para>Hepatic damage may be increased if chronically taking hepatotoxic medications. á
Pediatric Considerations
Hepatic damage at toxic acetaminophen levels is decreased in young children. This may be due to larger glutathione stores.
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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 since it may offer greater bioavailability.
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EPIDEMIOLOGY
- Predominant age: children and adults
- Predominant sex: no reported association
Incidence
>24,000 ED visits per year on average from 2004 to 2012 for acetaminophen-related overdoses in the United States á
Prevalence
- >38,000 hospitalizations per year on average from 1998 to 2011 for acetaminophen-related poisonings in the United States
- <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
- Previous toxic ingestions or suicide attempts
- Regular ingestion of large amounts of alcohol
GENERAL PREVENTION
Parent/caregiver education essential: á
- Education during well-child exams regarding poisoning prevention
- Emergency telephone numbers
DIAGNOSIS
- May present asymptomatic with history of ingestion in the last 8 hours, as signs and symptoms 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, 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
- Vomiting
- Diaphoresis
- Stage 2: 24 to 48 hours:
- Right upper quadrant pain
- Typically less nausea, vomiting, diaphoresis, and malaise than in stage 1
- Stage 3: 72 to 96 hours:
- Nausea, vomiting, and malaise reappear.
- Severe poisonings may result in jaundice, confusion, somnolence, and coma.
- Stage 4: 7 to 8 days:
- Resolution of clinical signs in survivors
- 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 á
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).
- ALT, AST, PT/NR, 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, aspartate transaminase (AST; serum glutamic-oxaloacetic transaminase), alanine transaminase (ALT; serum glutamic-pyruvic transaminase), and bilirubin levels begin to rise in stage 2 and peak in stage 3.
- In severe poisonings, the prothrombin time (PT)/international normalized ratio (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
ABG after hydration if pH is acidotic á
Test Interpretation
Centrilobular hepatic necrosis á
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"Ł or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 ╬╝g/mL (993 ╬╝mol/L), >75 ╬╝g/mL (497 ╬╝mol/L), and >37 ╬╝g/mL (244 ╬╝mol/L) at 4, 8, and 12 hours after ingestion, respectively. See http://www.ars-informatica.ca/toxicity_nomogram.php?calc=acetamin or http://www.merckmanuals.com/professional/resources/clinical_calculators/name/calculator.html?WT.z_resource=Clinical Calculators.
- 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 may be used if given within 1 hour of ingestion (especially in cases of coingestants) (1,2)[C],(3)[A], but not within 1 hour of administration of oral NAC. Never delay NAC for activated charcoal.
- Ipecac and gastric lavage are no longer recommended for routine use at home or in health care facilities (3)[C].
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 hour of ingestion. 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)
- 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, including rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (higher rates seen in asthmatics and those with atopy) (4,5)[C].
- Reactions usually occur with loading dose. Slow or temporarily stop the infusion; may concurrently treat with antihistamines
- Significant possible interactions: Activated charcoal given within 1 hour of oral NAC may adsorb NAC, limiting its effectiveness.
Second Line
Oral racemethionine (methionine) á
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
Admission Criteria/Initial Stabilization
- 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 transfer to a site capable of liver transplant.
- Activity may be restricted if significant hepatic damage is present.
- Outpatient management of nontoxic accidental ingestions
Patient Monitoring
Ask about possible ingestion by others (i.e., suicide pacts). á
DIET
No special diet, except with severe hepatic damage á
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 ╬╝mol/L]) is associated with a poor prognosis and possible need for liver transplant (6)[C]. Early referral increases the chance for transplant success (5)[A].
- Hepatic failure is very rare in children <6 years of age.
COMPLICATIONS
Rare following recovery from acute poisoning á
REFERENCES
11 Brok áJ, Buckley áN, Gluud áC. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2006;(2):CD003328.22 Gaudreault áP. Activated charcoal revisited. Clin Ped Emerg Med. 2005;6:76-80.33 Heard áK. Gastrointestinal decontamination. Med Clin North Am. 2005;89(6):1067-1078.44 Acetylcysteine (Acetadote) for acetaminophen overdosage. Med Lett Drugs Ther. 2005;47(1215-1216):70-71.55 Culley áCM, Krenzelok áEP. A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective. Toxicol Rev. 2005;24(2):131-143.66 O'Grady áJG, Alexander áGJ, Hayllar áKM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445.
ADDITIONAL READING
- Ferner áRE, Dear áJW, Bateman áDN. Management of paracetamol poisoning. BMJ. 2011;342:d2218.
- Larson áAM, Polson áJ, Fontana áRJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364-1372.
- Major áJM, Zhou áEH, Wong áHL, et al. Trends in rates of acetaminophen-related adverse events in the United States [published online ahead of print November 3, 2015]. Pharmacoepidemiol Drug Saf.
- Mund áME, Quarcoo áD, Gyo áC, et al. Paracetamol as a toxic substance for children: aspects of legislation in selected countries. J Occup Med Toxicol. 2005;10:43.
SEE ALSO
Acetaminophen Poisoning, Treatment á
CODES
ICD10
- T39.1X4A Poisoning by 4-Aminophenol derivatives, undetermined, init
- 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
ICD9
- 965.4 Poisoning by aromatic analgesics, not elsewhere classified
- 573.3 Hepatitis, unspecified
SNOMED
- 70273001 Poisoning by acetaminophen
- 197356006 Toxic liver disease with hepatic necrosis (disorder)
- 290134002 Accidental acetaminophen poisoning (disorder)
- 290136000 Acetaminophen poisoning of undetermined intent (disorder)
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"Ł or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 ╬╝g/mL (993 ╬╝mol/L), >75 ╬╝g/mL (497 ╬╝mol/L), and >40 ╬╝g/mL (265 ╬╝mol/L) at 4, 8, and 12 hours after ingestion, respectively.
- 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.