Acetaminophen Toxicity

Extensive medical use of acetaminophen began in 1947. Initially in the United States, acetaminophen was available by prescription only. In 1960, this changed to an over-the-counter (OTC) status. The availability of acetaminophen in OTC preparations and the contraindication of aspirin-containing products for pediatric use (due to the association between aspirin and Reye syndrome), have made acetaminophen one of the most commonly used analgesic-antipyretic medications in current pediatric medicine. This widespread use and availability also applies to the adult population, both in the United States and the rest of the world.[3]

Acetaminophen, also known as paracetamol (outside the United States and Canada) and by its chemical name, N-acetyl-p-aminophenol (APAP), is available in more than 200 OTC and prescription medications, either as a single agent or in combination with other pharmaceuticals. Worldwide, acetaminophen is cited as a primary drug in over 50 brand- or trade-name products (eg, Tylenol, Panadol, Tempra, Mapap, FeverAll).

In the United States, 325-mg and 500-mg immediate-release tablets and a 650-mg extended-release preparation marketed for the treatment of arthritis are commonly sold. Combination formulations such as codeine-acetaminophen (Tylenol #3) and oxycodone-acetaminophen (Percocet) are prescribed. Numerous formulations and preparations are readily available, including the following:

• Elixirs
• Suspensions
• Tablets (dissolvable (Meltaways) and chewable)
• Caplets
• Capsules
• Paraffin-base rectal suppositories (FeverAll)

Acetaminophen toxicity occurs relatively frequently. In fact, the American Association of Poison Control Centers (AAPCC) reports that acetaminophen is one of the most common pharmaceuticals associated with both intentional and unintentional poisoning and toxicity.[4] Although acetaminophen has an excellent safety profile when administered in proper therapeutic doses, hepatotoxicity can occur with misuse and overdose.

Overdose with acetaminophen can occur at any age. A therapeutic misadventure typically occurs in children younger than 1 year, when their caregivers give incorrect doses of a medication containing acetaminophen. Accidental poisoning (unintentional ingestion) can occur in toddlers and young children with unsupervised access to medications. Older patients (eg, teenagers and adults) may overdose with intent to do self-harm.[5]

While acetaminophen toxicity is particularly common in children, adults have accounted for most of the serious and fatal cases.[5] Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in the United Kingdom. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation.

In an attempt to decrease this potential for acetaminophen toxicity in the United States, a number of pharmaceutical regulatory changes have been introduced. In 2009, the US Food and Drug Administration (FDA) required that nonprescription and prescription acetaminophen-containing medications provide information regarding the risks of acetaminophen-induced hepatotoxicity. In 2015, the FDA clarified the language of over-the-counter (OTC) warning labels for adults and children to read that severe liver damage may occur in any of the following circumstances[6] :

• An adult takes more than 4,000 mg of acetaminophen in 24 hours.
• A child takes more than 5 doses in 24 hours.
• This product is taken with other drugs containing acetaminophen.
• An adult has 3 or more alcoholic drinks every day while using this product. 

In addition, the FDA has considered the removal of acetaminophen from some popular analgesic combination products (eg, hydrocodone-acetaminophen [Vicodin]) and possibly decreasing the recommended maximum daily dose. The FDA is also addressing other changes to acetaminophen-based medications, including the following:

• Safe daily dose for healthy individuals (all ages: children and adults)
• Safe daily dose for patients with chronic liver disease
• Safe daily dose for patients who concurrently drink alcohol
• Appropriate dose needed for efficacy
• Package size restrictions
• Current formulations of acetaminophen-narcotic combination drugs

In 2011, the FDA announced that it was asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of APAP in these products to 325 mg per tablet, capsule, or other dosage unit.[7] In 2014, the FDA issued a statement advising that combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit should no longer be prescribed because of a risk for liver damage.[8, 9]

Unrelated to dosage, another announcement from the FDA in 2013 advised that anyone who has a skin reaction, such as the development of a rash or blister, while taking acetaminophen should stop using the drug and seek immediate medical care. A review of the medical literature showed the painkiller poses the risk for three rare but potentially fatal skin disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.[10, 11]

An intravenous (IV) formulation of acetaminophen (Ofirmev) was approved by the FDA in 2011 for inpatient use in children older than 2 years to treat fever and pain.[12] Although this article focuses on single acute ingestions of oral formulations, iatrogenic medication errors with IV acetaminophen have caused hepatotoxicity.[13] The evaluation and treatment approach for an IV acetaminophen overdose is similar to that of an oral overdose.

Clinical evidence of end-organ toxicity is often delayed 24-48 hours after an acute ingestion of acetaminophen. Consequently, the diagnosis of potential acetaminophen toxicity is based on obtaining a history of acetaminophen ingestion and confirming a potentially toxic blood level. The modified Rumack-Matthew nomogram (the acetaminophen toxicity nomogram or acetaminophen nomogram) is used to interpret plasma acetaminophen concentrations relative to time post ingestion to assess for the hepatotoxicity risk in patients. See Workup.

Oral activated charcoal avidly adsorbs acetaminophen. This gastrointestinal (GI) decontaminant can afford significant treatment benefit if administered to the patient within 1 hour post ingestion, or later if the ingestion involves an agent that delays gastric emptying or slows GI motility. N-acetylcysteine (NAC), or acetylcysteine, is an extremely effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.[14] See Treatment and Medication.

