Pediatric Acetaminophen Toxicity



Acetaminophen toxicity is a relatively common occurrence, particularly in children; this drug is the most widely used analgesic-antipyretic medication taken by people in the United States and around the world.[1] Extensive medical use of this drug began in 1947. Initially in the United States, acetaminophen was available by prescription only. In 1960, it changed to over-the-counter (OTC) status. The availability of acetaminophen in OTC preparations and the contraindication of pediatric use for aspirin-containing products (due to the association between aspirin and Reye’s syndrome), have made acetaminophen one of the most commonly used drugs in current pediatric medicine.

Acetaminophen is available in more than 200 OTC and prescription medications as a single agent or in combination with other pharmaceuticals. It is cited as a drug in over 50 brand-name or trade-name products (eg, Tylenol, Panadol, Tempra, Feverall). Numerous oral formulations and preparations are also available and include liquids, tablets, caplets, capsules, and suppositories in immediate-release and sustained-release forms.

In 2011, an intravenous (IV) formulation of acetaminophen (registered name, Ofirmev) was approved by the US Food and Drug Administration (FDA) for in patient use in children (>2 y) to treat fever and pain.[2] This article focuses on single acute ingestions of oral formulations; however, of note, iatrogenic medication errors with IV acetaminophen have caused hepatotoxicity.[3] The evaluation and treatment approach for an IV acetaminophen overdose is similar to that of an oral overdose.

Acetaminophen, or paracetamol (as termed in world countries outside of the US and Canada), is also known by its chemical name, N -acetyl-p -aminophenol or APAP. It has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur with misuse and overdose. N -acetylcysteine (NAC), or acetylcysteine, is an effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.[4]

Acetaminophenor APAP metabolism is illustrated in the image below.

View Image

Acetaminophen metabolism.

Not only is acetaminophen 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 poisoning is the most common cause of nonfatal hepatic necrosis, acute liver failure and overdose deaths. In Great Britain, organ toxicity due to paracetamol (as acetaminophen is called in the United Kingdom) is the most common etiology of hepatic failure requiring liver transplantation.

Overdose with acetaminophen can occur at any age. A therapeutic misadventure typically occurs in patients younger than 1 year when caregivers give incorrect doses of a medication containing acetaminophen to a child. An 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]

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


Therapeutic oral doses of acetaminophen or APAP are rapidly absorbed by the GI tract, with body serum level concentration peaking 1-2 hours postingestion. Therapeutic levels are 5-20 mcg/mL (33-132 mcmol/L). Peak plasma 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 extended-release formulation may increase the peak serum level to more than 4 hours postingestion. The average elimination half-life of acetaminophen is 2 hours (range, 0.9-3.25 h). In patients with hepatic dysfunction, the half-life can be as long as 17 hours postingestion.

Metabolism of acetaminophen is primarily hepatic. Several pathways of hepatic metabolism are involved with their products being excreted by the kidneys. The liver metabolizes more than 90% of an acetaminophen dosage to sulfate and glucuronide conjugates, which are both 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 dose is excreted unchanged by the kidneys. The acetaminophen that remains (about 4%), is biotransformed by the hepatic cytochrome P450 (CYP450) system to form a reactive, highly toxic metabolite known as N -acetyl-p -benzoquinoneimine (NAPQI) (see the following image). Glutathione binds to NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine.

View Image

Acetaminophen metabolism.

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

Older age, restricted diet, underlying hepatic or renal disease, and medical conditions (eg, malnutrition due to prolonged fasting, eating disorders, cystic fibrosis, gastroenteritis, chronic alcoholism, or HIV disease) negatively impact 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 hepatic cytochrome system increases the production of NAPQI and, therefore, increases the risk of hepatocellular injury in patients who co-ingest these agents due to glutathione depletion.[6] Herbal supplements may also play a role in amplifying the risk for acetaminophen-induced hepatic injury.


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

Maximum APAP (Acetaminophen) dosages

The cited maximum daily adult dose of 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 APAP is 80 mg/kg (not to exceed a cumulative daily dose of 2.6 g).

