Evidence Based Strategies: Acetaminophen Overdose

Column Author: Kelsey P Gavin, DO | Resident PGY 3; Chief Resident

Column Editor: Angela D. Etzenhouser, MD, FAAP | Associate Director, Pediatric Residency Program

Acetaminophen is a common over-the-counter medication available in many formulations as a single drug and in combination with other medications. While acetaminophen is frequently found in medicine cabinets across the country, accidental and intentional overdoses are common, and a leading cause of acute liver injury in the pediatric population.¹ Understanding the management of acute acetaminophen overdose and its sequelae is essential to providing care to the pediatric population.

Recommended enteral dosing of acetaminophen is 10 to 15 mg/kg every four to six hours.¹ Sources of toxicity in pediatric patients include a single dose greater than 150 mg/kg, greater than 200 mg/kg/d in one day, or 150 mg/kg/d over two days.² Approximately 90%-95% of acetaminophen metabolism takes place in the liver.³ The primary metabolic pathway for children <12 years of age is via sulfation compared to glucuronidation in adolescents and adults.³ Following saturation of this pathway, approximately 4% of acetaminophen is biotransferred by hepatic cytochrome P450, creating the highly reactive and toxic metabolite N-acetyl-p-benzoquinone imine or NAPQI.³ With appropriate dosing, minimal NAPQI is produced.³ NAPQI that is not removed in the urine is conjugated by liver glutathione into non-toxic compounds, which are easily excreted.³ In supratherapeutic doses, NAPQI production exceeds enzyme capacity, causing build-up of toxic metabolites and resulting in oxidative hepatic injury.³

Presentation post-ingestion is classified in four stages, arranged in chronological order. Stage one occurs within 0.5-24 hours after ingestion.^2,3 Clinical status ranges from asymptomatic to nonspecific gastrointestinal and systemic symptoms, with preserved mentation.^2,3 Laboratory findings are typically normal, though transaminases can rise as early as 12 hours post-ingestion.^2,3 In stage two (24-72 hours post-ingestion), clinical symptoms include right upper quadrant pain, hepatomegaly, tachycardia and hypotension.^2,3 There may be elevation in transaminases within 24-36 hours of overdose.^2,3 Other lab abnormalities may include elevated PT/INR, hyperbilirubinemia and abnormal renal function markers.^2,3 Evidence of hepatotoxicity and ensuing liver failure will typically present in stage three (72-96 hours post-ingestion).^2,3 Patients can appear jaundiced with hepatic encephalopathy, have evidence of hepatorenal syndrome, or have multiorgan failure.^2,3 Labs can show significant elevations in transaminases, hyperbilirubinemia, metabolic (lactic) acidosis with elevated anion gap, and prolonged PT/INR.^2,3 Stage three is associated with the highest incidence of fatality.^2,3 Patients who survive to stage four (96 hours to two weeks post-ingestion) have resolution of clinical symptoms with return to normal lab findings.³

The first step in the diagnosis of acetaminophen toxicity is obtaining an acetaminophen level four hours after ingestion.³ One level of acetaminophen greater than 150 mcg/mL four hours post-ingestion is considered toxic and treatment should be initiated.³ Clinical management is guided by the Rumack-Matthew nomogram, a validated tool for predicting hepatotoxicity in patients following a single acute overdose.² It is not applicable in cases with acute liver failure, established hepatotoxicity, chronic overdose, or when time of ingestion is unknown.² Should the level fall within the treatment range per the nomogram, N-acetyl cysteine (NAC) is initiated.³ NAC works as a cysteine substrate to replenish hepatic glutathione stores by shuttling unmetabolized acetaminophen out of the NAPQI pathway.² NAC also reduces NAPQI back to acetaminophen directly, preventing hepatotoxic effects.²

Ideally, NAC administration should begin six to eight hours following ingestion. If for any reason treatment is delayed, NAC may be administered while the acetaminophen level is pending.² If the ingestion falls outside of the nomogram’s time parameters, NAC should be started if the serum acetaminophen level is >10 mcg/dL or if serum transaminases are elevated.² At Children’s Mercy Kansas City, NAC administration protocol is an IV load of 150 mg/kg followed by a continuous infusion of 15 mg/kg/hr until the patient shows improvement in aminotransferases, INR normalization, and an undetectable acetaminophen level. In critically ill patients who progress to fulminant hepatic failure and do not respond to NAC, liver transplantation may be indicated.²

While acetaminophen is a useful medication in the setting of analgesia and antipyretic needs, the sequelae from overdose range from mild transient liver injury to fatality. While providing guidance on use of acetaminophen, we also need to counsel families on appropriate dosing, frequency, and storage mechanisms to keep patients safe.

References:

1. Agrawal S, Khazaeni B. Acetaminophen toxicity. Updated June 9, 2023. In: StatPearls. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK441917/
2. Nadler A, Fein D. Acetaminophen poisoning. Pediatr Rev. 2018;39(6):316-318.
3. Defendi G. Acetaminophen toxicity in children: diagnosis, clinical assessment, and treatment of acute overingestion. Consultant 360. 2013;12(7).