Acetaminophen Toxicity in Children: Diagnosis, Clinical Assessment, and Treatment of Acute Overingestion
ABSTRACT: Acetaminophen is the most commonly used pain medication in the United States, and its ubiquity results in its being one of the most frequently implicated drugs in childhood poisonings. This article reviews the pathophysiology of acetaminophen metabolism, the clinical and diagnostic clues of an acute overdose, differential diagnoses, and management approaches including the use of the antidote, N-acetylcysteine (NAC), for acute acetaminophen overdose and toxicity in pediatric patients.
Key words: acetaminophen, paracetamol, N-acetyl-p-aminophenol (APAP), acetaminophen-induced hepatotoxicity, N-acetyl-p-benzoquinone imine (NAPQI), glutathione, sulfation, liver transaminases, centrilobular hepatic necrosis, Rumack-Matthew nomogram, N-acetylcysteine (NAC)
Acetaminophen is the most commonly used analgesic–antipyretic medication given to children in the United States and worldwide. In 2005 alone, U.S. consumers purchased more than 28 billion doses of products containing acetaminophen.1 The increased use of acetaminophen since the 1960s stems from the association of aspirin-containing medications with the occurrence of Reye syndrome in children. Today, acetaminophen (chemical name N-acetyl-p-aminophenol, or APAP; known as paracetamol in most countries outside of the United States and Canada) is readily accessible and is an ingredient in more than 200 over-the-counter and prescription medications, either as a single agent or in combination with other pharmaceuticals.
Many formulations with different concentrations of acetaminophen are available, including liquid suspensions, tablets, capsules, and rectal suppositories with a paraffin base. Brand names of some acetaminophen-based medications are Tylenol, Panadol, Māpap, FeverAll, and Tempra. In November 2010, the U.S. Food and Drug Administration (FDA) approved an intravenous preparation of acetaminophen (trade name Ofirmev) for inpatient use in children older than 2 years of age.2
Despite its excellent safety profile when properly dispensed, acetaminophen is cited as one of the drugs that is most often ingested in childhood poisonings.3 A single acute overdose can be life threatening due to the risk of acetaminophen-induced hepatotoxicity, potentially leading to liver failure and death.
This review article discusses the pathophysiology of acetaminophen metabolism, the clinical and diagnostic clues of an acute overdose, differential diagnoses, and management approaches for pediatric patients. Acetaminophen-induced hepatotoxicity due to chronic overdose (also known as repeated supratherapeutic acetaminophen ingestion) is not discussed.
Pathophysiology
Standard therapeutic oral doses of acetaminophen are rapidly absorbed from the gastrointestinal tract, primarily in the small intestine. Peak serum concentrations are achieved at about 2 hours postingestion. When an acute overdose occurs, the peak serum concentration increases to 4 hours for immediate-release preparations. The presence of a coingestant that delays gastric emptying, or an overdose with an extended-release formulation of acetaminophen, further increases this time.
After ingestion, 90% to 95% of acetaminophen metabolism takes place in the liver (Figure 1). The kidneys excrete the water-soluble byproducts of this hepatic metabolism, and a small amount (about 2%) is urinated as unchanged acetaminophen. The primary metabolic pathways occurring in hepatic tissue are sulfation, which predominates in children younger than 12 years old, and glucuronidation, which prevails in adolescents and adults. Four percent of the remaining acetaminophen dose is biotransformed by the hepatic cytochrome P-450 system. This biotransformation creates a reactive, highly toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). Glutathione, present in the hepatic tissue, binds to NAPQI and produces a nontoxic byproduct that subsequently is excreted by the kidneys. An acute acetaminophen overdose depletes hepatic glutathione stores by 70% to 80%; hence, not all NAPQI can be metabolized. Buildup of this toxic metabolite causes hepatic injury by binding covalently to the lipid bilayer of hepatocytes. Hepatic centrilobular necrosis occurs.