Therapeutic weight-based oral dosing of APAP 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 using the same time interval as for oral APAP.

Minimum Toxic APAP (Acetaminophen) dosages

In adults, the minimum toxic dose of APAP 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. 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 APAP poisoning. Possible differences in acetaminophen metabolism and their 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 APAP (Acetaminophen) dosages

In adults, an acute ingestion of> 150 mg/kg or of ≥ 12 g of APAP is considered a toxic dose and hashigh risk of liver damage.

Children who have acutely ingested 250 mg/kg or more of APAP pose significant concern for acetaminophen-induced hepatotoxicity. Acute ingestions of more than 350 mg/kg pose significant risk of severe hepatotoxicity, if the patient is not properly treated.

In June 2009, the FDA announced requirements for nonprescription and prescription medication to provide new information regarding acetaminophen–induced hepatotoxicity.[7, 8, 9] The FDA examined possible removal of acetaminophen from some popular analgesic combination products (eg, Vicodin) and/or lowering the maximum cited daily dose of acetaminophen. The following concerns were also addressed:

In January 2011, the FDA asked manufacturers of prescription acetaminophen combination products to limit the maximum amount of the drug in these products to 325 mg per tablet, capsule, or other dosage unit[10] Hopefully, establishing this limitation will help reduce the occurrence of acetaminophen overdosing, and decrease the number of acute ingestions that cause hepatotoxicity, leading to acute liver failure[10]


The proper medical use of the antidote N -acetylcysteine (NAC) has significantly lowered the mortality rate of patients with acetaminophen 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 (< 6y) than in older children, adolescents, and adults. The cause for this age-related difference is unclear but may be due to the following: 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 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 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.

Patient Education

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

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

Supply parents and caregivers with information, including the toll-free phone numbers for the National Poison Control Center hotline (1-800-222-1222) and their regional Poison Control hotline 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.[11]

For patient education information, see (Tylenol) Poisoning and Poisoning. The FDA has patient and caregiver education resources through its Consumer Health Information Website.[12, 10]

History and Physical Examination

Patients with acetaminophen-induced hepatotoxicity present in 4 clinical stages. Physical findings vary and primarily depend on the level of hepatotoxicity.

Stage 1 (0.5-24 h [0-1 d] post-ingestion)

The first stage lasts for 24 hours. Patients have anorexia, nausea, vomiting, malaise, and diaphoresis. These clinical signs are nonspecific, and, hence, patients might inadvertently be given additional doses of an acetaminophen-containing product for treatment of their symptoms.

Some patients remain asymptomatic, but they still have the risk to develop clinically significant toxicity.

Neurologic, respiratory, and cardiac symptoms are rare in stage 1. If central nervous system (CNS) involvement and/or severe metabolic acidosis (elevated anion gap [see the Anion Gap calculator]) are present, consider co-ingestants (eg, salicylate compounds).

The physical findings are typically nonspecific. Pallor, diaphoresis, and compromised hydration status due to repeated emesis and increased insensible losses may be present. Malaise and fatigue are reported.

Serum studies are typically within normal limits. About 12 hours post-ingestion, subclinical elevation of serum liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) occurs.

Stage 2 (24-72 h [1-3 d] post-ingestion)

The second stage begins 24 hours after ingestion and lasts for another 48 hours. Stage 1 symptoms become less evident than before and/or resolve.

Patients present with pain and tenderness in the right upper quadrant. Liver enlargement (hepatomegaly) can be present. Some patients may report decreased urinary output (oliguria). Vital signs show tachycardia and hypotension as indicators of ongoing volume losses.

Acute pancreatitis (eg, abdominal pain, elevated lipase, p-amylase) has been reported in patients who concurrently drink alcohol.

Serum studies reveal elevated ALT and AST levels, prothrombin (PT) times, and bilirubin values. Renal function abnormalities (eg, blood urea nitrogen [BUN], creatinine (Cr)) may also be present and indicate nephrotoxicity.

