Pediatric Acetaminophen Toxicity 

It is not surprising that acetaminophen toxicity is a relatively common occurrence, particularly in children, given that this drug is the most widely used analgesic-antipyretic medication taken by people in the United States and around the world.^[1] Since the 1950s, the availability of acetaminophen in over-the-counter (OTC) preparations and the contraindication of pediatric use for aspirin-containing products have made acetaminophen one of the most commonly used drugs in pediatric medicine.

Acetaminophen is available in more than 200 OTC and prescription medications as a single agent or in combination with other pharmaceuticals. Numerous formulations and preparations are also available and include liquids, tablets, caplets, capsules, and suppositories in immediate-release and sustained-release forms.

Acetaminophen, or paracetamol, is also known by its chemical name, N -acetyl-p -aminophenol (APAP). It has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur with misuse and overdoses. N -acetylcysteine (NAC) is an effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.^[2]

Acetaminophen (APAP) metabolism is illustrated in the image below.

Not only is acetaminophen (APAP) the drug most commonly ingested in overdoses, it is also a common co-ingestant. Owing to its widespread availability and the underestimation of its potential toxicity, acetaminophen (APAP) poisoning is the most common cause of acute liver failure and overdose deaths. In Great Britain, acetaminophen (APAP) toxicity is cited as the most common etiology of hepatic failure requiring liver transplantation.

Overdose with this agent can present at any age. A therapeutic misadventure typically occurs in patients younger than 1 year when caregivers give improper doses of a medication that contains acetaminophen (APAP) to a child. An accidental poisoning (unintentional ingestion) can occur in toddlers and young children. Older patients (eg, teenagers and adults) may overdose with intent to do self-harm.

See also Acetaminophen Toxicity, Pediatric Liver Transplantation, Liver Transplantation, and Transfusion Requirements in Liver Transplantation.

Therapeutic oral doses of acetaminophen (APAP) are rapidly absorbed by the gastrointestinal (GI) tract, with body serum levels peaking at 0.5-2 hours postingestion. Therapeutic levels are 10-20 mcg/mL (66-132 mcmol/L). Serum peak levels occur after an overdose within 4 hours postingestion for an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (such as opiates, anticholinergic agents) or ingestion of an acetaminophen (APAP) extended-release formulation may increase the peak serum level to more than 4 hours postingestion. The elimination half-life of acetaminophen is estimated to be 2-4 hours.

Metabolism of acetaminophen (APAP) is primarily hepatic. The liver metabolizes more than 90% of an acetaminophen (APAP) dosage to sulfate and glucuronide conjugates, which are water soluble and are then eliminated in the urine. Sulfation is the primary metabolic pathway in children aged 12 years and younger. Glucuronidation predominates in adolescents and adults. Two percent of an acetaminophen (APAP) dose is excreted unchanged by the kidneys. The remaining acetaminophen (APAP) is metabolized by the hepatic cytochrome P450 (CYP450) system to form a reactive, highly toxic metabolite known as N -acetyl-p -benzoquinone imine (NAPQI) (see the following image). Glutathione binds NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine.

Therapeutic doses of acetaminophen (APAP) do not cause hepatic injury; however, because hepatic glutathione stores are depleted (by 70-80%) in an overdose, NAPQI cannot be detoxified and covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Necrosis primarily occurs in this hepatic region due to the greater production of NAPQI by these cells. Glutathione stores to enable metabolism of this toxic metabolite are replaced by sulfhydryl compounds from the diet (eg, fruits and vegetables) or from drugs, such as the antidote, N -acetylcysteine (NAC).

Age, diet, liver disease, and medical conditions (eg, malnutrition due to prolonged fasting, gastroenteritis, chronic alcoholism, or human immunodeficiency virus (HIV) disease) affect glutathione stores in the body. Ethanol and drugs such as isoniazid (INH), rifampin, phenytoin, phenobarbital, barbiturates, carbamazepine, trimethoprim-sulfamethoxazole (TMP-SMX), and zidovudine induce CYP2E1 enzymes (part of the CYP450 system). Activation of the cytochrome system increases the production of NAPQI and, therefore, can increase the risk of hepatocellular injury in patients who ingest these agents. Herbal supplements may also play a role in amplifying the risk for acetaminophen (APAP)–induced hepatic injury.

Production of N -acetyl-p -benzoquinone imine (NAPQI) by the cytochrome P (CYP) system is the cause of liver toxicity in acetaminophen (APAP) overdose.