The drug N-acetylcysteine (NAC) prevents hepatic injury by replenishing glutathione stores to metabolize the excess NAPQI created in an acute acetaminophen overdose. Glutathione is replaced under normal conditions from dietary sulfhydryl compounds, especially fruits and vegetables.4
Acetaminophen overdose can occur at any age. The patient’s age helps clarify the cause of the ingestion. Improper dosing of a patient younger than 1 year of age is termed a therapeutic misadventure, indicating that the infant’s caregiver administered an incorrect dosage. Accidental or unintentional poisonings occur in toddlers and young children who can access toxic substances and/or medications in an unsupervised environment. Teenagers and adults may ingest toxic amounts of acetaminophen to self-harm as a cry for help.5-7
The recommended weight-based single dose of oral acetaminophen is 10 to 15 mg/kg every 4 to 6 hours, with no more than 5 doses per 24-hour period. These guidelines apply to most children under 12 years of age. If the child weighs 50 kg or more, an adult dosage regimen is used. With the use of acetaminophen rectal suppositories, differences in bodily absorption increase the weight-based dose to 20 mg/kg, with the same dosage time interval as with oral acetaminophen.
The minimum toxic single dose of acetaminophen for children is 150 mg/kg. Medical toxicologists have recommended increasing this potential toxicity dose to 200 mg/kg in healthy children aged 1 to 6 years. Children at this young age are able to metabolize acetaminophen and to detoxify NAPQI more efficiently due to their greater hepatic mass (comparing organ weight to total body weight). For adult-size patients (greater than 50 kg), the minimum toxic single dose is 7.5 to 10 g.
Children who ingest a single dose greater than 250 mg/kg have significant risk of developing acetaminophen-induced hepatotoxicity. Adults who acutely ingest greater than 150 mg/kg or more than 12 g of acetaminophen have severe hepatic risk. In these situations, immediate medical care is imperative to prevent liver injury.
Patient risk for hepatic injury after a single acute ingestion is interpreted by the Rumack-Matthew nomogram (Figure 2).8 This logarithmic graph, also called the acetaminophen nomogram, plots the plasma acetaminophen level starting at 4 hours postingestion and ending at 24 hours postingestion. Plasma acetaminophen levels greater than 150 µg/mL at 4 hours on the x-axis indicate possible toxicity.
Clinical Assessment
The early symptoms of acute acetaminophen overdose are outlined in Table 1. Four clinical stages (or phases) are defined for untreated patients with a history of acetaminophen poisoning who subsequently develop acetaminophen-induced hepatotoxicity and liver failure (Table 2).9,10
Stage 1: 0.5 to 24 hours postingestion. Overall clinical findings are nonspecific and range from asymptomatic to nausea, anorexia, emesis, diaphoresis, and fatigue. Given these nonspecific symptoms, patients are at risk of being given an acetaminophen-based product to treat their complaints. Physical findings may reveal compromised hydration status resulting from repeated emesis and increased insensible fluid losses. Elevation of liver transaminases (alanine transaminase and aspartate transaminase) is seen on laboratory study results 12 hours postingestion.
Stage 2: 24 to 72 hours postingestion. Clinical findings include abdominal pain and tenderness localized to the right upper quadrant. Hepatomegaly and midline abdominal tenderness (as seen in acute pancreatitis) may be detected on physical examination with a report of deceased urinary output. Ongoing volume losses occur, with vital signs indicating tachycardia and hypotension. Laboratory test results show liver transaminase abnormalities, elevated prothrombin times, and elevated bilirubin, along with abnormalities in renal function test results (ie, blood urea nitrogen and creatinine).
Stage 3: 3 to 5 days postingestion. This stage, also called the hepatic stage, is characterized by clinical indicators of hepatic failure, such as jaundice, hypoglycemia, and bleeding due to coagulopathies. Concurrent symptoms of anorexia, nausea, vomiting, and fatigue, as in stage 1, are reported. Symptoms reflect multiorgan failure. Laboratory test values continue to worsen, with evidence of lactic acidosis, prolonged prothrombin time, markedly elevated liver transaminases, elevated bilirubin (primarily indirect), renal function abnormalities, and hyperammonemia. Liver biopsy pathology shows centrilobular necrosis. Acute tubular necrosis leads to renal failure. Encephalopathy emerges due to hyperammonemia and uremia. Death occurs most often in this stage.
Stage 4: 5 to 14 days postingestion, up to 21 days. This stage marks either death or resolution of symptoms with eventual normalization of blood laboratory values.