Stage 3 (72-120 h [3-5 d] post-ingestion)

Stage 3, also called the hepatic stage, develops 3-5 days after ingestion. Symptoms seen in stage 1 (eg, anorexia, nausea, vomiting, malaise) reappear along with signs of hepatic failure with jaundice, hypoglycemia, bleeding (coagulopathies), encephalopathy, and/or sepsis. Renal failure and cardiomyopathy may also occur.

Physical findings reflect clinically significant hepatic injury, such as abdominal pain, jaundice, and gastrointestinal (GI) bleeding due to coagulopathy. Encephalopathy and cerebral edema due to severe hepatic injury occurs. Clinical signs and symptoms of multiorgan failure are present.

Severe toxicity is evident on sera laboratory studies. Lactic acidosis, prolonged PT or international normalized ratio (INR), markedly elevated ALT and AST (≥10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect) and hyperammonemia are reported.

Hepatic centrilobular necrosis is diagnosed on liver biopsy. About 4% of patients who develop this degree of hepatotoxicity progress to fulminant hepatic failure.

Renal involvement from acute tubular necrosis is evident with abnormal renal function studies, proteinuria, hematuria and granular casts on urinalysis. Acute renal failure occurs in 25% of patients with significant hepatotoxicity and in more than 50% of those with hepatic failure.

Death is most common during stage 3, with multiorgan failure as the primary cause.

Stage 4 (5-14 d [5-21 d] post-ingestion)

Stage 4, the recovery phase, occurs 5-14 days after ingestion. This stage can last as long as 21 days. Patients either have a complete recovery of liver function and resolution of physical findings or they die.

In patients who recover, the period to normalization may take several weeks. Hepatic histologic recovery lags behind clinical recovery and can take as long as 3 months to resolve.

Acetaminophen-induced hepatotoxicity does not cause chronic hepatic dysfunction.

Approach Considerations

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 doses of acetaminophen to relieve their symptoms.

In chronic acetaminophen toxicity, the importance of fasting, reduced glutathione stores, and enhanced metabolism is unclear. Risk factors for chronic acetaminophen toxicity include repeated supratherapeutic overdose (a repeated administration of high doses), fever, poor oral intake, and young age.[13] As reference, the 24-hour dosage of acetaminophenfor children should not exceed 80 mg/kg/d.

The Rumack-Matthew nomogram was developed to access hepatotoxicity risk for single acute ingestions of acetaminophenand should not be used to evaluate chronic or repeated exposures. Elevated values on liver function testing are better than nomographic measures as predictors of toxicity.

Diagnosing chronic acetaminophentoxicity can be difficult, because the patient's presentation may appear to reflect the initial illness. In these situations, consider consulting a poison control center or a medical toxicologist in regard to management strategies.

Laboratory tests to consider

If mental status changes or clinical signs of encephalopathy are noted, obtain serum ammonia levels (an arterial sample is best).

Assess for pancreatic injury by obtaining lipase and amylase levels, especially if the patient has evidence of clinically significant hepatotoxicity and complaints of severe abdominal pain.

Hepatic injury can cause coagulopathy; hence, blood products may be needed. Blood typing, crossmatching, and antibody screening should be performed.

Order a quantitative pregnancy test (serum level of human chorionic gonadotropin) in all females of childbearing age. Acetaminophen crosses the placental barrier. Delayed antidotal treatment in pregnant women has been associated with fetal loss.

Check the salicylate serum level to address concern for co-ingestants and the potential need to initiate medical care for salicylate poisoning. Be especially concerned if there is evidence of metabolic acidosis, as based on the serum electrolyte values.

Radiologic studies

In some circumstances, imaging studies may be helpful.

CT scanning of the head is indicated for patients who present with or who develop altered mental status or encephalopathy. Encephalopathy due to cerebral edema occurs in the late clinical presentation of acetaminophen overdose (stage 3 or 4) and is detectable on CT scanning. Additional neuroimaging with MRI may be indicated to further define cerebral changes.

Ultrasonography is helpful in defining hepatic and/or renal abnormalities as well as in assessing for involvement of other abdominal organs (eg, pancreatic tissue).

