Acetaminophen Poisoning

Basics

Description

  • A disorder characterized by hepatic necrosis following large ingestions of acetaminophen. Symptoms may vary from an asymptomatic presentation to nausea, vomiting, diaphoresis, malaise, jaundice, confusion, somnolence, coma, and potentially death. The clinical hallmark is the onset of symptoms within 24 hours of ingestion of acetaminophen-only or combination products. Ideally, ingestion is treated before symptoms develop.
  • Acetaminophen poisoning is most often encountered following large, single ingestions of acetaminophen-containing medications. Usual toxic doses are >10 g in adults and >200 mg/kg in children. However, poisoning also occurs after acute and chronic ingestions of lesser amounts in susceptible individuals, including those who regularly abuse alcohol, are chronically malnourished, or take medications that affect hepatic metabolism of acetaminophen.
  • Therapeutic adult doses are 0.5 to 1 g q4–6h, up to a maximum of 4 g/day. Therapeutic pediatric doses are 10 to 15 mg/kg q4–6h, not to exceed 5 doses in 24 hours.
  • System(s) affected: gastrointestinal, cardiovascular, renal/urologic, CNS
    • Multisystem organ failure can occur.
  • Synonym(s): paracetamol poisoning

Geriatric Considerations
Increased risk of hepatic damage in frail elderly patients due to decreased hepatic phase II metabolism and likely coingestion of enzyme-inducing hepatotoxic medications. Expert opinion recommendations are to keep dose of acetaminophen at ≤3,000 mg/day in senior citizens, those with liver disease, and those with alcohol abuse disorders.

Pediatric Considerations
Hepatic damage at toxic acetaminophen levels is decreased in young children. This may be due to larger glutathione stores.

Pregnancy Considerations
  • Increased incidence of spontaneous abortion, especially with overdose at early gestational age
  • Incidence of spontaneous abortion or fetal death appears to be increased when N-acetylcysteine (NAC) treatment is delayed.
  • IV NAC is generally preferred in pregnancy because it may offer greater bioavailability.

Epidemiology

  • Predominant age: children and adults
  • Predominant sex: no reported association
  • Intentional versus unintentional ingestion (52% vs. 48%)

Incidence
The annual incidence of APAP in the ED increased from 2.0 (95% CI 0.2–7.2) cases per 10,000 patients in 2005 to 3.4 (95% CI 1.1–8.8) in 2010.

Prevalence
  • >38,000 hospitalizations per year on average from 1998 to 2011 for acetaminophen-related poisonings in the United States, nearly one half were unintentional largely related to opioid–acetaminophen combinations.
  • <1% of hospitalizations in those <18 years old had coexistent liver toxicity.

Etiology and Pathophysiology

  • Accidental or intentional ingestion of acetaminophen or combination medications containing acetaminophen
  • 96% of ingested acetaminophen is metabolized in the liver, with only 2–4% excreted unchanged in the urine. When taken in therapeutic doses, 90–95% of hepatic metabolism occurs via glucuronidation and sulfation and results in the formation of benign metabolites. 5–10% of hepatic metabolism is by oxidation through the cytochrome P450 enzyme system (CYP 3A4 and CYP 2E1), which results in the formation of the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is rapidly conjugated with glutathione to form a nontoxic metabolite. The metabolites are excreted in the urine along with a small amount of unchanged drug. Hepatocellular damage typically occurs when toxic doses of acetaminophen result in saturation of the glucuronidation and sulfation pathways with subsequent production of excessive amounts of NAPQI. Available glutathione stores become depleted, NAPQI accumulates, and hepatocellular damage occurs.