Differential Diagnosis
Other diagnoses should be considered in patients who present with acute hepatic tissue injury. Among the diagnoses that are worthy of attention are inborn errors of metabolism, such as α1-antitrypsin deficiency or fatty acid oxidation abnormalities; gastroenteritis; Reye syndrome (if a child has a history of aspirin ingestion); hepatitis A, B, and C; and hepatitis caused by cytomegalovirus, Epstein-Barr virus, or varicella. Other possible diagnoses include drug-induced or toxin-induced hepatitis (eg, amatoxin from mushroom ingestion), hepatobiliary disease, hepatorenal syndrome, Wilson disease, pancreatitis, and pancreatic pseudocyst.9
Complete medical histories (inclusive of past and present clinical illnesses, past hospitalizations and surgeries, travel history, family history, medication history, allergies to medications or foods, and immunization status) in conjunction with a thorough physical examination can offer clues to other possible causes of hepatic insult.
Therapeutic Approach
A patient with a clinical history of acetaminophen poisoning should be immediately assessed in an emergency department or other hospital facility. Stabilization of the patient is critical, including completing the ABC (airway, breathing, circulation) checklist. Possible coingestion of medications including salicylates must be addressed with patients and/or caregivers, since this knowledge influences medical treatment.
In the emergency department setting, the patient may be a candidate for oral gastrointestinal decontamination using activated charcoal. Standard treatment guidelines should be followed with attention paid to protecting the patient’s airway. Information about ingestion time is critical for this intervention, since the ideal time to successfully decontaminate with activated charcoal is within 2 hours postingestion. An upper limit of 4 hours postingestion also is cited for decontamination efficacy, especially if there is a coingestant that delays gastric motility or if the ingestant is an extended-release preparation.11
The next step is to assess the patient’s risk for acetaminophen-induced hepatotoxicity. Laboratory studies inclusive of plasma acetaminophen and plasma salicylate levels (if there is any concern of a coingestant) should be obtained, in addition to a complete blood count, electrolytes, coagulation studies (prothrombin time and partial thromboplastin time), liver transaminase (alanine transaminase and aspartate transaminase) levels, and bilirubin level. Girls and women of childbearing age require a pregnancy test, because acetaminophen crosses the placental barrier and can pose a fetal risk. The ammonia level should be checked in patients with altered mental status or an encephalopathic presentation.
Treatment With NAC
The therapeutic goal with NAC is to reduce the amount of hepatotoxic metabolite, NAPQI, by biotransforming it into a nontoxic form. NAC becomes cysteine, replenishing glutathione stores and serving as the substrate utilized in sulfation, the primary biochemical pathway for acetaminophen metabolism in children.
Oral NAC is safe and effective therapy if administered up to 24 hours postingestion. Independent of the initial plasma acetaminophen level, NAC effectively provides hepatoprotection, especially if initiated within 8 hours postingestion.12
Patients with 4-hour postingestion plasma acetaminophen levels above the possible line on the Rumack-Matthew nomogram must be admitted as hospital inpatients for treatment with the antidote, NAC, and to enable ongoing clinical evaluation for signs of hepatotoxicity. Maximum hepatoprotective effect is achieved if NAC is started 8 to 10 hours postingestion. The oral form of NAC (trade name Mucomyst) is the antidote formulation of choice and is used for the treatment of acute, chronic, or late-presenting toxic acetaminophen ingestions. It also can be used successfully if gastrointestinal decontamination was done before starting the oral dosage regimen.13 The FDA-approved dosage regimen for oral NAC is as follows13:
• Loading dose of 140 mg/kg, followed by 17 doses at 70 mg/kg each
• Medication is administered every 4 hours until completed
• Duration of treatment is 72 hours
A drawback to the oral NAC regimen is the solution’s sulfur odor. Even when mixed in fruit juice or in a clear carbonated beverage, the smell can induce nausea and vomiting. These gastrointestinal issues can be compounded by acetaminophen-induced hepatic injury. Concurrent use of antiemetics such as metoclopramide or ondansetron may be required to continue treatment successfully. Emesis of the NAC solution within 1 hour of administration requires repeating the dose for effective treatment.
An intravenous formulation of NAC (trade name Acetadote), FDA-approved in 2004, is reserved for patients with altered mental status, gastrointestinal bleeding, history of a caustic ingestion, or refractory emesis despite the use of antiemetics. Two protocols are recognized: a 21-hour intravenous course or a 48-hour intravenous course. Up to 9% of patients who receive the intravenous antidote experience anaphylactoid reactions, triggering symptoms of flushing, pruritus, rash, and, rarely, bronchospasm and hypotension. This histamine-release response responds well to intravenous antihistamines and to slowing or stopping the infusion.14
Inpatient Consultation
Additional medical support can be provided by a medical toxicologist, especially for the care of patients with a concern for coingestions, complicated past or present medical histories, or an atypical clinical presentation. For patients with a significant risk of hepatotoxicity based on their initial acetaminophen plasma value as plotted on the Rumack-Matthew nomogram, consultation with a pediatric gastroenterologist who specializes in hepatology and who is affiliated with a liver transplant center is highly recommended. Ingestions carried out with intent to self-harm require intervention by the hospital’s social work and mental health teams.
