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DESCRIPTION
- Acetaminophen is a common over-the-counter pain reliever.
- "Chronic" or "repeated supratherapeutic" acetaminophen ingestion is defined as repetitive ingestion of more than the recommended maximum daily dose.
- Adult dose: Greater than 4 g over a 24-hour period
- Pediatric dose: Greater than 90/mg/kg over a 24-hour period
FORMS AND USES
- Numerous brands contain acetaminophen alone, whereas others are combination products.
- The product label should be checked carefully to determine whether the main ingredient is acetaminophen or acetylsalicylic acid (aspirin) and for other constituents such as decongestants, stimulants, or opioids.
TOXIC DOSE
- For repeated ingestions, the precise dose of acetaminophen and the time course of ingestion required to produce hepatotoxicity are unknown.
- In children, repeated ingestion of more than 150 mg/kg/day may lead to liver injury.
PATHOPHYSIOLOGY
- Acetaminophen is primarily metabolized to nontoxic products in the liver.
- An additional pathway, involving cytochrome P450, produces a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which causes liver injury if not detoxified.
- With therapeutic dosing, NAPQI is detoxified by liver.
- However, depletion of glutathione stores allows NAPQI to injure liver cells.
EPIDEMIOLOGY
Chronic acetaminophen poisonings are usually unintentional and occur in adults with acute, prolonged pain syndromes or in young children with persistent fever.
CAUSES
- Chronic supratherapeutic ingestion is common; patients may repeatedly ingest supratherapeutic doses of acetaminophen in the belief that no harm will result.
- Child abuse has been suspected in several cases of "chronic" acetaminophen toxicity in infants.
RISK FACTORS
In an overdose, adults with malnutrition and underlying liver disease (e.g., alcoholics) may be more susceptible to "chronic" acetaminophen toxicity.
DRUG AND DISEASE INTERACTIONS
Chronic ingestion of cytochrome P450 enzyme inducers, such as alcohol, isoniazid, and carbamazepine, may potentiate chronic supratherapeutic acetaminophen toxicity.
PREGNANCY AND LACTATION
- US FDA Pregnancy Category B. Animal studies indicate no fetal risk, and there are no controlled human studies, or animal studies show an adverse fetal effect, but well-controlled studies in women do not exist.
- Acetaminophen crosses the placenta, but documented fetal death or hepatotoxicity from maternal overdose is rare.
- In the absence of fetal distress, induction of labor or termination of pregnancy based on maternal acetaminophen toxicity is not indicated.
- Preliminary evidence indicates that N-acetylcysteine (NAC) crosses the placenta and should be administered to the mother according to the same indications as for patients who are not pregnant.
- An infant delivered to a woman with acetaminophen toxicity should receive a 48-hour course of intravenous NAC.
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DIFFERENTIAL DIAGNOSIS
- Toxicologic agents that cause right upper quadrant pain and elevated liver function tests include salicylate, carbamezapine, valproic acid, phenytoin, isoniazid, halothane, disulfuram, procainamide, and methotrexate, among many others.
- Nontoxicologic causes include biliary tract disease or viral or alcoholic hepatitis.
SIGNS AND SYMPTOMS
- Patients with chronic acetaminophen overdose often present with liver injury: elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, and prolonged prothrombin time (PT) or international normalized ratio (INR).
- Infants typically have a febrile illness and may present with lethargy and dehydration.
Vital signs
Patients with dehydration may have tachycardia.
HEENT
Scleral icterus occurs if hepatic injury develops.
Dermatologic
Jaundice occurs if hepatic injury develops.
Gastrointestinal
Nausea and vomiting may occur.
Hepatic
- Liver injury ranges from mild, asymptomatic liver injury to fulminant hepatic failure.
- Right upper quadrant pain and abnormal liver function test results may be observed days to weeks after initiation of repetitive, supratherapeutic ingestion.
- PT and INR elevation are sensitive indicators of liver injury and may precede the increase in AST and ALT.
Renal
Acute renal insufficiency and failure may occur in severe cases and may be independent of liver injury.
Hematologic
Thrombocytopenia may occur.
Fluids and Electrolytes
Dehydration is common.
Neurologic
Hepatic encephalopathy may be associated with liver failure.
PROCEDURES AND LABORATORY TESTS
Essential Tests
If a history of repetitive, supratherapeutic ingestion is elicited, the clinician should obtain:
- Serum acetaminophen level.
- Serum electrolytes, BUN, and creatinine are ordered to assess changes in electrolytes and kidney injury.
- AST, ALT, and PT or INR are used to determine whether liver injury has occurred.
Recommended Tests
- Glucose, amylase are assayed if evidence of liver injury exists.
- Fulminant hepatic failure may result in acidosis, electrolyte abnormalities, and hypoglycemia.
