   2. If level will not return w/in 8hr post-ingestion give first dose before obtaining level
      1. Discontinue if level comes back non-toxic
3. Dosing
   1. PO:
      1. 140mg/kg PO load
      2. 70mg/kg PO q4hr x17 doses additional; dilute to 5% soln
   2. IV
      1. Loading dose: 150mg/kg in 200 mL D5W over 60min
      2. Second (maintenance) dose: 50mg/kg in 500 mL D5W over 4hr
      3. Third dose: 100mg/kg in 1000 mL D5W over 16hr
4. Side-effect
   1. PO: N/V due to sulfur-smell (may require concomitant anti-emetic)
   2. IV: anaphylactoid reaction

<4hr after ingestion

1. GI decontamination
   1. Activated Charcoal if <3 hr post-ingestion
   2. Gastric Lavage if high-morbidity coingestants and <1 hr post-ingestion
2. Send 4hr APAP level
   1. Toxic level: Give NAC
   2. Nontoxic level: No treatment necessary

Between 4-24hr after ingestion

1. Send APAP level
   1. If level will be available within 8hr post-ingestion: wait for level before treating
   2. If level will not be available within 8hr post-ingestion: do not wait for level before treating
      1. Discontinue treatment if level returns non-toxic

Unknown or >24hr after ingestion

1. Consider GI decontamination for unknown ingestion time
2. Give 1st dose of NAC
3. Send APAP level, LFT, coags
   1. APAP level >10 OR elevated transaminases? If yes then continue NAC
      1. pH <7.3 or PT >100 or Cr >3.3 or AMS? If yes refer to liver transplant unit
   2. APAP level and LFT both normal? If yes then stop NAC (treatment not indicated)

Disposition

• Consider discharge for asymptomatic pts who do not require NAC

Rumack-Matthew Nomogram