Risk Factors

  • Concurrent poisoning with other substances
  • Psychiatric illness, history of suicide attempts
  • Regular ingestion of large amounts of alcohol
  • Possible risk related to previous weight loss surgery

General Prevention

Parent/caregiver education recommended during well-child exams regarding poisoning prevention

Diagnosis

  • May initially present as asymptomatic with history of ingestion in the last 8 hours. Signs and symptoms of poisoning are related to liver toxicity and develop over the first 24 hours following large ingestions; may last as long as 8 days
  • Symptoms may develop gradually following long-term ingestion of near-maximal therapeutic amounts of acetaminophen. Such patients may present in stages 1 to 3 as below, without a history of ingestion of the usual toxic doses.
  • Severe symptoms indicate large ingestions or coingestants:
    • Stage 1: first 24 hours after time of ingestion:
      • Nausea and anorexia
      • Vomiting
      • Diaphoresis
    • Stage 2: days 2 to 3:
      • Right upper quadrant pain
      • Typically less nausea, vomiting, diaphoresis, and malaise than in stage 1
    • Stage 3: days 3 to 4:
      • Nausea, vomiting, and malaise reappear.
      • Severe poisonings may result in jaundice, confusion, somnolence, and coma.
    • Stage 4: after day 5:
      • Resolution of clinical signs in survivors’ possible deterioration due to multiorgan failure and death
  • Fulminant hepatic failure occurs in <1% of adults and is very rare in children <6 years of age.
  • Patients with an unexplained rise in liver function tests (LFTs) with negative acetaminophen levels may be overdose patients presenting in stage 3.

History

Ingestion or suspected ingestion of acetaminophen-containing product

Differential Diagnosis

  • Consider presence of coingestants, especially alcohol and aspirin.
  • Other ingested toxins that produce severe acute hepatic injury, including the mushroom Amanita phalloides, and products containing yellow phosphorus or carbon tetrachloride

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)
  • Plasma acetaminophen levels should be drawn on all patients ≥4 hours after ingestion (levels prior to 4 hours not helpful).
  • Alanine transaminase (ALT), aspartate transaminase (AST), prothrombin time (PT)/international normalized ratio (INR), bilirubin, lactate dehydrogenase (LDH)
  • Electrolytes, glucose, BUN, creatinine
  • Pregnancy screen in females (urine or serum)
  • Urinalysis
  • Consider arterial blood gas (ABG) if pH disturbance is suspected on clinical or lab grounds.
  • Screens for suspected coingestants (aspirin, iron, etc.) may be positive (especially when suicide attempt is a possibility).
  • With toxic ingestions, AST (serum glutamic-oxaloacetic transaminase), ALT (serum glutamic-pyruvic transaminase), and bilirubin levels begin to rise in stage 2 and peak in stage 3.
  • In severe poisonings, the PT/INR will parallel these changes and should be monitored.
  • Markedly elevated ALT levels are consistent with the diagnosis, and improvement in ALT is a good sign.
  • Laboratory abnormalities usually resolve by stage 4.
  • Renal function abnormalities are common in patients with hepatotoxicity.
  • Evidence of damage to pancreas and heart may present following severe poisonings.
  • Anion gap metabolic acidosis due to accumulation of 5-oxoprolene may rarely be seen.
  • Drugs that may alter lab results: none with clinically significant cross-reactivity with plasma acetaminophen assay
  • Disorders that may alter lab results: diseases or toxic substances that damage the liver, particularly alcohol
  • No specific imaging required

Follow-Up Tests & Special Considerations
During recovery, liver tests should normalize.