- Renal injury or pancreatitis also may develop.
- Serum ammonia may be elevated if hepatic encephalopathy develops.
- Arterial blood gases, if acidosis is suspected from low serum bicarbonate.
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- Treatment should focus on prevention of absorption, control of emesis, and administration of NAC if indicated.
- The dose and time of exposure must be determined for all substances involved.
- Aggressive anti-emetic therapy is important for patients with vomiting who require NAC.
DIRECTING PATIENT COURSE
The health-care professional should call the poison control center when:
- Metabolic acidosis, renal insufficiency, encephalopathy, or fulminant hepatic failure develops.
- Ingestion involves Tylenol Arthritis Extended Relief Caplets (a prolonged release formulation).
- Toxic effects are not consistent with acetaminophen poisoning.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
Patients should be referred to a health-care facility when:
- History of repetitive, supratherapeutic acetaminophen ingestion is obtained.
- Patient or caregiver seems unreliable.
- Any toxic effects are present.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
Admission Considerations
- Inpatient treatment is warranted for patients who are treated with NAC.
- Consultation with a liver transplantation center is recommended if the following signs develop:
- Acidosis. pH less than 7.3
- Encephalopathy. Grade III or IV
- Renal insufficiency. Creatinine higher than 3.4 mg/dl
- Coagulopathy. PT greater than 35 to 40 seconds (without treatment with coagulation factors), or rapidly rising
DECONTAMINATION
One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.
ANTIDOTES
NAC (N-Acetylcysteine) is the antidote for acetaminophen poisoning.
- Indications. Patients with a history of repetitive, supratherapeutic ingestion who have evidence of liver injury (elevated PT/INR, AST, or ALT, or right upper quadrant pain), or measurable acetaminophen level should be treated.
- Contraindications. History of anaphylactic reaction to NAC precludes use.
- Method of administration
- Patients who meet criteria for NAC treatment should be treated for a minimum of 36 hours after the last ingested dose.
- NAC should be discontinued if liver function test levels do not increase during this time, or if previously elevated liver function test results are near normal or at patient's baseline.
- Further details on administration of NAC are found in SECTION III, N-acetylcysteine chapter).
ADJUNCTIVE TREATMENT
- Antiemetic therapy. Patients may require aggressive antiemetic therapy to ensure that NAC is retained.
- Not recommended therapies
- Fresh frozen plasma administration is not recommended to correct PT of less than 40 seconds unless frank bleeding develops, because PT is an important prognostic indicator.
- Cimetidine is an unproven therapy and is not recommended.
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PATIENT MONITORING
- PT/INR, AST, ALT, bilirubin, hematocrit, electrolytes, creatinine, and glucose tests should be repeated daily during NAC therapy.
- Ammonia and platelet count should be followed as clinically indicated.
EXPECTED COURSE AND PROGNOSIS
- Most patients who are treated with NAC recover without sequelae, even if liver injury complicates course.
- Renal failure is usually reversible but may last for several weeks and require hemodialysis.
- Fulminant hepatic failure is the main cause of death.
- Renal insufficiency or pancreatitis occur in a small number of patients.
DISCHARGE CRITERIA/INSTRUCTIONS
- From the emergency department
- Patients may be discharged if liver tests are normal or baseline, there is no right upper quadrant abdominal tenderness, and no acetaminophen is detectable in blood samples.
- A psychiatric evaluation should be obtained, if indicated.
- From the hospital
- Patients may be discharged when liver function test results, including PT, are normal or progressively decreasing and the course of NAC has been completed.
- A psychiatric evaluation should be obtained, if indicated.
PATIENT EDUCATION
- Patients should be cautioned that simultaneous use of more than one acetaminophen product may lead to inadvertent overdose.
- Repeated substitution of inappropriate formulation (e.g., use of an adult acetaminophen suppository in a child instead of a pediatric one) may result in toxicity.
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DIAGNOSIS
Chronic acetaminophen poisoning may be subtle; history of marked subacute pain syndrome such as tooth pain should elicit an evaluation.
TREATMENT
Failure to treat vomiting aggressively may result in delayed NAC treatment and less favorable outcome.
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ICD-9-CM 965.4Poisoning by analgesics, antipyretics, and antirheumatics: aromatic analgesics, not elsewhere classified.
See Also: SECTION III, N-acetylcysteine chapter; and SECTION IV, Acetaminophen—Acute Single Ingestion chapter.
RECOMMENDED READING
Henretig FM, Selbst SM, Forrest C, et al. Repeated acetaminophen overdosing causing hepatotoxicity in children. Clin Pediatr 1989;28:525-528.
Author: Rivka S. Horowitz
Reviewer: Richard C. Dart