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Management of Acetaminophen Toxicity Guideline

Guideline/Protocol Title Management of Acetaminophen Toxicity Guideline
Authors Peter Akpunonu, MD
Abby M. Bailey, PharmD
Committee Review Regan A. Baum, PharmD
Gavin Howington, PharmD
Andrew Micciche, MD
Jordan Woolum, PharmD
Formulary P&T Subcommittee
P&T Committee
Target Population Patients with suspected or known ingestion of acetaminophen
Overview Approved therapies for the management strategies include gastric decontamination and N-acetylcysteine (NAC). Symptomatic treatment is also recommended.
Effective Date 10/15/2024
Expiration Date 10/15/2026
Schedule for Periodic Review Every 2 years
Implementation Strategy Posting to CareWeb, Epic updates, education to pharmacists, physicians, advanced practice providers, and nurses.
Education Strategy Protocol shared on CareWeb
Primary Outcome(s) / Assessment Utilization review as needed
Associated Epic Order Sets & Panels TOX Acetaminophen Overdose (order set)

Initial Management Recommendations

  1. Establish intravenous access
  2. Establish clear history, substance(s) ingested, time and amount of ingestion(s)
    • Calculate maximum potential acetaminophen ingestion per kg in last 24 hours
    • Determine acetaminophen formulation (mono-product vs combination product, extended-release) and assess the need to treat for other co-ingestants (anticholinergic or opioid containing products)
    • Determine symptomatology (abdominal pain, vomiting, jaundice, etc.)
  3. Obtain baseline vital signs and evaluate mental status (GCS)
  4. Continuous ECG monitoring
  5. Immediately obtain:
      a. Finger stick blood glucose b. CMP to monitor electrolytes and liver function tests (transaminases) c. PT/INR d. Lactate e. Urine drug screen f. May consider obtaining drugs of abuse panel, toxic alcohol panel, and/or ethylene glycol level. g. Serum salicylate level h. Serum acetaminophen level (based on guidance below)
Time of Acetaminophen ingestion is known:
Drawn <4 hours post-ingestion
  • Offer limited clinical utility
  • May wait to draw 4-hour level
Levels drawn between 1 to <4 hour from ingestion:
  • If acetaminophen level <20 mcg/mL and AST/ALT normal, no further levels are warranted.
  • If acetaminophen level is ≥20 mcg/mL and AST/ALT normal, redraw level at 4 hours post ingestion.
  • If AST/ALT elevated, treat as acute ingestion.
Drawn between 4- and 24-hours post-ingestion
  • Above treatment line on the Modified Rumack-Matthew Nomogram, then antidote therapy with N-acetylcysteine (NAC) should begin immediately
Time of ingestion is unknown:
  • Acetaminophen level <20 mcg/mL and AST/ALT normal: no further levels or treatment are necessary.
  • Acetaminophen level ≥20 mcg/mL or AST/ALT>100; treat as acute overdose.
    • Initiate NAC therapy
  • Elevated AST/ALT on presentation with an unclear history of ingestion.
    • Initiate NAC therapy
Delayed presentation (>8 hours post ingestion):
  • NAC therapy should not be delayed for acetaminophen levels to result
Repeated Ingestions over >24 hours
  • Acetaminophen level ≥20 mcg/mL or AST/ALT>100; treat as acute overdose.
  1. Declining mental status may necessitate intubation of the patient.
Consultation with the Kentucky Poison Control Center is strongly encouraged for all patients (1-800-222-1222).
Direct contact with the UK medical toxicologist (UKMDs) is recommended for critically ill patients.

Special Considerations for Early Consultation with Medical Toxicology

Please consult medical toxicology for advanced treatment modalities in the following settings:

  • 4-hour [APAP]>300 mcg/mL OR estimated acetaminophen ingestion >30 g (300 mg/kg in pediatrics)
  • Arterial pH <7.3 despite aggressive resuscitation measures
  • Hepatic encephalopathy, grade 3 or 4
  • INR >6.5
  • Serum creatinine ≥3.4 mg/dL
  • When considering either intermittent hemodialysis (iHD) or continuous venovenous hemodialysis (CVVHD) to aid in the elimination of APAP

Monitoring

  • Vital signs, neurologic status, respiratory status, and fluid status should be monitored closely.
  • Acetaminophen level, transaminases, and PT/INR should be checked approximately 2-hours prior to completion of the 2-Step NAC protocol to assess whether continuation of NAC is warranted.
  • Phosphate levels should be monitored and replaced in all patients with evidence of hepatotoxicity as hypophosphatemia may occur while liver function improves.