Ingested acetaminophen is rapidly absorbed from the stomach and small intestine. The serum concentration peaks 1-2 hours post ingestion. Therapeutic levels are 5-20 µg/mL (33-132 µmol/L). Peak plasma levels occur within 4 hours after ingestion of an overdose of an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (eg, opiates, anticholinergic agents) or ingestion of an acetaminophen extended-release formulation may result in peak serum levels being achieved more than 4 hours post ingestion.

Generally, the elimination half-life of acetaminophen is 2 hours (range 0.9-3.25 h). In patients with underlying hepatic dysfunction, the half-life can last as long as 17 hours post ingestion.

Acetaminophen is primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine. In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, and 3A4) to the hepatotoxic reactive metabolite N-acetyl-p -benzoquinoneimine (NAPQI).

NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is then renally excreted. Under conditions of excessive NAPQI formation or a reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins, forming NAPQI-protein adducts. This causes an ensuing cascade of oxidative damage and mitochondrial dysfunction. The subsequent inflammatory response propagates hepatocellular injury and death. Necrosis primarily occurs in the centrilobular (zone III) region, owing to the greater production of NAPQI by these cells.

Thus, the production of NAPQI, in excess of an adequate store of conjugating glutathione in the liver tissue, is associated with hepatocellular damage, necrosis, and hepatic failure. Similar enzymatic reactions occur in extrahepatic organs, such as the kidney, and can contribute to some degree of extrahepatic organ dysfunction

Currently, the maximum recommended daily dose of APAP is 75 mg/kg for children and 4 g for adults. The minimum hepatotoxic dose of APAP as a single acute ingestion is 150 mg/kg for a child and 7.5-10 g for an adult.

The ingested amount of APAP at which toxicity may occur may be less in the setting of chronic ethanol use, compromised nutritional states, fasting, or viral illness with dehydration. Co-ingestions of substances or medications known to induce the activity of the APAP-metabolizing cytochrome P (CYP) oxidative enzymes also increase the risk of hepatotoxicity; however, when proper dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

The antidote for acetaminophen poisoning, NAC, is theorized to work through a number of protective mechanisms. Since NAC is a precursor of glutathione, it increases the concentration of glutathione available for the conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP, functions as an anti-inflammatory and antioxidant, and has positive inotropic effects.

In addition, NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality, even when NAC is administered in the setting of established hepatotoxicity.

NAC is maximally hepatoprotective when administered within 8 hours of an acute acetaminophen ingestion. When indicated, however, NAC should be administered, regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure, even in the absence of measurable serum APAP levels.

See the image below.

Acetaminophen metabolism.

Production of NAPQI by the CYP system in amounts greater than can be conjugated with existing stores of glutathione is the cause of liver toxicity in acetaminophen overdose. Susceptibility is enhanced by conditions that reduce glutathione stores in the body, which include the following:

• Older age
• Restricted diet
• Underlying hepatic or renal disease
• Compromised nutritional status (eg, from prolonged fasting, eating disorders, cystic fibrosis, gastroenteritis, chronic alcoholism, or HIV disease)

In addition, the production of NAPQI (and thus the risk of hepatocellular injury) is increased by activation of the hepatic cytochrome system. Agents and medications that induce CYP enzyme activity are numerous, and include some of the following:

• Ethanol ingestion
• Tobacco smoking
• Isoniazid (INH)
• Rifampin
• Phenytoin
• Phenobarbital
• Barbiturates
• Carbamazepine
• Trimethoprim-sulfamethoxazole (TMP-SMZ)
• Zidovudine

Maximum acetaminophen dosages

Historically, the maximum daily adult dose of acetaminophen is 4 g, with a recommended dosage of 352-650 mg every 4-6 hours or 1 g every 6 hours. In 2012, the FDA suggested, but did not mandate, a maximum daily dose for adults of 3 g, with no more than 650 mg every 6 hours, as needed. McNeil Consumer Healthcare, which produces the Tylenol brand of acetaminophen, has voluntarily reduced the maximum recommended daily adult dose of its 500 mg tablet product to 3 g and of its regular-strength 325 mg tablet to 3250 mg,[15]

For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dose is 75 mg/kg, with a recommended dosage of 10-15 mg/kg every 4-6 hours as needed and no more than 5 doses per 24-hour period. Because of absorption differences, weight-based rectal suppository dosing for children is higher, at 15-20 mg/kg per dose, using the same time interval as for oral acetaminophen.

Minimum toxic acetaminophen dosages

In adults, the minimum toxic dose of acetaminophen for a single ingestion is 7.5-10 g. In children, the minimum toxic dose of APAP for a single acute ingestion is 150 mg/kg.

In healthy children aged 1-6 years, medical toxicologists recommend increasing this threshold to 200 mg/kg. Children in this age group are less susceptible to hepatotoxicity from acute acetaminophen poisoning. Differences in medication metabolism within this age group and a relatively larger hepatic mass (ie, ratio of organ weight to total body weight) may both play roles in more efficiently detoxifying and eliminating NAPQI.

Toxic acetaminophen dosages

In adults, an acute ingestion of more than 150 mg/kg or 12 g of acetaminophen is considered a toxic dose and poses a high risk of liver damage. In children, acute ingestion of 250 mg/kg or more poses significant risk for acetaminophen-induced hepatotoxicity. Children who ingest more than 350 mg/kg are at great risk for severe hepatotoxicity if not properly treated.