Test Interpretation
Centrilobular hepatic necrosis

Treatment

  • Contact a regional/local poison control center for recommendations; in the United States: (800) 222-1222
  • NAC should be given when plasma acetaminophen concentrations measured ≥4 hours after ingestion are in the “possible risk” or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 μg/mL (993 μmol/L), >75 μg/mL (497 μmol/L), and >37 μg/mL (244 μmol/L) at 4, 8, and 12 hours after ingestion, respectively. See http://www.ars-informatica.ca/toxicity_nomogram.php....
    • The nomogram is not helpful in determining the need for NAC for sustained-release products or chronic ingestions. If a sustained-released product has been ingested, two serum acetaminophen levels should be obtained 4 to 6 hours apart and treatment given if either level is above the possible toxicity line.
  • For chronic toxicity or for those patients who present after 24 hours postingestion, treatment is based on clinical effects, LFTs, and the acetaminophen level.
  • NAC should be started within 8 hours of ingestion for best chance of hepatic protection. Patients presenting near 8 hours should empirically receive NAC while waiting for labs.
  • All patients with acetaminophen liver injury (even after 8 hours) should receive NAC.
  • NAC therapy may be effective up to ≥36 hours after ingestion.
  • Single-dose activated charcoal should be given within 1 to 2 hours (and possibly up to 4 hours) of ingestion (especially in cases of coingestants) (1,2)[C].
ALERT
Never delay NAC administration for use of activated charcoal.
  • Ipecac and gastric lavage are no longer recommended for routine use at home or in health care facilities.

Medication

First Line
  • Acetylcysteine (NAC, Mucomyst) should be initiated within 8 hours of ingestion whenever possible; single-dose activated charcoal (1 g/kg PO) may be effective if given within 1 to 2 hours of ingestion especially if other substances concomitantly ingested. Never delay oral NAC for activated charcoal.
  • Acetylcysteine may be given PO or IV, depending on situation and availability:
    • IV loading dose of Acetadote 150 mg/kg over 60 minutes followed by an infusion of 50 mg/kg over 4 hours (12.5 mg/kg/hr); this is followed by an infusion of 100 mg/kg over the next 16 hours (6.25 mg/kg/hr) (20-hour regimen).
    • Oral loading dose of 140 mg/kg, followed by 70 mg/kg q4h for 17 additional doses (72-hour regimen)
    • No treatment regimen has been shown to be superior over the other (1)[A].
  • Contraindications: medication allergies
  • Precautions:
    • Oral NAC may cause significant nausea and vomiting due to its sulfur content; consider nasogastric tube.
    • Nausea can be treated with metoclopramide (Reglan), 1 to 2 mg/kg IV, or ondansetron (Zofran), 0.15 mg/kg IV (for age >4 years, usually 4 mg/dose).
    • IV NAC (Acetadote) may cause anaphylactoid reactions (3–6%), including rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (higher rates seen in asthmatics and those with atopy) (3,4)[C].
  • Reactions usually occur with loading dose. Slow or temporarily stop the infusion; may concurrently treat with antihistamines
  • Failure rates of NAC of 3–7% have been observed (3)[C].

Second Line
  • Oral racemethionine (methionine)
  • In cases of massive ingestions (e.g., levels >1,000 mg/L, acidosis, coma/ hypotension), hemodialysis may be a beneficial adjunct therapy and improve survival (5)[C].

Issues For Referral

  • Psychological evaluation in emergency room and close follow-up after intentional ingestions
  • Consider child abuse reporting if neglect led to overdose.

Inpatient Considerations

  • Toxic and intentional ingestions
  • Any reported ingestion with increased LFTs, acidosis on ABG, elevated creatinine, and so forth
  • Initiate aggressive age- and weight-appropriate IV hydration.

Ongoing Care

Follow-up Recommendations

  • All patients should be evaluated at a health care facility.
  • Patients with evidence of organ failure, increased LFTs, or coagulopathy should be evaluated for ELT (emergency liver transplant) at a transplant center.
  • Activity may be restricted if significant hepatic damage is present.
  • Outpatient management is adequate for nontoxic accidental ingestions.

Patient Monitoring
Ask about possible ingestion by others (i.e., suicide pacts).

Diet

No special diet, except with severe hepatic damage

Patient Education

  • Patients should be counseled to avoid Tylenol if already using combination product(s) containing acetaminophen.
  • Education of parents/caregivers during well-child visits
  • Anticipatory guidance for caregivers, family, and cohabitants of potentially suicidal patients
  • Education of patients taking long-term acetaminophen therapy

Prognosis

  • Complete recovery with early therapy
  • <1% of adult patients develop hepatic failure. King criteria (pH <7.3, PT >100 s [INR >65], creatinine >3.4 mg/dL [>300 μmol/L]) is associated with a poor prognosis and possible need for liver transplant (6)[C]. Early referral increases the chance for transplant success (4)[A].
  • Hepatic failure is very rare in children <6 years of age.