Gastrointestinal Decontamination

Modality Dosing Notes
Activated charcoal (AC) Single-dose: 0.5-1 g/kg (maximum: 50 g) Consider AC within 4 hours of ingestion if airway is protected or patient is intubated.
May be warranted longer than 4 hours post ingestion in large burden overdoses or for extended release products due to prolonged absorption products due to prolonged absorption
Not recommended in repeated ingestions over >24 hours

Dosing and Administration of 2-Step N-Acetylcysteine

Initiation of Therapy - Intravenous Administration:

  • Step 1 - Load with 150 mg/kg (maximum: 15,000 mg) in 200 mL D5W; Infuse over 60 minutes
  • Step 2 - Begin continuous Infusion NAC at a rate of 12.5 mg/kg/hr for 20 hours (weight capped at 100 kg)

NAC recommendations for patients that have received a partial dose of therapy:

Patients who received ≥150 mg/kg NAC in the last 8 hours

Continue Step 2 - Begin continuous Infusion NAC at a rate of 12.5 mg/kg/hr for 20 hours (weight capped at 100 kg)

Patients who received <150 mg/kg NAC in the last 8 hours

Step 1 - Load with 150 mg/kg (maximum: 15,000 mg) in 200 mL D5W; Infuse over 60 minutes
Step 2 - Begin continuous Infusion NAC at a rate of 12.5 mg/kg/hr for 20 hours (weight capped at 100 kg)

Discontinuation criteria of NAC therapy:

Acetaminophen level, transaminases, and INR should be checked approximately 2 hours prior to completion of the 2-Step NAC protocol to assess whether continuation is warranted.

  1. Acetaminophen level <20 mcg/mL INR <2.0, AST/ALT are normal for patient or have decreased from peak (25-50%), and patient is clinically well: no further treatment is required.
  2. Acetaminophen level ≥20 mcg/ml but AST/ALT and INR are normal, recommend continuing protocol (continuous infusion NAC at a rate of 6.25 mg/kg/hr [weight capped at 100 kg]) and re-check acetaminophen level and AST/ALT 2 hours prior to completion of 16-hour therapy.
  3. AST/ALT and INR elevated above normal AND undetectable acetaminophen level, recommend continuing protocol (continuous infusion NAC at a rate of 6.25 mg/kg/hr [weight capped at 100 kg]) until after AST/ALT have peaked, are down trending (2 consecutive measurements), decreased from peak (25-50%), plus INR is <2.0.

Large Burden Overdose (High Risk Ingestion)

An ingestion of APAP >30 g (300 mg/kg in pediatric patients) or an initial [APAP]>300 mcg/mL. Previous cases of hepatotoxicity have been published after large burden overdoses despite "adequate" NAC doses being initiated within 8 hours of ingestion using the traditional 3-step FDA-approved protocol. No data exists to determine the most optimal dosing strategy in this setting. Close monitoring and increased NAC doses have been utilized successfully. Theoretically, equimolar dosing of NAC is administered to match NAPQI generation. Although not feasible to calculate clinically, administration of the UK HealthCare institutional 2-Step protocol provides supratherapeutic amounts of NAC, potentially protective in the setting of large burden overdose.

Recommendations:

  • Please consult the Medical Toxicology service for recommendations.
  • Initiate 2-Step NAC protocol.
  • Acetaminophen level, transaminases and INR need to be trended every 4-6 hours to assess for downward trends.
  • NAC infusions should not exceed the 600 to 900 mosmol/L range when treating large burden overdoses.
  • Fomepizole may be considered. For guidance on use please consult medical toxicology.

References:

  1. Hendrickson RG. Acetaminophen. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. 3210. =11638
  2. Hendrickson RG, Howland M. Antidotes in Depth. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. 6919. =6508
  3. Rumack BH: Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40:3-20
  4. Rumack BH, Bateman DN: Acetaminophen and acetylcysteine dose and duration: past, present, and future. Clin Toxicol. 2012;50:91-98.
  5. The Extracorporeal Treatments in poisoning workgroup (EXTRIP) http://www.extrip-workgroup.org.
  6. Gosselin S, Juurlink DN, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD; EXTRIP workgroup. (2014) "Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup." Clinical toxicology. 52(8):856-67.
  7. Filip AB, Mullins ME. Fomepizole should be used more liberally in paracetamol overdose. Br J Clin Pharmacol. 2023 Feb;89(2):594-598.
  8. Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity. Ann Pharmacother. 2011 Jun;45(6):713-20.
  9. Pauley KA, Sandritter TL, Lowry JA, Algren DA. Evaluation of an Alternative Intravenous N-Acetylcysteine Regimen in Pediatric Patients. J Pediatr Pharmacol Ther. 2015 May-Jun;20(3):178-85.
  10. Gosselin S et al. (2014) "Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup." Clin Toxicol. 52(8):856-67.
  11. Dart RC, Mullins ME, Matoushek T, Ruha AM, Burns MM, Simone K, Beuhler MC, Heard KJ, Mazer-Amirshahi M, Stork CM, Varney SM, Funk AR, Cantrell LF, Cole JB, Banner W, Stolbach Al, Hendrickson RG, Lucyk SN, Sivilotti MLA, Su MK, Nelson LS, Rumack BH. Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement. JAMA Netw Open. 2023 Aug 1;6(8):e2327739.

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