In 2009, the FDA announced requirements for nonprescription and prescription medications to provide new information regarding acetaminophen–induced hepatotoxicity.[16, 17, 18] The FDA addressed the possibility of removing acetaminophen from some popular analgesic combination products (eg, hydrocodone-acetaminophen [Vicodin]) and/or lowering the maximum cited daily dose of acetaminophen. The following concerns were also addressed:

• Safe daily dose for healthy individuals (all ages: children and adults)
• Safe daily dose for patients with chronic liver disease
• Safe daily dose for patients who concurrently drink alcohol
• Appropriate dose needed for efficacy
• Package size restrictions
• Current formulations of acetaminophen-narcotic combination drugs

In 2011, the FDA asked manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit.7 In 2014, the FDA issued a statement advising doctors to stop prescribing combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit.[8, 9]

In addition, in 2011 an industry-wide transition to one standard concentration of 160 mg/5 mL for all single-ingredient OTC pediatric liquid acetaminophen products was announced. Previously, mainly two concentrations of OTC acetaminophen formulations were available: 80 mg/0.8 mL (Infant Concentrated Drops) and 160 mg/5 mL (Children's Liquid Suspension or Syrup). The move to a single standard concentration was intended to minimize confusion of administration of acetaminophen preparations by caregivers, in the hope of reducing the occurrence of acetaminophen overdosing and decreasing the number of acute ingestions that cause hepatotoxicity leading to acute liver failure.[7]

Chronic acetaminophen toxicity

Chronic acetaminophen toxicity has been recognized in pediatric patients. This condition occurs in young, febrile children with reduced oral intake who are treated with repeated high doses of acetaminophen to relieve their symptoms. As a reference, the 24-hour dosage of acetaminophen for children should not exceed 75 mg/kg/d.

In chronic acetaminophen toxicity, the role of fasting, reduced glutathione stores, and enhanced metabolism remains unclear. Risk factors for chronic acetaminophen toxicity include the following[19] :

• Repeated administration of high doses
• Repeated administration of proper doses at shortened time intervals
• Fever
• Poor oral intake
• Young age (as due to caregiver mismanagement)

The American Association of Poison Control Centers' National Poison Data System reported 53,295 single exposures to acetaminophen alone in 2019, and 28,789 single exposures to acetaminophen in combination with other drugs. Acetaminophen exposure alone resulted in 198 deaths, and acetaminophen combinations resulted in 99 deaths.[4]

Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in the United Kingdom. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation. Although acetaminophen toxicity is particularly common in children, adults have accounted for most of the serious and fatal cases.[5]

With aggressive supportive care and antidotal therapy, the mortality rate associated with acetaminophen hepatotoxicity is less than 2%. If correctly treated in a timely manner, most patients do not suffer significant sequelae; patients who survive are expected to have return of normal hepatic function. In case series, fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or the need for liver transplantation occurs in less than half of these patients.

Chronic ethanol use or diminished nutritional status may increase the risk for morbidity because these conditions result in deficient glutathione stores and a subsequent inability to conjugate and detoxify NAPQI. Use of substances that induce the activity of the APAP-metabolizing CYP enzymes may increase the risk of morbidity by enhancing the production of NAPQI (see Etiology).

Pediatric patients younger than 6 years appear to fare better than adults after acute acetaminophen poisoning, perhaps owing to their greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, as no controlled studies have supported an alternative pediatric-specific therapy, treatment in children is the same as in adults.

A number of screening measurements have been studied as prognostic indicators after acetaminophen ingestion. The most widely used predictors are the King’s College Criteria, which have been well-validated to predict poor outcome and need for liver transplantation after an isolated acetaminophen overdose. The criteria consist of the following laboratory abnormalities; any serological or clinical finding should prompt urgent transplantation consultation:

• Arterial pH less than 7.30 after fluid resuscitation
• Creatinine level greater than 3.4 mg/dL
• Prothrombin time (PT) greater than 1.8 times control or greater than 100 seconds, or International Normalized Ratio (INR) greater than 6.5
• Grade III or IV encephalopathy

Levine et al reported that the combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King's College criteria for predicting death or transplant. In their retrospective cohort study of 334 adult patients with a discharge diagnosis of acetaminophen-induced liver failure, the presence of hypoglycemia increased the odds of reaching the composite endpoint (death or transplantation) by 3.39-fold. For the combination of hypoglycemia, coagulopathy, and lactic acidosis, the pseudo R2 for the area under the curve was 0.93, versus 0.20 for the King's College criteria.[20]

Another prognostic screening tool that has been studied in regard to predicting the need for liver transplantation is the Acute Physiology and Chronic Health Evaluation II (APACHE II) score completed on the patient’s first inpatient hospital stay. In one study, the APACHE II score was found to be accurate, but cumbersome to apply.[21]

Additional early predictors include changes in serum phosphate levels, which indirectly represent the balance between the development of renal failure and hepatic regeneration. Serum phosphate concentrations greater than 1.2 mmol/L measured at 48-96 hours after overdose were sensitive and specific for increased mortality.[22]

Finally, elevations in blood lactate levels have been studied as prognostic indicators after acute acetaminophen overdose.[23] Blood lactate levels greater than 3.5 mmol/L before fluid resuscitation or greater than 3 mmol/L after fluid resuscitation were found to be sensitive and specific indicators of survival. When compared to the King’s College Criteria, there was no significant time difference to clearly identify patients who required transplantation.

Acetaminophen is commonly considered an innocuous OTC drug; hence, it is extremely important to advise patients of the potential risks associated with its inappropriate use. Inform parents and caregivers that acetaminophen, although safe when dosed properly, can cause significant harm if misused.

