eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Acetaminophen

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

Updated: Aug 25, 2009

Introduction

Background

Acetaminophen is the most widely used analgesic-antipyretic medication taken by people in the United States and the world.¹  Since the 1950s, its availability in over-the-counter (OTC) preparations and the contraindication of pediatric use for aspirin-containing products has made acetaminophen one of the most commonly used drugs in pediatric medicine.
 
Acetaminophen is available in more than 200 OTC and prescription medications as a single agent or in combination with other pharmaceuticals. Numerous formulations and preparations are also available and include liquids, tablets, caplets, capsules, and suppositories in immediate-release and sustained-release forms.

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

Acetaminophen metabolism.

Pathophysiology

Therapeutic oral doses of acetaminophen are rapidly absorbed by the GI tract, with body serum levels peaking at 0.5-2 hours postingestion. Therapeutic levels are 10-20 mcg/mL (66-132 mcmol/L). Serum peak levels occur after an overdose within 4 hours postingestion for an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (such as opiates, anticholinergic agents) or ingestion of an APAP extended-release formulation may increase the peak serum level to more than 4 hours postingestion. The elimination half-life of acetaminophen is estimated to be 2-4 hours.
 
Metabolism of acetaminophen is primarily hepatic. The liver metabolizes more than 90% of an acetaminophen dosage to sulfate and glucuronide conjugates, which are water soluble and are then eliminated in the urine. Sulfation is the primary metabolic pathway in children aged 12 years and younger. Glucuronidation predominates in adolescents and adults. Two percent of an acetaminophen dose is excreted unchanged by the kidneys. The remaining acetaminophen is metabolized by the hepatic cytochrome P450 (CYP450) system to form a reactive, highly toxic metabolite known as N -acetyl-benzoquinoneimine (NAPQI). Glutathione binds NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine.
 
Therapeutic doses of acetaminophen do not cause hepatic injury; however because hepatic glutathione stores are depleted (by 70-80%) in an acetaminophen overdose, NAPQI cannot be detoxified and covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Necrosis primarily occurs in this hepatic region due to the greater production of NAPQI by these cells. Glutathione stores to enable metabolism of this toxic metabolite are replaced by sulfhydryl compounds from the diet (eg, fruits and vegetables) or from drugs, such as the antidote, NAC.

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

Frequency

United States

Acetaminophen is the drug most commonly ingested in overdoses. It is also a common co-ingestant. Because of acetaminophen's widespread availability and the underestimation of its potential toxicity, acetaminophen poisoning is the most common cause of acute liver failure and overdose deaths.

Mortality/Morbidity

The proper medical use of the antidote, 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 (£ 5 years old) than in older children, adolescents, and adults. The cause for this age-related difference is unclear but may be due to an increased capacity for conjugation with sulphate, an increased supply and regeneration of glutathione stores, lower ingested doses, or a greater likelihood to vomit after an acute ingestion.

Age

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

Clinical

History

Patients with acetaminophen-induced hepatotoxicity present in 4 clinical stages.

• Stage 1 (0.5-24 h postingestion)
  • 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.
  • Some patients remain asymptomatic but still have a risk for developing clinically significant toxicity.
  • Neurologic, respiratory, and cardiac symptoms are rare in stage 1. If CNS involvement and/or severe metabolic acidosis (elevated anion gap) are present, consider co-ingestants.
  • 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 postingestion)
  • 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).
  • Acute pancreatitis 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, BUN, creatinine) may also be present.
• Stage 3 (72-120 h postingestion)
  • Stage 3 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, or encephalopathy. Renal failure and cardiomyopathy may also occur.
  • 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. Almost 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 > 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 postingestion)
  • Stage 4 occurs 5-14 days after ingestion. This stage can last as long as 21 days.
  • Patients either have a complete recovery of liver function or they die.
  • In patients who recover, the period to normalization may take several weeks. Hepatic histiologic recovery lags behind clinical recovery and can take months to resolve.
  • Acetaminophen-induced hepatotoxicity does not cause chronic hepatic dysfunction.