Rumack-Matthew Nomogram

The modified Rumack-Matthew nomogram, (the acetaminophen toxicity nomogram or acetaminophen nomogram), is used to interpret plasma acetaminophen values to assess hepatotoxicity risk in patients. It was developed for single, acute ingestions of acetaminophen and is based on observational data from patients who overdosed and who did not receive antidote therapy.

The nomogram predicts the risk of hepatotoxicity at a single level in time. It is not a prognostic tool and, hence, does not predict fulminant hepatic failure or death.

Nomogram tracking begins 4 hours after ingestion and ends 24 hours after ingestion. APAP plasma levels drawn earlier than 4 hours may not be reliable. Levels obtained 4-18 hours postingestion are most reliable. An APAP level 4 hours post ingestion of >150 mcg/mL (> 993 mcmol/L) reflects possible toxicity.

The upper line of the nomogram is the probable line. About 60% of patients with values above this line develop hepatotoxicity. The lower line is the possible line, which was added to the nomogram to give a 25% margin of error to allow for variations in measurements of the acetaminophen plasma concentration (mcg/mL or mcmol/L [SI units]) or for uncertainty regarding the time of ingestion.

The nomogram cannot be used if the patient has a delayed presentation of more than 24 hours after ingestion or a history of multiple acetaminophen ingestions. Its reliability also decreases for ingestions involving extended-release acetaminophen tablets or for co-ingestions of acetaminophen with anticholinergics or opioids.

Serum APAP (Acetaminophen) Concentration

Obtain a plasma APAP level in patients who have a history of a potentially toxic ingestion, who ingested an unknown amount of APAP, who have altered mental status, or who have attempted suicide.

Routine assessment of APAP levels is controversial, but it is recommended because deaths from occult overdoses with this drug have occurred.

Negligible APAP values from an acute ingestion occurring within 4 hours can be used to rule out hepatotoxicity.

Any serum concentration based on a sample drawn 4 hours or longer after a single ingestion may be plotted on an acetaminophen toxicity nomogram (Rumack-Matthew nomogram) to estimate the risk of hepatotoxicity. Plotting this value on the nomogram is most useful 4-18 hours after the acute ingestion.

Liver Function Tests

Hepatic transaminase levels start to rise within 24 hours after ingestion (stage 1) and peak 48-72 hours after ingestion (stage 2). In severe overdose, transaminase elevation can be detected as early as 12-16 hours post-ingestion.

Evidence of hepatic injury due to acetaminophen overdose is defined by elevation of the plasma transaminase values of more than 1000 IU/L. A rapid progression of transaminase values to 3000 IU/L or higher reflects worsening hepatotoxicity.

Additional serum measurements of hepatic function such as glucose (concern for hypoglycemia), prothrombin time (PT) and bilirubin may be useful.

Renal Function Tests

Renal function tests of electrolytes, blood urea nitrogen (BUN), and creatinine levels can reveal evidence of renal failure, which often occurs with hepatic failure.[14] Urinalysis to check for proteinuria and hematuria helps in diagnosing acute tubular necrosis (ATN) that can also occur in this clinical setting. Renal injury becomes apparent 2-3 days after an acute acetaminophen ingestion (stage 2). Renal failure is rare and it can occur independently of hepatic failure.[15]

Histologic Features

Patients who reach stage 4 hepatotoxicity have hepatic histologic changes. These changes can range from cytolysis to centrilobular necrosis. Centrilobular involvement is seen due to the increased concentration of CYP2E1 enzymes in these cells, a site of maximal NAPQI production (the hepato-toxic metabolite). Improvement and recovery of these histologic changes takes longer than clinical recovery (about 3 mo.).

Approach Considerations

Treatment for acetaminophen overdose with antidotal therapy must be managed in an inpatient medical facility.


A medical toxicologist or a regional poison control center may be helpful in treating patients with possible co-ingestions, complicated histories, or atypical clinical presentations.

Consultation with a hospital-based pediatric gastroenterologist affiliated with a transplant center is needed for patients who have signs of clinically significant hepatotoxicity.

If the ingestion is due to an attempt to do self-harm, psychosocial, psychological and/or psychiatric evaluation is indicated.