Educate parents in the proper dosing for children and the danger associated with misusing various acetaminophen preparations of different concentrations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Currently, one standard concentration (160 mg/5 mL) of liquid acetaminophen medication is available for infants and children. Before 2011, OTC APAP formulations for infants and children were 80 mg/0.8 mL (Infant Concentrated Drops) and 160 mg/5 mL (Children's Liquid Suspension or Syrup). Despite the change to one standard formulation, the older concentrations (80 mg/0.8 mL) of infant acetaminophen may still be found in some homes. If an older APAP product is to be used, confirm the correct concentration of infant acetaminophen with the caregiver to prevent therapeutic error.

Parents should always be given clear dose and formulation instructions based on the age and weight of the child. Preferably, caregivers should use the dropper or syringe-measuring tool that accompanies the product. Parents must be instructed to carefully examine the labels of OTC medications that may contain acetaminophen in combination formulations.

Educate patients and caregivers about the increased potential for renal toxicity associated with concurrent acetaminophen and nonsteroidal anti-inflammatory drug (NSAID) analgesic use or with chronic ethanol use.

Parents and caregivers must ensure proper storage of medications within the home. This is critical in order to prevent unsupervised access to drugs or other toxic substances by children. The goal is to minimize the risk of an unintentional ingestion of a potentially toxic agent.

Supply parents and caregivers with contact information for their local Poison Control Center and the telephone number for the toll-free Poison Help Line (1-800-222-1222). In addition, McNeil pharmaceuticals (makers of the brand name “Tylenol” products) sponsors a toll-free number through the Rocky Mountain Poison and Drug Center, 1-800-525-6115, available 24 hours/d, for further consultation and guidance.[24]

For patient education information, see Tylenol Poisoning and Poison Proofing Your Home. 

Most patients who have taken an overdose of acetaminophen will initially be asymptomatic, as clinical evidence of end-organ toxicity often does not manifest until 24-48 hours after an acute ingestion.

However, because antidotal therapy is most effective when initiated within 8 hours after an ingestion, it is important to obtain an accurate history of the time(s) of ingestion, the quantity, and the formulation of acetaminophen ingested. Knowledge of the maximum recommended and minimum toxic dosages, as well as underlying conditions that increase susceptibility, can help the clinician determine the risk for hepatotoxicity (see Etiology). In addition, the history should include any co-ingestants, such as salicylates or medications that may delay gastric emptying and acetaminophen absorption (eg, anticholinergic drugs or opioids).

The clinical course of acetaminophen toxicity generally is divided into 4 phases. Physical findings vary, depending on the degree of hepatotoxicity.

In phase 1 (0.5-24 hours after ingestion), patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise. Physical examination may reveal pallor, diaphoresis, malaise, and fatigue. It is during this phase, if the ingestion is unknown, that patients may be given an APAP-containing medication to alleviate their nonspecific symptoms.

In phase 2 (18-72 h after ingestion), patients generally develop right upper quadrant abdominal pain, anorexia, nausea, and vomiting. Right upper quadrant tenderness may be present. Tachycardia and hypotension may indicate volume losses. Some patients may report decreased urine output (oliguria).

Phase 3 (72-96 h after ingestion), is also called the hepatic phase. Patients may have continued nausea and vomiting, abdominal pain, and a tender hepatic edge. Hepatic necrosis and synthetic dysfunction manifest as jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy. Acute renal failure develops in some critically ill patients. Death from multiorgan failure may occur.

Phase 4 is the recovery phase (4 d to 3 wk after ingestion). Patients who survive critical illness in phase 3 have complete resolution of symptoms and resolution of organ failure. Clinical recovery may take up to 21 days; however, complete hepatic histologic recovery requires several months.

The serum acetaminophen (APAP) concentration is the basis for diagnosis and treatment.  It is important to measure, even in the absence of clinical symptoms, because of the delay in onset of clinical toxicity. After a single ingestion, N-acetylcysteine (NAC) therapy is guided by the serum APAP concentration. An APAP level 4 hours post ingestion of greater than 150 mcg/mL (> 993 µmol/L) reflects possible toxicity.

The Rumack-Matthew nomogram uses the serum acetaminophen concentration, in relation to the time after ingestion, to assess potential hepatotoxicity after a single, acute ingestion of acetaminophen. It should not be used to evaluate long-term or repeated ingestions. Diagnosing chronic acetaminophen toxicity can be difficult, because the patient's presentation may appear to reflect other nonspecific illnesses. In these situations, consult a poison control center or a medical toxicologist to discuss treatment strategies.

Obtain an electrocardiogram (ECG) in order to exclude the presence of co-ingested cardiotoxic substances. Order a serum salicylate level to properly address concerns for salicylate poisoning.

Obtain liver function tests (LFTs). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations begin to rise within 24 hours after an acute ingestion and peak at about 72 hours. In severe overdose, transaminase elevation can be detected as early as 12-16 hours post-ingestion. Toxicity is defined as serum AST or ALT concentrations greater than 1000 IU/L. A rapid progression of transaminase values to 3000 IU/L or greater reflects severe hepatotoxicity. Include bilirubin and alkaline phosphatase concentrations.