Physical

Physical findings vary and primarily depend on the stage of hepatotoxicity.

• Stage 1 (0-1 d)
  • Physical findings are nonspecific.
  • Pallor, diaphoresis, and compromised hydration status due to repeated emesis and increased insensible losses may be present.
  • Malaise and fatigue are reported.
• Stage 2 (1-3 d)
  • Abdominal examination reveals tenderness in the right upper quadrant and hepatomegaly.
  • Vital signs show tachycardia and hypotension as indicators of ongoing volume losses.
• Stage 3 (3-5 d)
  • Physical findings reflect clinically significant hepatic injury, such as abdominal pain, jaundice, and GI bleeding due to coagulopathy.
  • Encephalopathy due to severe hepatic injury occurs.
  • Clinical signs and symptoms of multiorgan failure are noted.
• Stage 4 (5-21 d): Physical findings resolve or death occurs.

Causes

Production of N -acetyl-benzoquinoneimine (NAPQI) by the CYP system is the cause of liver toxicity.

• 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. For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dosage of acetaminophen is 80 mg/kg (not to exceed a cumulative daily dose of 2.6 g). Therapeutic weight-based oral dosing for children 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.
• In adults, the minimum toxic dose of acetaminophen for a single ingestion is 7.5-10 g. Single ingestions of 12 g or higher have high potential for hepatotoxicity.
• In children, the minimum toxic dose of acetaminophen 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 than others to hepatotoxicity due to acute N -acetyl-p -aminophenol (APAP) poisoning because of their relatively larger hepatic mass (ie, ratio of organ weight to total body weight), which efficiently eliminates and detoxifies NAPQI.
• Children who have acutely ingested 250 mg/kg or more of acetaminophen pose significant concern for acetaminophen-induced hepatotoxicity.
• Patients who ingest more than 350 mg/kg develop severe hepatotoxicity, if they are not appropriately treated.
• In June 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription medication to provide new information regarding acetaminophen-induced hepatotoxicity.^3,4 Additionally, the FDA is examining possible removal of acetaminophen from some popular analgesic combination products (eg, Vicodin) and possibly lowering the maximum daily dose. The FDA is currently evaluating whether changes need to be made for acetaminophen regarding the following:
  • Safe daily dose for healthy individuals
  • Safe daily dose in chronic liver disease
  • Safe daily dose when used with alcohol
  • Appropriate dose for efficacy
  • Package size restrictions
  • Pediatric dosing
  • Acetaminophen narcotic combinations

Differential Diagnoses

Other Problems to Be Considered

Drug-induced or toxin-induced hepatitis
Alcoholic hepatitis
Hepatobiliary disease
Inborn errors of metabolism, including alpha1-antitrypsin deficiency or fatty acid oxidation abnormalities
Ischemic hepatitis (shock liver)
Reye syndrome
Viral hepatitis due to Epstein-Barr virus or varicella
Vomiting of unclear etiology

Workup

Laboratory Studies

• Measurement of acetaminophen serum concentration
  • Obtain a plasma acetaminophen level in patients who have a history of a potentially toxic ingestion, who ingested an unknown amount of acetaminophen, who have altered mental status, or who have attempted suicide.
  • Routine assessment of acetaminophen levels is controversial but recommended because deaths from occult acetaminophen overdoses have occurred.
  • Negligible acetaminophen values from an 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.
• Interpretation of acetaminophen values by using the acetaminophen toxicity nomogram (Rumack-Matthew nomogram)
  • The Rumack-Matthew nomogram was developed for single acute ingestions of acetaminophen and is based on observational data from a large number of overdose patients who did not receive antidote therapy. Today, a modified version of this nomogram is used to assess hepatotoxicity risk in these patients.
  • The nomogram predicts the risk of hepatotoxicity at a single level in time. It does not predict fulminant hepatic failure or death.
  • Nomogram tracking begins 4 hours after ingestion and ends 24 hours after ingestion.
  • 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 level 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 N -acetyl-p -aminophenol (APAP) ingestions. Its reliability also decreases for ingestions involving extended-release acetaminophen tablets or for co-ingestions of acetaminophen with anticholinergics or opioids.
• Measurement of hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
  • 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 after ingestion.
  • Evidence of hepatic injury due to acetaminophen overdose is defined by elevation of the plasma transaminases values 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 include glucose, prothrombin time (PT) and bilirubin may be useful.
• Other laboratory studies
  • If mental status changes or clinical signs of encephalopathy are noted, obtain serum ammonia levels.
  • Renal function tests of electrolyte, BUN, and creatinine levels can reveal evidence of renal failure, which often occurs with hepatic failure. 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). Although renal failure is rare, it can occur independent of hepatic failure.
  • 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. Typing and crossmatching should be performed.
  • Order a pregnancy test (level of human chorionic gonadotropin) in all women of childbearing age. Acetaminophen crosses the placental barrier. Delayed antidotal treatment in pregnant women has been associated with fetal loss.
  • Assess the salicylate serum level to address concern for co-ingestants and the potential need to start medical care for salicylate poisoning.