Delayed presentation of an acute single ingestion of APAP

Until recently, the standard of care for acetaminophen overdose management in the United States was administration of N- acetylcysteine (NAC) to patients who presented within but not later than 24 hours after ingestion. Data from England suggest that NAC may, in fact, be beneficial for acetaminophen-induced hepatic failure when patients present more than 24 hours after ingestion.

To date, no known clinical studies have evaluated the use of NAC in patients who present late with hepatotoxicity but without signs of hepatic failure. However, the approach of the medical community (hepatologists, toxicologists) is that NAC can be initiated at any stage after a toxic acetaminophen exposure, if hepatotoxicity is evident. NAC seems to benefit any stage of hepatotoxicity status post ingestion due to its multiple mechanisms of action; namely, glutathione regeneration, antioxidant capability, and improving hepatic circulation. Studies have shown that the maximal effect of NAC is achieved, if administered 8-10 hours postingestion; however, the benign nature of this antidote as related to adverse effects and the potential for overall greater benefit with minimal risk, favor its use beyond the 10-hour recommendation.

Medical toxicologists recommend treatment with NAC in patients who present more than 24 hours after ingestion, if an APAP plasma level is detected and if hepatic injury is evident. Laboratory findings of hepatic injury or impaired hepatic function include increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, elevated total bilirubin values, and prolonged prothrombin times (PTs).

Continuation of NAC therapy is based on the patient's clinical status, on detectable serum values of APAP, and liver function (PT and ALT, AST, total bilirubin levels). The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide medical management in these cases.

The beneficial effect of NAC in late treatment when liver damage has occurred suggests that additional repair mechanisms may be present. 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.

Surgical intervention

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 metabolic acidosis, renal failure, coagulopathy, and encephalopathy.

Clinical Management

Initial appropriate supportive care is essential in acetaminophen poisoning. Immediate assessment of the patient's airway, breathing, and fluid status (ie, ABCs) is critical before treatment for suspected acetaminophen overdose is started. In addition, assessing for other potential life-threatening co-ingestions (eg, salicylate) is important.

Admit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew nomogram for treatment with N -acetylcysteine (NAC). Treat patients with evidence of hepatic failure, metabolic acidosis, encephalopathy, or coagulopathy in an intensive care unit (ICU).

Transfer patients with evidence of clinically significant hepatotoxicity to a hospital with intensive care support and organ transplant services.

GI decontamination

Standard treatment guidelines should be followed for GI decontamination. Consider GI decontamination with activated charcoal in any patient who presents within 4 hours of ingestion (ideal efficacy is within 2 h). Consider gastric lavage if ingestion occurred within 1 hour of evaluation, as effectiveness diminishes with increasingtime. Protecting the patient’s airway is critical with these procedures.

Oral N-acetylcysteine (Mucomyst)

The antidote for acetaminophen toxicity is N -acetylcysteine (NAC), which has several mechanisms to prevent hepatotoxicity. The oral formulation is the drug of choice for the treatment of acute, chronic, or late-presenting acetaminophen ingestions. GI decontamination with activated charcoal prior to starting NAC therapy, does not change the therapeutic schedule for treatment. The US 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.[11]

NAC is converted to cysteine, which replenishes glutathione stores, as well as directly detoxifies N -acetyl-benzoquinoneimine (NAPQI) to nontoxic metabolites. This agent provides a substrate for sulfation, increasing the capacity for nontoxic metabolism, and can directly conjugate to NAPQI to reduce toxicity.

A national multicenter study revealed that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion.[16] Treatment with oral NAC effectively prevented hepatotoxicity, regardless of the initial plasma acetaminophen level, if it was started within 8 hours of the ingestion. Its effectiveness did not depend on whether NAC was started 0-4 or 4-8 hours after ingestion.[16]

Intravenous N-acetylcysteine (Acetadote)

In 2004, the US FDA approved an intravenous (IV) formulation of N -acetylcysteine (NAC) for use in adults. In February 2006, this FDA approval was modified to include children (patients < 40 kg).