Complications

Rare following recovery from acute poisoning

Additional Reading

  • Major JM, Zhou EH, Wong HL, et al. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf. 2016;25(5):590–598. [PMID:26530380]
  • Mund ME, Quarcoo D, Gyo C, et al. Paracetamol as a toxic substance for children: aspects of legislation in selected countries. J Occup Med Toxicol. 2015;10:43. [PMID:26664414]
  • Serper M, Wolf MS, Parikh NA, et al. Risk factors, clinical presentation, and outcomes in overdose with acetaminophen alone or with combination products: results from the acute liver failure study group. J Clin Gastroenterol. 2016;50(1):85–91. [PMID:26166142]

See Also

Algorithm: Acetaminophen Poisoning, Treatment

Codes

ICD-10

  • K71.10 Toxic liver disease with hepatic necrosis, without coma
  • T39.1X1A Poisoning by 4-Aminophenol derivatives, accidental, init
  • T39.1X2A Poisoning by 4-Aminophenol derivatives, self-harm, init
  • T39.1X4A Poisoning by 4-Aminophenol derivatives, undetermined, init

ICD-9

  • 573.3 Hepatitis, unspecified
  • 965.4 Poisoning by aromatic analgesics, not elsewhere classified

SNOMED

  • 197356006 Toxic liver disease with hepatic necrosis (disorder)
  • 290134002 Accidental acetaminophen poisoning (disorder)
  • 290136000 Acetaminophen poisoning of undetermined intent (disorder)
  • 70273001 Poisoning by acetaminophen

Clinical Pearls

  • Contact a regional poison control center for management recommendations; in the United States: (800) 222-1222
  • NAC should be given when plasma acetaminophen concentrations measured ≥4 hours after ingestion are in the “possible risk” or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 μg/mL (993 μmol/L), >75 μg/mL (497 μmol/L), and>37 μg/mL (244 μmol/L) at 4, 8, and 12 hours after ingestion, respectively.
  • Never delay oral NAC for activated charcoal.
  • NAC should be started within 8 hours of ingestion for best chance of hepatic protection. Patients presenting near 8 hours should empirically receive NAC while waiting for labs.
  • All patients with acetaminophen liver injury (even after 8 hours) should receive NAC.
  • To enhance palatability, oral NAC can be diluted with a beverage of choice and served in a cup with lid and straw.
  • In January 2016, Cetylev, an effervescent lemon mint flavored tablet, was approved by the FDA. Tablets come in strengths of 500 mg and 2.5 g of NAC.

Authors


Luis T. Garcia, MD
Kenneth Polezoes, MD

Bibliography

  1. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2006;(2):CD003328. [PMID:16625578]
  2. Spiller HA, Winter ML, Klein-Schwartz W, et al. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006;30(1):1.  [PMID:16434328]
  3. Chiew AL, Isbister GK, Duffull SB, et al. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol. 2016;81(3):471–481.  [PMID:26387650]
  4. Culley CM, Krenzelok EP. A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective. Toxicol Rev. 2005;24(2):131–143.  [PMID:16180933]
  5. Gosselin S, Juurlink DN, Kielstein JT, et al; and the EXTRIP Workgroup. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila). 2014;52(8):856–867.  [PMID:25133498]
  6. McPhail MJ, Farne H, Senvar N, et al. Ability of King’s College Criteria and model for end-stage liver disease scores to predict mortality of patients with acute liver failure: a meta-analysis. Clin Gastroenterol Hepatol. 2016;14(4):516–525.  [PMID:26499930]


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TY - ELEC T1 - Acetaminophen Poisoning ID - 816753 Y1 - 2019 PB - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816753/all/Acetaminophen_Poisoning ER -