Imaging Studies

• Imaging studies can be helpful in some circumstances. 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.
• Ultrasonography is helpful in defining hepatic and/or renal abnormalities as well as in assessing for involvement of other abdominal organs.

Histologic Findings

• Patients who reach stage 4 have hepatic histiologic 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 N -acetyl-benzoquinoneimine (NAPQI) production. 
• Improvement and recovery of these histiologic changes takes longer than clinical recovery (about 3 mo).

Treatment

Medical Care

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

• GI decontamination: Consider decontamination with activated charcoal in any patient who presents within 4 hours of ingestion. Consider gastric lavage if ingestion occurred within 1 hour of evaluation. In regard to young children, a small-bore nasogastric (NG) tube may limit the ability to perform effective gastric lavage.
• 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.
  • NAC is converted to cysteine, which replenishes glutathione stores. NAC also directly detoxifies N -acetyl-benzoquinoneimine (NAPQI) to nontoxic metabolites. NAC provides a substrate for sulfation, increasing the capacity for nontoxic metabolism. NAC can directly conjugate to NAPQI to reduce toxicity.
  • The National Multicenter study revealed that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion.⁵ 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.
• Intravenous (IV) NAC (Acetadote)
  • In 2004, the US Food and Drug Administration (FDA) approved an IV formulation of 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 the Medication section.
  • 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).

Surgical Care

• 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.

Consultations

• A medical toxicologist or a regional poison control center may be helpful in treating patients with possible co-ingestions, complicated histories, or atypical 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 harm oneself, psychosocial and/or psychiatric evaluation is indicated.

Medication

N -acetylcysteine (NAC), antiemetics, and activated charcoal are helpful in the treatment of acetaminophen toxicity. The American College of Emergency Physicians (ACEP) has recently issued guidelines for acetaminophen overdose.⁶

Antidotes

NAC, a glutathione precursor, is the antidote of choice to prevent and treat acetaminophen-induced hepatotoxicity. It is indicated for all ingestions above the possible toxicity line on the Rumack-Matthew nomogram. The FDA has approved both oral (Mucomyst) and intravenous (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.

N-acetylcysteine (Mucomyst, Acetadote)

PO antidote (Mucomyst) available as a 20% solution (200 mg/mL). Should be diluted to 5% solution (50 mg/mL) with fruit juice or carbonated beverage. Aggressive antiemetic therapy indicated in patients with nausea or vomiting due to acetaminophen-induced hepatic injury or foul smell of the solution. If patient vomits within 60 min of administration, repeat dose. IV formulation (Acetadote) diluted in 5% dextrose in water (D5W) and infused according to protocol for acute (within 8-10 h) or late-presenting or chronic acetaminophen ingestion.
Entire PO or IV regimen should be completed even if acetaminophen plasma levels decrease below toxic range on nomogram.