A proposed strategy for predicting hepatotoxicity involves multiplying the acetaminophen concentration times the ALT concentration.[25] Products and risk levels are as follows:

• < 1500 - Low risk
• 1500-10,000 - Low to moderate risk
• > 10,000 - High risk

However, rises in ALT tend to be late events, which may limit the usefulness of this strategy in less severe overdoses.[26]

Prothrombin time (PT) and international normalized ratio (INR) should be measured and followed closely, as indicators of impaired hepatic synthetic function in the setting of hepatic dysfunction and developing liver failure. Abnormalities in these laboratory components are also predictors of mortality. Obtain a blood type and cross-match in the event of coagulopathy and active bleeding, requiring blood product transfusion.

Obtain serum glucose concentration to assess hypoglycemia as the result of impaired hepatic gluconeogenesis.

Kidney function tests (ie, electrolyte, blood urea nitrogen [BUN], and creatinine concentrations) can reveal evidence of co-existing kidney failure and hepatorenal syndrome.[27] An elevated serum creatinine concentration is also a predictor of mortality. Urinalysis showing proteinuria and hematuria may indicate acute tubular necrosis.

Kidney injury becomes apparent 2-3 days after an acute acetaminophen ingestion (phase 2). Rarely, kidney failure can occur independently of liver failure.[28] One study indicated that this is more likely to occur in persons who have history of ethanol abuse.

Assess for pancreatic injury by obtaining a lipase concentration.

Abdominal ultrasonography is a noninvasive diagnostic tool that may reveal mild hepatic enlargement or renal abnormalities, as well as inflammatory changes of other abdominal organs (eg, pancreatic tissue).

In females of childbearing age, obtain a serum concentration of human chorionic gonadotropin (hCG).[29] If that is positive, ultrasound can confirm gestational age of the fetus. Acetaminophen crosses the placenta, and the fetal liver is able to elaborate the hepatotoxic metabolite of APAP, N-acetyl-p-benzoquinone imine (NAPQI), by 14 weeks’ gestation. Delayed antidotal treatment in pregnant women has been associated with fetal loss, so antidotal therapy should be initiated as soon as acetaminophen ingestion is diagnosed in pregnant patients.

Arterial blood gas and serum lactate concentrations should be followed. A pH of less than 7.3 or a lactate concentration greater than 3.5 after fluid resuscitation are laboratory indicators predictive of mortality.[23]

Serum phosphate values have also been used as an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. However, these values are not considered strong enough prognostic indicators to guide antidotal treatment.[22]

The presence of altered mental status or clinical signs of encephalopathy warrant obtaining serum ammonia levels. Research indicates that arterial ammonia concentrations are higher than venous ammonia concentrations in a patient with acute liver failure and may be predictive of neurologic death. However, in a clinical picture that is consistent with acute hepatic dysfunction and encephalopathy, a venous sample can be considered sufficient in the context of other indicators of acute liver failure.

Computed tomography (CT) scanning of the brain should also be considered in patients with altered mental status. CT may reveal cerebral edema in patients with late presentation and encephalopathy (grade III or IV). Additional neuroimaging with magnetic resonance imaging (MRI) may be indicated to further define cerebral changes.

Key laboratory findings during the first 3 phases of acetaminophen hepatotoxicity are as follows:

• Phase 1: Approximately 12 hours after an acute ingestion, liver function studies show a subclinical rise in serum transaminase levels (ie, ALT, AST)

• Phase 2: Serum studies reveal elevated ALT and AST concentrations, PT, and bilirubin concentration; renal function abnormalities may also be present and indicate nephrotoxicity

• Phase 3: Severe toxicity is evident on serum studies, and include: lactic acidosis, prolonged PT or INR, markedly elevated ALT and AST (≥10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect), hypoglycemia, and hyperammonemia are reported; hepatic centrilobular necrosis is diagnosed on liver biopsy

The Rumack-Matthew nomogram (the acetaminophen toxicity nomogram or acetaminophen nomogram), is used to interpret serum acetaminophen concentrations in relation to time since ingestion, in order to assess potential hepatotoxicity. It was retrospectively developed, based on observational date from pateints who overdosed on single, acute ingestions of acetaminophen and did not recieve antidote therapy. See the image below.

Semilogarithmic plot of plasma acetaminophen levels vs time. From: Rumack BH, Matthew H. Acetaminophen Poisoning and Toxicity. Pediatrics. 1975 (55)871-876.

The nomogram predicts the risk of hepatotoxicity on a single acetaminophen concentraion, measured at one time. It is not a prognostic tool and, hence, does not predict fulminant hepatic failure or death.

The nomogram predicts potential toxicity beginning at 4 hours after ingestion up to 24 hours after ingestion. Acetaminophen concentraions measured earlier than 4 hours post-ingestion may not be reliable. Concentrations measured 4-18 hours post-ingestion are most reliable.

The upper line of the nomogram is the “probable” line, also known as the Rumack-Matthew line. About 60% of patients with values above this line develop hepatotoxicity. The lower line on the nomogram is the “possible” line, which was subsequently added later per request of the U.S. FDA. The possible line, also known as the “treatment” line, incorporates a 25% margin of error in measurement variations or uncertainty regarding the time of ingestion.

The nomogram cannot be used if the patient presents more than 24 hours after ingestion or has a history of multiple acetaminophen ingestions. Its reliability decreases for ingestions of extended-release acetaminophen formulations or for co-ingestions of acetaminophen with agents that delay gastric emptying and acetaminophen absorption (e.g.anticholinergics or opioids).

A high anion gap (see the Anion Gap calculator) may be found in clinically ill patients who present soon after acetaminophen ingestion; the etiology is hypothesized to be an elevated serum lactate concentration.[30] In critically ill patients, an elevated serum lactate is a laboratory predictor of mortality. However, this laboratory result is not predictive of clinical course or outcome if patients receive proper medical care.