Maximum APAP dosages

The maximum daily adult dose of acetaminophen (APAP) is 4 g with a recommended dosage of 352-650 mg every 4-6 hours or 1 g every 6 hours. For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dosage of acetaminophen (APAP) is 80 mg/kg (not to exceed a cumulative daily dose of 2.6 g).

Therapeutic weight-based oral dosing for children younger than 12 years is 10-15 mg/kg every 4-6 hours with a maximum of 5 doses per 24-hour period. Weight-based rectal suppository dosing for children is higher at 15-20 mg/kg per dose.

Minimum APAP dosages

In adults, the minimum toxic dose of acetaminophen (APAP) for a single ingestion is 7.5-10 g. Single ingestions of 12 g or higher have high potential for hepatotoxicity.

In children, the minimum toxic dose of acetaminophen (APAP) for a single acute ingestion is 150 mg/kg. Medical toxicologists recommend increasing this threshold to 200 mg/kg in healthy children aged 1-6 years. Children in this age group are less susceptible to hepatotoxicity due to acute acetaminophen (APAP) poisoning because of their relatively larger hepatic mass (ie, ratio of organ weight to total body weight), which efficiently eliminates and detoxifies N -acetyl-p -benzoquinone imine (NAPQI).

Toxic APAP dosages

Children who have acutely ingested 250 mg/kg or more of acetaminophen (APAP) pose significant concern for acetaminophen (APAP)-induced hepatotoxicity. Patients who ingest more than 350 mg/kg develop severe hepatotoxicity, if they are not appropriately treated.

In June 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription medication to provide new information regarding acetaminophen (APAP)–induced hepatotoxicity.^{[3, 4, 5]} Additionally, the FDA is: (1) examining possible removal of acetaminophen (APAP) from some popular analgesic combination products (eg, Vicodin) and/or lowering the maximum cited daily dose, and (2) evaluating whether changes need to be made for acetaminophen (APAP) regarding the following:

• Safe daily dose for healthy individuals
• Safe daily dose in patients with chronic liver disease
• Safe daily dose when ingested concurrently with alcohol
• Appropriate dose for efficacy
• Package size restrictions
• Pediatric dosing
• Acetaminophen (APAP) narcotic combinations

In January 2011, the FDA announced it was asking manufacturers of prescription acetaminophen (APAP) combination products to limit the maximum amount of the drug in these products to 325 mg per tablet, capsule, or other dosage unit.^[6] The FDA believes such a limitation will reduce the risk of hepatoxicity from acetaminophen (APAP) overdosing, an ingestion that could lead to liver failure, liver transplantation, and death.^[6]

The proper medical use of the antidote N -acetylcysteine (NAC) has significantly lowered the mortality rate of patients with acetaminophen (APAP) toxicity. Most patients do not have clinically significant sequelae if they are treated in a timely manner with antidotal therapy and appropriate supportive care.

In acute exposures, mortality and morbidity rates are lower in young children (≤5 y) than in older children, adolescents, and adults. The cause for this age-related difference is unclear but may be due to an increased capacity for conjugation with sulfate, an increased supply and regeneration of glutathione stores, lower ingested doses, or a greater likelihood to vomit after an acute ingestion.

Patients with acetaminophen (APAP) levels below the possible line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared. If the ingestion occurred with an intent to harm oneself, a thorough psychosocial and/or psychiatric evaluation is indicated before the patient can be discharged from the hospital.

Inform parents and caregivers of the risks associated with acetaminophen (APAP) overdose in children and adolescents and that this drug, although it is safe when dosed properly, can cause harm if misused.

Educate parents and caregivers about the proper dose of acetaminophen (APAP) in children based on weight, and inform them that various preparations have different concentrations of acetaminophen (APAP). Adult formulations of this agent should not be used to treat children. Also educate parents and caregivers that many over-the-counter (OTC) cold and cough preparations contain acetaminophen (APAP). Therefore, they should carefully read medication labels before they give these preparations to children.

Give parents and caregivers information, including the toll-free phone numbers for the National Poison Control Center hotline (1-800-222-1222) and their regional Poison Control hotline.

For patient education information, see (Tylenol) Poisoning and Poisoning. The US Food and Drug Administration (FDA) has patient and caregiver education resources through its Consumer Health Information Website.^{[7, 6]}