Dosing

Adult

PO
Loading dose: 140 mg/kg PO once
Maintenance dosage (start 4 h after loading dose): 70 mg/kg PO q4h for 17 doses; total 18 doses administered equaling 1330 mg/kg over 72 h
IV (patients >40 kg)
Acute (8-10 h after ingestion)
Loading dose: 150 mg/kg IV infused over 1 h; dilute in 250 mL D5W
First maintenance dose: 50 mg/kg IV infused over 4 h; dilute in 500 mL D5W
Second maintenance dose: 100 mg/kg IV infused over 16 h; dilute in 1000 mL D5W
Each infusion immediately follows the previous; total treatment time 21 h
Late presenting or chronic (>10 h after ingestion)
Loading dose: 140 mg/kg IV infused over 1 h; dilute in 500 mL D5W
Maintenance doses: 70 mg/kg IV q4h for at least 12 doses; dilute each dose in 250 mL of D5W and infuse over minimum 1 h; total treatment time 48 h
Decrease total volume of D5W if fluid restriction required

Pediatric

PO: Administer as in adults
IV (patients <40 kg)
Acute ingestion: Administer as in adults except decrease volume of D5W with each dose for pediatric patient

Interactions

May decrease carbamazepine serum levels; coadministration with nitroglycerin increases risk of hypotension

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

PO commonly causes nausea and vomiting; anaphylactoid reaction reported in patient starting PO therapy; IV can cause various infusion rate-dependent erythema at infusion site and/or generalized flushing; other adverse effects include diarrhea, headache, and anaphylactoid reactions with bronchospasm, hypotension, tachycardia, flushing, angioedema, or rash; adverse reactions respond well to antihistamines and to slowing or stopping infusion; patients with history of asthma or bronchospasm at increased risk for reactions; adverse reactions occur in about 3-9% and thought to be due to histamine release

Antiemetic agents

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

Metoclopramide (Reglan)

Antiemetic effect appears to be due to ability to block dopamine receptors in chemoreceptor trigger zone (CTZ) of CNS. Also enhances GI motility and accelerates gastric emptying time.

Dosing

Adult

10-20 mg/dose IV; not to exceed 1 mg/kg/dose or 3 mg/kg/d in divided doses as needed

Pediatric

1-2 mg/kg/d IV in divided doses

Interactions

Anticholinergics may antagonize effects; opiate analgesics may increase toxicity and cause CNS depression

Contraindications

Documented hypersensitivity; pheochromocytoma or GI hemorrhage; obstruction or perforation

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse reactions include drowsiness, diarrhea, and hypotension; acute dystonic reactions most common at high doses; caution in epilepsy (may increase seizure activity), mental illness, and Parkinson disease

Ondansetron (Zofran)

Selective 5-hydroxytryptamine (5HT3) receptor antagonist. Blocks serotonin by acting on vagus nerve peripherally and at CTZ in CNS. Considered more effective than metoclopramide with fewer adverse effects. More expensive antiemetic than metoclopramide.

Dosing

Adult

8 mg IV q8h, not to exceed 3 doses/d

Pediatric

0.15 mg/kg IV q8h, not to exceed 3 doses/d

Interactions

CYP inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) can potentially change half-life and clearance, but dosage adjustment not usually required

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Headache common

Decontamination agents

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 a 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 NAC. Although activated charcoal significantly reduces the bioavailability of NAC, the small decrease in the NAC bioavailability is unlikely to reduce the effectiveness of oral NAC as an antidote.

Activated charcoal (Actidose-Aqua, Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores absorbs 100-1000 mg of drug per gram of charcoal. Prevents absorption by adsorbing drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. In theory, by constantly bathing GI tract with charcoal, intestinal lumen serves as dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Does not dissolve in water.
For maximum effect, administer within 30 min after ingestion or poison.

Dosing

Adult

50-100 g, 1 g/kg, or 10 times the weight of ingested poison given PO as suspension in 4-8 oz. of water.

Pediatric

<1 year: Not recommended
>1 year: Administer as in adults

Interactions

Effectiveness of other medications decrease with coadministration; do not mix with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not effective in poisonings of ethanol, methanol, or iron salts; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns black

Follow-up

Further Inpatient Care

• Admit patients with acetaminophen 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 ICU.