Serum concentrations of NAPQI-protein adducts have been measured as evidence of acetaminophen–induced hepatotoxicity.[31] The peak serum concentrations of NAPQI adducts correlate with peak AST and ALT concentrations, and they may be diagnostic of APAP-induced hepatotoxicity in late-presenting patients with acute liver failure of unknown etiology.

However, the measurement of NAPQI-protein adducts is not available in real-time clinical practice and requires the resources of specialized laboratories. These laboratory measurements should not guide treatment decisions.

Patients who develop phase 4 hepatotoxicity have hepatic histologic changes. These changes can range from cytolysis to centrilobular necrosis. Centrilobular hepatic tissue injury is due to the increased concentration of CYP2E1 enzymes in this cellular area and a subsequently high local concentration of NAPQI in this zone of the liver. Improvement and recovery of these histologic changes takes longer than clinical recovery (about 3 mo).

In addition to antidote therapy, supportive care is essential in acetaminophen toxicity. Immediate assessment of the patient's airway, breathing, and hemodynamic status (ie, ABCs) is critical, while considering and initiating treatment for suspected acetaminophen overdose. As with any ingestion, assessing for other potential life-threatening co-ingestants is very important.

Administer activated charcoal (AC) if the patient has a stable mental and clinical status, patent airway, and presents to the emergency department within 1 hour of ingestion. Measure a 4-hour serum acetaminophen concentration to assess the potential risk for hepatotoxicity, using the Rumack-Matthew nomogram.

Patients with acetaminophen concentrations 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 intent to do self-harm, a thorough psychosocial, psychological and/or psychiatric evaluation is indicated before the patient can be discharged safely from the medical care facility.

Admit patients with acetaminophen concentrations above the "possible" line on the Rumack-Matthew nomogram for treatment with N-acetylcysteine (NAC). Treat patients with evidence of hepatic failure, metabolic acidosis, coagulopathy, and/or encephalopathy in an intensive care unit (ICU). Transfer patients with evidence of clinically significant hepatotoxicity to a medical facility with intensive care support and liver transplant services.

Early administration of NAC after suspected acetaminophen overdose is most essential.[32] NAC is nearly 100% hepatoprotective when it is given within 8 hours after an acute acetaminophen ingestion. Guidelines from the American College of Emergency Physicians recommend the use of NAC to treat acute acetaminophen overdose in patients with either possible or probable risk for hepatotoxicity, according to the Rumack-Matthew nomogram, and ideally within 8-10 hours post ingestion.[33]

Because of the relatively benign nature of NAC administration, and the risk of adverse effects from acetaminophen toxicity, NAC should be given even if the history is unclear but a potentially toxic acetaminophen ingestion is suspected. NAC should be administered while awaiting an acetaminophen concentration if the patient presents close to, or later than, 8 hours after an acute ingestion, or if the patient is pregnant.

A late presentation should not preclude NAC administration if the history or presentation suggests potential toxicity.[34] Failure to administer NAC because of late presentation is considered medically and legally inappropriate.

Investigational agents for the treatment of acetaminophen toxicity, which have the potential to be used together with NAC or even instead of NAC, include 4-methylpyrazole (a c-jun N-terminal kinase inhibitor)[35] and calmangafodipir (a superoxide dismutase mimetic).[36]  A Scottish study concluded that the combination of NAC and calmangafodipir is safe and tolerated in patients with acetaminophen overdose, and found evidence that the combination may reduce liver injury biomarkers more than NAC alone.[37]

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the following:

• Metabolic acidosis, unresponsive to resuscitaton
• Kidney failure
• Coagulopathy
• Encephalopathy

Oral activated charcoal (AC) avidly adsorbs acetaminophen and may be administered if the patient presents within 1 hour after ingesting a potentially toxic dose. AC should not be administered if the patient is mentally compromised and does not have an intact or protected airway.[38]

Oral AC may be of potential benefit longer than 1 hour after the ingestion if the ingestion involves an agent that delays gastric emptying or slows gastrointestinal (GI) motility. In one case series, oral AC administered with NAC 4 hours after ingestion was shown to be effective in reducing the incidence of transaminitis after toxic APAP ingestion.[34] However, it is well documented that the effectiveness of oral AC diminishes over time, especially beyond 60 minutes after a toxic ingestion. Administration of NAC is of highest priority in this case.

The oral formulation of NAC (Mucomyst) is the drug of choice for the treatment of acetaminophen overdose. GI decontamination with activated charcoal prior to starting NAC therapy does not change the recommended NAC administration schedule. The FDA-approved dosage regimen for oral NAC starts with a loading dose of 140 mg/kg, followed by 17 doses, each at 70 mg/kg, given every 4 hours. The total duration of the treatment course is 72 hours.[24]

A national multicenter study found that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion.[39] Treatment with oral NAC effectively prevented hepatotoxicity, regardless of the initial serum acetaminophen level, if it was started within 8 hours of the ingestion. NAC's treatment effectiveness did not depend on whether it was started 0-4 or 4-8 hours after ingestion.[39]

In 2004, the FDA approved an intravenous (IV) formulation of NAC (Acetadote) for use in adults. In 2006, this FDA approval was modified to include children (patients < 40 kg). IV NAC is the therapeutic formulation used in many hospitals. Additional indications for IV administration of NAC include the following:

• Altered mental status
• GI bleeding and/or obstruction
• A history of caustic ingestion
• Potential acetaminophen toxicity in a pregnant woman
• Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

Pharmaceutical guidelines for IV NAC administration depend on the patient's body weight and/or on whether the ingestion is acute or chronic. Continuous IV infusion is recommended for acute ingestion, as follows:

• Loading dose: 150 mg/kg IV; mix in 200 mL of 5% dextrose in water (D5W) and infuse over 1 h
• Dose 2: 50 mg/kg IV in 500 mL D5W over 4 h
• Dose 3: 100 mg/kg IV in 1000 mL D5W over 16 h

In patients who weigh more than 100 kg, limited data suggest a loading dose of 15,000 mg infused IV over 1 hours, then a first maintenance dose of 5,000 mg IV over 4 hours and a second maintenance dose of 10,000 mg over 16 hours.

To reduce the risk of reconstitution and administration errors, simpler IV NAC regimens have been developed.[40] One such off-label regimen consists of a loading dose of 150 mg/kg, given over 60 minutes, followed by a maintenance infusion of 15 mg/kg/hr, which is continued until the serum acetaminophen concentration measures less than 10 mg/L and the liver enzyme concentrations remain normal or are trending downward.[41]

In a retrospective study in 59 pediatric patients, age 2 months to 18 years, the above described regimen appeared effective and well tolerated. Treatment durations ranged from 4.25 to 89 hours.Two patients developed hepatoxicity, but none experienced liver failure. The only documented adverse reactions to NAC were minor anaphylactoid reactions, including flushing, facial redness, and itching. These reactions occurred at the end of the loading dose infusion of IV NAC, and responded to IV diphenhydramine or slowing of the infusion rate.[41]

A randomized, controlled trial by Bateman et al reported less vomiting, retching, or need for rescue antiemetic treatment at 2 hours with a modified regimen in which IV NAC was given in a dose of 100 mg/kg over 2 hours followed by 200 mg/kg over 10 hours. The study was not powered to detect non-inferiority of the shorter protocol versus the standard approach, but the proportion of patients with a 50% increase in alanine aminotransferase concentrations did not differ between the standard and shorter modified regimen.[42]

Intermittent IV infusion may be considered for late-presenting or chronic ingestion. A loading dose of 140 mg/kg IV (diluted in 500 mL D5W) is infused over 1 h. Maintenance doses of 70 mg/kg IV are given every 4 hours for at least 12 doses (dilute each dose in 250 mL of D5W and infuse over a minimum of 1 hour).

Adverse side effects associated with IV administration include flushing, pruritus, and rash (seen in about 15% of patients). Stopping the infusion, administering an antihistamine, and restarting NAC at a slower infusion rate remedy those adverse effects. Bronchospasm and hypotension can occur, but those adverse effects are rare (< 2% of patients).[43]

In cases of acetaminophen overdose, early administration of NAC takes priority over GI decontamination with oral activated charcoal (AC). Although AC does bind to NAC, AC adsorbs APAP more avidly. Therefore, any decrease in the bioavailability of oral NAC that may result from the administration of AC is clinically inconsequential. Importantly, AC administration may prevent significant APAP absorption from the GI tract and obviate the need for NAC if AC is administered within 60 minutes of an acute ingestion.[44]

Oral NAC administration may be staggered with AC administration in the rare cases where the patient needs multiple doses of AC for the treatment of a co-ingestant.[45] Treatment with intravenous NAC is preferable in this situation.

Consider and evaluate for possible co-ingestants and consider the possible effects of decreased GI motility on the absorption of APAP, because the predictive value of the treatment nomogram may be less reliable in these situations. Therefore, in the absence of good data on multidrug ingestions or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

If a patient presents 8-24 hours or later after an acute ingestion, initiate NAC therapy immediately and evaluate for laboratory evidence of hepatotoxicity. If evidence of hepatotoxicity exists, continue NAC therapy and consult a regional poison control center for guidance on a treatment regimen.

NAC administration in cases of hepatic failure has been associated with a decreased incidence of cerebral edema and improved survival. Therefore, NAC therapy should be initiated if concern exists for potential toxicity while awaiting confirmatory laboratory studies.

Because NAC can be beneficial for acetaminophen-induced hepatic failure when patients present more than 24 hours after a single ingestion, medical toxicologists recommend initiating treatment with NAC in patients who present after 24 hours if an acetaminophen concentration is detected and if hepatic injury is evident from liver function studies.

The beneficial effect of NAC in late treatment, when liver damage has already occurred, suggests that additional local hepatic repair mechanisms may be result from NAC administration. Proposed mechanisms of NAC in this setting include an antioxidant effect, decreased neutrophil accumulation, and improved microcirculatory blood flow supporting increased oxygen delivery to hepatic tissue.

Continuation of NAC therapy is based on the patient's clinical status, on detectable serum acetaminophen, and liver function test results. The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide medical management in these cases.

If a patient presents after multiple ingestions or chronic ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for the presence of a persistent serum APAP concentration and laboratory indicators of hepatotoxicity. Begin NAC therapy if the patient has elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels or a measurable serum APAP concentration. Consult a regional poison control center for guidance on a treatment regimen.

Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the reliability of the Rumack-Matthew nomogram to predict potential hepatotoxicity and subsequent treatment based on serum APAP concentrations.

Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.

Given these findings, recommended management for overdose of ER preparations includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy. More prolonged monitoring of APAP levels may be necessary if the patient has food in his or her stomach or has taken co-ingestants that delay gastric emptying.

