Background
- APAP toxicity may be caused by a single large overdose or repeated supratherapeutic dosing, rarely by chronic low doses (≤ 3-4 g/day). Severe liver toxicity (peak AST or ALT >1000 IU/L) develops in virtually all patients who ingest doses in excess of 350 mg/kg.
- Accounts for up to half of all cases of acute liver failure in U.S.
Etiology/Risk Factors
- Normal metabolism: supratherapeutic doses (>4g) lead to oxidation to a reactive intermediate (NAPQI) and glutathione depletion. NAPQI binds to cellular proteins, leading to hepatocyte necrosis. Zone 3 hepatocytes are rich in CYP2E1 and are most susceptible to injury (characteristic “centrilobular pattern” of hepatic necrosis).
- Conditions that predispose to APAP toxicity:
- States of decreased glucuronidation, sulfation, glutathione depletion, or CYP450 system induction.
- Chronic alcohol use induces CYP2E1, depletes glutathione.
- Medications that induce CYP450 (rifampin, phenytoin, phenobarbital, carbamazepime, INH).
- Pregnancy, prolonged fasting, or Gilbert’s syndrome.
Evaluation
- Always consider alternative causes of severe liver toxicity/liver failure: toxins, viral (HBV +/- HDV, HAV, HEV, rarely VZV, HSV, CMV, EBV), vascular (ischemic hepatitis, Budd-Chiari), other (Reye’s syndrome, acute fatty liver of pregnancy, autoimmune hepatitis, acute biliary obstruction).
- Clinical presentation: where time 0 = time of ingestion.
- 0-24 hours: +/- nausea, vomiting, abdominal pain, malaise. Labs may be normal.
- 24-72 hours: RUQ pain, +/- nonspecific symptoms.
- 72-96 hours: LFT elevation, may develop jaundice, HE, hyperammonemia, lactic acidosis, ARF. Transaminases elevation peaks at 3-5 days.
- 4d-2wks: recovery, if it occurs. Thought to be complete w/o chronic liver dysfunction.
- Labs – serum acetaminophen level (repeat at 4h if unsure of time of ingestion), chem 10, BUN/Cr, coags, pH, lipase/amylase, UA.
- Monitor and treat for glucose and electrolyte dyscrasias.
- Recheck acetaminophen level and ALT when patient is finishing treatment course (see below).
- Use Rumack-Matthew nomogram to determine risk of hepatotoxicity.
- Limitations of the treatment nomogram:
- Useful only in acute ingestions when the time of ingestion is known.
- Not valid for patients presenting 24 hours after acute overdose, if unknown time of ingestion, history of staggered overdose, history of repeated supratherapeutic ingestion.
- Does not account for patients at higher risk of toxicity (chronic alcohol use, malnourishment).
Management
- Activated charcoal: consider giving at 1g/kg (max dose 50g) within 2-4 hours of known ingestion. Contraindicated if concern for airway protection, unless patient is already intubated.
- Start NAC if:
- Serum APAP concentration (drawn at least 4 hours after ingestion) is above the treatment line on the treatment nomogram.
- Serum APAP concentration is unavailable or will not return within 8 hours of time of ingestion.
- Time of ingestion is unknown and serum APAP level >10 mcg/mL.
- ANY evidence of hepatotoxicity with history of ingestion.
- PO NAC (72 hr) preferred over IV (21 hr) due to lower risk of anaphylaxis but is poorly tolerated.
- Indications for IV NAC: GIB, pregnant, fulminant hepatic failure, unable to tolerate PO, encephalopathy.
- NAC administration: PO 72 hour protocol vs. 21 hour IV protocol.
- 72h PO protocol: loading dose 140mg/kg PO, then 17 doses 70 mg/kg PO q4h.
- IV protocol (Acetadote):
- Loading dose: 150 mg/kg (maximum: 15g) over 1 hour.
- Second dose: 50 mg/kg (maximum: 5g) infused over 4 hours.
- Third dose: 100 mg/kg (maximum: 10g) infused over 16 hours.
- Extension of NAC therapy: use if ALT remains high or serum acetaminophen still detectable as treatment course is finishing.
- Continue at 6.25mg/kg/hr and recheck ALT, INR, and acetaminophen levels every 12h until ALT decreasing/normal, acetaminophen undetectable, and INR <2.
- Adverse effects of NAC therapy:
- Nausea/vomiting.
- For urticaria/angioedema: stop infusion and administer IV Benadryl. May consider re-starting after resolution of reaction.
- If patient develops bronchospasm or hemodynamic instability (10-20% develop anaphylactoid reactions) during IV therapy, discuss PO administration or alternatives with poison control.
- Alert poison control (1-800-222-1222) and consider consultation with hepatology.
- If NAC unavailable, consider hemodialysis for acetaminophen clearance.
- FFP should only be used in instances of active hemorrhage or prior to procedures. Prophylactic administration has no mortality benefit and can interfere with clinical evaluation.
- If patient develops acute liver failure, alert hepatology for consideration of transplantation and continue IV protocol as above except NAC administration should continue at final rate 6.25mg/kg/h until transplantation or resolution of encephalopathy and coagulopathy (INR <2).
- According to King’s College Criteria, acetaminophen-induced ALF defined as:
- Arterial pH <7.3, OR
- INR >6.5, Cr >3.4, AND severe encephalopathy.
- According to King’s College Criteria, acetaminophen-induced ALF defined as:
- Consider referral to hepatology for consideration of transplant if the patient continues to have a 12-hr lactate >3.5 despite fluid resuscitation or a 2-4 day phosphate >3.7.
Key Points
- Begin NAC for all suspected cases of acetaminophen overdose and call Poison Control (1-800-222-1222).
- Prognosis very favorable if NAC is given within 8h of ingestion, but still helpful when given late (48-72 hours after ingestion).
- Mortality <1% when NAC given early.
- Monitor for anaphylactoid reaction during NAC administration.
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