Further Outpatient Care

• 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 an intent to harm oneself, a thorough psychosocial and/or psychiatric evaluation is indicated before the patient is discharged from the hospital.

Inpatient & Outpatient Medications

• Treatment for acetaminophen overdose with antidotal therapy must be managed on an inpatient basis.

Transfer

• Transfer patients with evidence of clinically significant hepatotoxicity to a hospital with organ transplant services.

Patient Education

• Inform parents and caregivers of the risks associated with acetaminophen overdose and that this drug, though it is safe when dosed properly, can cause harm if misused.
• Educate parents and caregivers about the proper dose of 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.
• Educate parents and caregivers that many over-the-counter (OTC) cold and cough preparations contain acetaminophen. They should carefully read medication labels before they give these preparations to children.
• Give parents and caregivers information, including the toll-free phone numbers for the National Poison Control hotline (1-800-222-1222) and their regional Poison Control hotline.
• For excellent patient education resources, visit eMedicine's Poisoning Center. Also, see eMedicine's patient education articles, Acetaminophen (Tylenol) Poisoning, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Special Concerns

• Delayed presentation of an acute single ingestion of acetaminophen
  • Until recently, the standard of care for acetaminophen 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 be beneficial for acetaminophen-induced hepatic failure when patients present more than 24 hours after ingestion. The authors know of no studies conducted to evaluate the use of NAC in patients who present late with hepatotoxicity but without signs of hepatic failure.
  • Medical toxicologists recommend treatment with NAC in patients who present more than 24 hours after ingestion, if unmetabolized acetaminophen is detected in the serum 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 acetaminophen, 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 decisions 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 with increased oxygen delivery to hepatic tissue.
• Chronic toxicity
  • Chronic acetaminophen toxicity is being recognized in pediatric patients. Chronic acetaminophen toxicity has occurred in young, febrile children with reduced oral intake who were treated with repeated doses of acetaminophen.
  • In chronic acetaminophen toxicity, the importance of fasting, reduced glutathione stores, and enhanced metabolism is unclear. Risk factors for chronic acetaminophen toxicity include sustained administration of high doses, fever, poor oral intake, and young age. The daily dose of acetaminophen for children should not exceed 80 mg/kg/d.
  • The Rumack-Matthew nomogram was developed for single acute exposures for acetaminophen and should not be used to evaluate chronic exposures. Elevated values on liver function testing are better than nomographic measures as predictors of toxicity. Diagnosing chronic acetaminophen toxicity 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.

Multimedia

Media file 1: Acetaminophen metabolism.

References

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4. Health and Human Services. Federal Register. 74(81). April 29, 2009. [Full Text].

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Keywords

acetaminophen overdose, acetaminophen toxicity, acetaminophen toxicity nomogram, acetaminophen-induced hepatotoxicity, alanine aminotransferase, ALT, aspartate aminotransferase, AST, APAP, APAP toxicity, N -acetylcysteine, NAC, N -acetyl-p -aminophenol, analgesics, activated charcoal, AC, hepatic centrilobular necrosis, hepatic cytochrome P450 system, CYP system, hepatotoxicity, N -acetyl-benzoquinoneimine, NAPQI, acetaminophen-induced hepatic failure, liver transaminases, paracetamol, Rumack-Matthew nomogram, hypoglycemia, coagulopathy, renal failure, malnutrition, gastroenteritis, alcoholism, HIV, hepatic failure, liver transplantation, hepatomegaly, acute tubular necrosis, proteinuria, hematuria

Contributor Information and Disclosures

Author

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: Ambulatory Pediatric Association and American Academy of Pediatrics
Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Jeffrey R Tucker, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Pediatrics, and Massachusetts Medical Society
Disclosure: Merck Salary Employment

Medical Editor

Halim Hennes, MD, MS, Pediatric Emergency Medicine Research Director, Professor, Departments of Pediatrics and Emergency Medicine, Medical College of Wisconsin
Halim Hennes, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Jeffrey R Tucker, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Pediatrics, and Massachusetts Medical Society
Disclosure: Merck Salary Employment

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

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
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.

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