Consult a regional poison control center for guidance in the evaluation and optimal treatment regimen for these cases.

Consultation with a medical toxicologist is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants. Medical toxicologists are available through consultation with a regional poison control center. For ingestions seen as a "cry for help" or as an intent to self-harm, psychosocial, psychological and/or psychiatric evaluations are required.

A hepatologist who is directly affiliated with a transplantation medical center should be consulted in the setting of hepatic dysfunction and liver failure. Concurrently, consult a transplantation surgeon in the setting of clinical and laboratory indicators that are highly predictive of death unless urgent transplantation is undertaken (see Prognosis). The United Kingdom King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen-induced fulminant hepatic failure include any one of the following:

• Arterial pH less than 7.3 after fluid resuscitation
• Grade III or IV encephalopathy
• Prothrombin time (PT) greater than 100 seconds
• Serum creatinine level greater than 3.4 mg/dL

Activated charcoal (AC) and N-acetylcysteine (NAC) are used in the treatment of acetaminophen toxicity. Antiemetics are used to relieve nausea and vomiting, which can result from both acetaminophen toxicity and from AC and oral NAC administration.

Class Summary

Gastrointestinal (GI) decontamination with oral AC is selectively used in the emergency treatment of poisoning caused by some drugs and chemicals. The network of pores present in AC adsorbs 100-1000 mg of drug per gram of charcoal. AC does not dissolve in water.

Consider GI decontamination with AC in any patient who presents within 1 hour after the ingestion. Maximum effect is achieved if AC is used within 1 hour post ingestion. AC may be helpful more than 4 hours post-ingestion, if co-ingestion with an agent that slows gut motility occurred or if a sustained-release preparation was ingested.

AC adsorbs acetaminophen, but its use has been controversial, because AC may absorb oral NAC. Although AC reduces the bioavailability of NAC, the small decrease in the NAC bioavailability is unlikely to reduce the effectiveness of oral NAC as an antidote.

NAC counteracts acetaminophen toxicity both directly and indirectly. NAC is converted to cysteine, which replenishes glutathione stores, thus providing a substrate for conjugation with the toxic metabolite of APAP, N -acetyl-p -benzoquinoneimine (NAPQI). NAC also directly detoxifies NAPQI to nontoxic metabolites.

Administer all doses of NAC as directed under the guidance of a regional poison control center. Shortened courses of NAC administration have been found to be effective in preventing liver toxicity in select patients with APAP overdose.[45, 46]

Activated charcoal (Actidose-Aqua, EZ-Char, Kerr Insta-Char)

Activated charcoal (AC) is the drug of choice for gastric decontamination and is used for emergency treatment in poisoning caused by drugs and chemicals. A network of pores absorbs 100-1000 mg of drug per gram of charcoal. AC prevents absorption by adsorbing the drug in the intestine.  AC does not dissolve in water and for maximum effect, administer this agent within 1 hour after ingestion of poison.

N-acetylcysteine (Acetadote)

N-acetylcysteine (NAC) is the drug of choice for the prevention and treatment of APAP-induced hepatotoxicity. This medication is approved by the US Food and Drug Administration (FDA) for both oral and intravenous (IV) administration. For the maximum hepatoprotective effects, administer NAC within 8-10 hours of an acute APAP ingestion.

Three treatment protocols are recognized: 72-hour oral, 21-hour IV, and 48-hour IV. The entire NAC protocol, either oral or IV regimen, should be completed even if serumacetaminophen concentrations decrease.

The oral form of NAC, Mucomyst, is available as a 20% solution (200 mg/mL). This should be diluted to 5% solution (50 mg/mL) with fruit juice or carbonated beverage. Aggressive antiemetic therapy is indicated in patients with nausea or vomiting due to acetaminophen-induced hepatic injury or foul sulfur odor of the solution. If the patient vomits within 60 min of administration, repeat the dose.

If failure to tolerate oral formulation persists, switch to the IV preparation (Acetadote). When administered intravenously, dilute NAC in 5% dextrose solution (D5W) and infuse per the recommended intravenous protocol for acute (within 8-10 h) or late-presenting or chronic acetaminophen ingestion.

Class Summary

Emesis is frequently associated with APAP toxicity and is a common adverse effect of both AC and oral NAC administration. For these reasons, antiemetic therapy is often necessary to facilitate the successful administration of oral NAC. Persistent nausea or vomiting precludes oral NAC administration; in this situation, NAC should be administered intravenously.

Antiemetics that do not decrease gastric motility or significantly alter mental status are the drugs of choice; anticholinergic drugs such as prochlorperazine are not considered beneficial, in part because of their propensity to cause both of these adverse effects. Phenothiazines may also contribute to the potential toxicity associated with other anticholinergic drugs, if they are co-ingested with APAP-containing formulations.

Metoclopramide (Reglan, Metozolv)

Metoclopramide functions as an antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the central nervous system. It also enhances gastrointestinal motility and accelerates gastric emptying time. This agent is of low cost and is generally considered an initial drug of choice for the treatment of nausea.

Ondansetron (Zofran, Zuplenz)

Ondansetron is a selective 5-hydroxytryptamine (5HT3) receptor antagonist. This drug blocks serotonin by acting on the vagus nerve peripherally and at the chemoreceptor trigger zone of the central nervous system (CNS). Ondansetron is considered more effective than metoclopramide, with fewer adverse effects, but it is more costly than metoclopramide.