Prognosis
Mortality from acetaminophen-induced hepatotoxicity is uncommon. Fatalities resulting from hepatic and multiorgan failure occur in less than 4% of untreated adolescents and adults with history of a single acetaminophen ingestion of less than 15 g.13 Patients with acetaminophen poisoning who receive NAC within 8 to 10 hours postingestion have a positive prognosis for recovery.
Summary
Acetaminophen poisoning is a serious medical concern given the known risk for hepatotoxicity leading to hepatic failure and death. Acetaminophen is readily accessible, has an excellent safety profile, and relieves pain and fever when administered properly; nevertheless, acetaminophen toxicity is the leading cause of acute liver failure in the United States.
The recent modifications to dosage guidelines and the addition of product warnings have placed acetaminophen in the medical and pharmaceutical spotlights. Continued awareness and ongoing public education about the risks of acetaminophen toxicity aim at further minimizing this hazard and increasing the medication’s safety profile (Sidebar).
REFERENCES:
1. US Food and Drug Administration. Acetaminophen overdose and liver injury—background and options for reducing injury. http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf. Accessed June 18, 2013.
2. Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics. 2012;129(2):349-353.
3. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC. 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila). 2011;49(10):910-941.
4. Hendrickson RG, Bizovi KE. Acetaminophen. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York, NY: McGraw-Hill; 2006:523-543.
5. Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol. 1991:32(2):143-149.
6. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr. 1998;132(1):22-27.
7. Myers WC, Otto TA, Harris E, Diaco D, Moreno A. Acetaminophen overdose as a suicidal gesture: a survey of adolescents’ knowledge of its potential for toxicity. J Am Acad Child Adolesc Psychiatry. 1992;31(4):686-690.
8. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871-876.
9. Defendi GL, Tucker JR. Pediatric acetaminophen toxicity. Medscape Reference. http://emedicine.medscape.com/article/1008683-overview. Updated April 2, 2013. Accessed June 18, 2013.
10. Young LL. Acetaminophen overdose. In: Yamamoto LG, Inaba AS, Okamoto JK, Patrinos ME, Yamashiroya VK, eds. Case Based Pediatrics for Medical Students and Residents. Honolulu, HI: University of Hawaii; 2004:505-506. http://www.hawaii.edu/medicine/pediatrics/pedtext/pedtext5.pdf. Accessed June 18, 2013.
11. Mottram AR, Kumar AM. Focus on: acetaminophen toxicity and treatment. ACEP News. May 2007. http://www.acep.org/Clinical---Practice-Management/Focus-On--Acetaminophen-Toxicity-and-Treatment/. Accessed June 18, 2013.
12. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the National Multicenter Study (1976 to 1985). N Engl J Med. 1988;319(24):1557-1562.
13. Temple AR, Baggish JS. Guidelines for the Management of Acetaminophen Overdose. Fort Washington, PA: McNeil Consumer & Specialty Pharmaceuticals. 2005. http://www.tylenolprofessional.com/assets/Overdose_Monograph.pdf. Accessed June 18, 2013.
14. Blackford MG, Felter T, Gothard MD, Reed MD. Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review. Clin Ther. 2011;33(9):1322-1330.
15. US Food and Drug Administration. June 29-30, 2009: Joint meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee: meeting announcement. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Updated July 7, 2009. Accessed June 18, 2013.
16. FDA drug safety communication: prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure [safety announcement]. Rockville, MD: US Food and Drug Administration; January 13, 2011. http://www.fda.gov/drugs/drugsafety/ucm239821.htm. Accessed June 18, 2013.
17. US Food and Drug Administration. Acetaminophen information. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107. Updated July 6, 2012. Accessed June 18, 2013.
18. FDA acetaminophen dosage announcement. Announcement 468. http://www.medicaid.nv.gov/Downloads/provider/web_announcement_468_
20120425.pdf. Published April 25, 2012. Accessed June 18, 2013.