IV administration of NAC is recommended for use in selected patients, including those with an altered mental status, GI bleeding and/or obstruction or a history of caustic ingestion, potential fetal toxicity from maternal toxicity, or an inability to tolerate oral NAC because of refractory emesis despite proper use of antiemetics.

Pharmaceutical guidelines for IV NAC administration differ depending on the patient's body weight and/or on whether the ingestion is acute or chronic. Guidelines for IV dosage and administration are discussed in Medications.

Adverse side effects associated with the IV administration include flushing, pruritus, and a rash (seen in about 15% of patients). These side effects are remedied by stopping the infusion, administering an antihistamine, and restarting this antidote at a slower infusion rate. Bronchospasm and hypotension can occur; however these effects are rare (< 2% of patients).[17]

Medication Summary

N -acetylcysteine (NAC), antiemetics, and activated charcoal are usedin the treatment of acetaminophen toxicity. The American College of Emergency Physicians (ACEP) has issued guidelines for acetaminophen overdose.[18, 19]

N-acetylcysteine (NAC), Acetylcysteine

Clinical Context:  Oral (PO) antidote, 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 IV preparation.

The intravenous (IV) formulation (Acetadote) is diluted in 5% dextrose in water (D5W) and infused according to the protocol for acute (within 8-10 h) or late-presenting or chronic acetaminophen ingestion.

The entire NAC protocol, either PO or IV regimen, should be completed even if the acetaminophen plasma levels decrease

Class Summary

N -acetylcysteine (NAC), a glutathione precursor, is the antidote of choice to prevent and treat acetaminophen-induced hepatotoxicity. This agent is indicated for all ingestions above the possible toxicity line on the Rumack-Matthew nomogram. The US Food and Drug Administration (FDA) approved both oral (PO) (Mucomyst) and intravenous (IV) (Acetadote) formulations. Three treatment protocols are recognized: 72-hour oral, 21-hour intravenous, and 48-hour intravenous. For maximum hepatoprotective effect, the antidote should be given within 8-10 hours of the acetaminophen ingestion.

Metoclopramide (Reglan, Metozolv)

Clinical Context:  The antiemetic effect of metoclopramide appears to be due to its ability to block dopamine receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS). This agent also enhances gastrointestinal motility and accelerates gastric emptying time.

Ondansetron (Zofran, Zuplenz)

Clinical Context:  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 (CTZ) of the central nervous system (CNS). Ondansetron is considered more effective than metoclopramide, with fewer adverse effects, but this agent tends to be more expensive than metoclopramide.

Class Summary

Nausea and vomiting in acetaminophen-induced hepatotoxicity may due to acetaminophen, activated charcoal, or oral N -acetylcysteine (NAC). Antiemetic therapy is indicated in patients with these symptoms to enable successful treatment with oral NAC.

Activated charcoal (Actidose-Aqua, EZ-Char, CharcoCaps, Charcoal Plus)

Clinical Context:  Activated charcoal 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. Activated charcoal prevents absorption by adsorbing the drug in the intestine; multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. In theory, by constantly bathing the gastrointestinal (GI) tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of the drug from the intestinal villous capillary blood into the intestine. Activated charcoal does not dissolve in water.

For maximum effect, administer this agent within 30 minutes after ingestion or poison.

Class Summary

Consider decontamination with activated charcoal in any patient who presents within 4 hours after the ingestion. Activated charcoal may be helpful more than 4 hours postingestion if co-ingestion with an agent that slows gut motility occurred or if a sustained-release preparation was ingested.

Activated charcoal adsorbs acetaminophen, but its use has been controversial, because activated charcoal may absorb oral N -acetylcysteine (NAC). Although activated charcoal reduces the bioavailability of NAC, the small decrease in the NAC bioavailability is unlikely to reduce the effectiveness of oral NAC as an antidote.


Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.


Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

Specialty Editors

Halim Hennes, MD, MS, Division Director, Pediatric Emergency Medicine, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School; Director of Emergency Services, Children's Medical Center

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Disclosure: Nothing to disclose.


  1. [Guideline] AAP. Acetaminophen toxicity in children. Pediatrics. Oct 2001;108(4):1020-4. [View Abstract]
  2. Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics. Feb 2012;129(2):349-53. [View Abstract]
  3. Berling I, Anscombe M, Isbister GK. Intravenous paracetamol toxicity in a malnourished child. Clin Toxicol (Phila). Jan 2012;50(1):74-6. [View Abstract]
  4. Anker AL, Smilkstein MJ. Acetaminophen. Concepts and controversies. Emerg Med Clin North Am. May 1994;12(2):335-49. [View Abstract]
  5. Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol. Aug 1991;32(2):143-9. [View Abstract]
  6. Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. BMJ. Apr 19 2011;342:d2218. [View Abstract]
  7. US Food and Drug Administration. Public health problem of liver injury related to the use of acetaminophen in both over-the-counter (OTC) and prescription (RX) products. Available at Accessed August 5, 2009.
  8. Health and Human Services. Federal Register. 74(81). April 29, 2009.
  9. Department of Health and Human Services; Food and Drug Administration. Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph. Federal Register [serial online]. April 29, 2009;74:19385-409. Accessed March 30, 2010. Available at
  10. US Food and Drug Administration. Acetaminophen information. Available at Accessed August 18, 2011.
  11. McNeil Consumer and Specialty Pharmaceuticals. Guidelines for the Management of Acetaminophen Overdose. Available at
  12. Acetaminophen and Liver Injury: Q & A for Consumers. FDA Consumer Health Information: US Food and Drug Administration; June 2009. 1-3.
  13. Heard K, Bui A, Mlynarchek SL, Green JL, Bond GR, Clark RF. Toxicity From Repeated Doses of Acetaminophen in Children: Assessment of Causality and Dose in Reported Cases. Am J Ther. Mar 8 2012;[View Abstract]
  14. Zyoud SH, Awang R, Sulaiman SA, Al-Jabi SW. Impact of serum acetaminophen concentration on changes in serum potassium, creatinine and urea concentrations among patients with acetaminophen overdose. Pharmacoepidemiol Drug Saf. Feb 2011;20(2):203-8. [View Abstract]
  15. Ozkaya O, Genc G, Bek K, Sullu Y. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Ren Fail. 2010;32(9):1125-7. [View Abstract]
  16. 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. Dec 15 1988;319(24):1557-62. [View Abstract]
  17. 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. Sep 2011;33(9):1322-30. [View Abstract]
  18. Wolf SJ, Heard K, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. Sep 2007;50(3):292-313. [View Abstract]
  19. Mottram AR, Kumar AM. Focus On: Acetaminophen Toxicity and Treatment. American College of Emergency Physicians. Available at Accessed July 21, 2009.
  20. Dart RC, Erdman AR, Olson KR, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(1):1-18. [View Abstract]
  21. Farrell, SE. Toxicity, Acetaminophen. Medscape Reference [serial online]. Sep 2009;Accessed August 18, 2011. Available at
  22. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. Jul 17 2008;359(3):285-92. [View Abstract]
  23. James LP, Capparelli EV, Simpson PM, et al. Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose. Clin Pharmacol Ther. Dec 2008;84(6):684-90. [View Abstract]
  24. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. Dec 2005;42(6):1364-72. [View Abstract]
  25. Marzullo L. An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr. Apr 2005;17(2):239-45. [View Abstract]
  26. Micheal J Burns, Scott L Friedman, Anne M Larson. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis. UpToDate. Available at Accessed February 24, 2010.
  27. Miller MA, Navarro M, Bird SB, Donovan JL. Antiemetic use in acetaminophen poisoning: how does the route of N-acetylcysteine administration affect utilization?. J Med Toxicol. Dec 2007;3(4):152-6. [View Abstract]
  28. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr. Feb 1997;130(2):300-4. [View Abstract]
  29. Smith SW, Howland MA, Hoffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. Sep 2008;42(9):1333-9. [View Abstract]

Acetaminophen metabolism.

Acetaminophen metabolism.

Acetaminophen metabolism.