eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Acetaminophen

Susan E Farrell, MD, Assistant Professor of Medicine, Harvard Medical School; Education Consultant, Office for Graduate Medical Education, Partners HealthCare Systems; Attending Physician, Department of Emergency Medicine, Brigham and Women's Hospital

Updated: Sep 23, 2009

Introduction

Background

Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and unintentional poisoning.

Acetaminophen is also known as paracetamol and N -acetyl-p-aminophenol (APAP). It is available in the United States as 325-mg and 500-mg immediate-release tablets, and as a 650-mg extended-release preparation marketed for the treatment of arthritis. Various children's dissolvable, chewable, suspension, and elixir formulations of acetaminophen are available. Acetaminophen is a component of many over-the-counter cold and analgesic medications and prescription combinations, including propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet). Hepatotoxicity associated with acetaminophen misuse and overdose is well recognized.

In 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription containing medication to provide new information regarding acetaminophen-induced hepatotoxicity.^1,2 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

Pathophysiology

The maximum recommended daily dose of acetaminophen is 4 g in adults and 90 mg/kg in children. Toxicity is associated with a single acute APAP ingestion of 150 mg/kg or approximately 7-10 g in adults. The ingested amount at which toxicity may occur may be lower in the settings of chronic ethanol use, malnourishment, or diminished nutritional status, fasting, or viral illness with dehydration, or if substances or medications that are known to induce the activity of the CYP oxidative enzymes are being used. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen is rapidly absorbed from the stomach and small intestine and 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, 3A4) to a reactive metabolite, N -acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation, or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts.

An ensuing cascade of oxidative damage, mitochondrial dysfunction, and the subsequent inflammatory response propagate hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extra-hepatic organs, such as the kidney, and can contribute to some degree of extra-hepatic organ dysfunction.

The antidote for acetaminophen poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and as such, increases glutathione conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP. NAC functions as an anti-inflammatory and antioxidant and has positive inotropic effects. 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 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 acetaminophen levels.

Frequency

United States

Acetaminophen is one of the most common pharmaceutical agents involved in overdose, as reported to the American Association of Poison Control Centers. APAP toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure, and it is the second most common cause of liver failure requiring transplantation in the United States.

Mortality/Morbidity

The majority of patients with acetaminophen overdose survive with supportive care alone, in conjunction with antidotal therapy. If correctly treated in a timely manner, most patients do not suffer significant sequelae.

• Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or liver transplantation occurs in less than one half of these patients.
• Patients with chronic ethanol use or diminished nutritional status may be at increased risk for morbidity because of deficient glutathione stores and a subsequent inability to conjugate and detoxify NAPQI. Patients who use substances that are known to induce the activity of the oxidative CYP enzymes, CYP2E1, CYP1A2, CYP2A6, or CYP3A4, may be at increased risk of morbidity due to enhanced production of NAPQI. Agents and substances that induce CYP enzyme activity are numerous but include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, chronic ethanol ingestion, and tobacco use.
• Pediatric patients younger than 5 years of age appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported an alternative pediatric-specific therapy, treatment in children should be the same as in adults.

Clinical

History

The course of acetaminophen toxicity generally is divided into 4 phases. Clinical evidence of end-organ (hepatic or occasionally renal) toxicity is often delayed 24-48 hours postingestion.

• Because antidotal therapy is most effective when initiated within 8 hours post-ingestion, the clinician must obtain an accurate history of the time(s) of ingestion, the quantity, and formulation of acetaminophen ingested, and any co-ingestants, which may delay APAP absorption (eg, anticholinergic drugs or opioids).
• Because a patient's history may be inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms. After a single ingestion, NAC therapy is guided by the serum APAP concentration.
• Phase 1 (0-24 h)
  • Asymptomatic
  • Anorexia
  • Nausea or vomiting
  • Malaise
  • Subclinical rise in serum transaminases levels begins at about 12 hours postingestion
• Phase 2 (18-72 h)
  • Right upper quadrant abdominal pain, anorexia, nausea, vomiting
  • Continued rise in serum transaminases levels
• Phase 3 (72-96 h)
  • Centrilobular hepatic necrosis with continued abdominal pain
  • Jaundice
  • Coagulopathy
  • Hepatic encephalopathy
  • Nausea and vomiting
  • Renal failure
  • Fatality
• Phase 4 (4 d to 3 wk)
  • Complete resolution of symptoms
  • Complete resolution of organ failure

Physical

Physical examination findings vary, depending on the phase of toxicity.

• Phase 1
  • Pallor
  • Malaise
  • Vomiting
  • Diaphoresis
• Phase 2
  • Right upper quadrant abdominal tenderness
  • Tachycardia
  • Hypotension
• Phase 3
  • Tender hepatic edge
  • Jaundice
  • Evidence of coagulopathy, including gastrointestinal (GI) bleeding
  • Evidence of hepatic encephalopathy
• Phase 4: Resolution

Causes

• Production of APAP's toxic metabolite, NAPQI, in excess of an adequate store of conjugating glutathione, is associated with hepatocellular damage, necrosis, and hepatic failure.
• Additional mechanisms of acetaminophen-induced toxicity are postulated as well.

Differential Diagnoses

Other Problems to Be Considered

Vomiting of unclear etiology
Hepatic failure
Hepatorenal syndrome

Workup

Laboratory Studies

• Acetaminophen serum concentration
  • A serum acetaminophen concentration drawn 4 or more hours after a SINGLE ingestion may be plotted on the Rumack-Matthew nomogram as a guide to the likelihood of potential hepatotoxicity and the indication for NAC therapy. The nomogram is NOT applicable in the cases of multiple or chronic acetaminophen ingestion. It may be less reliable for the prediction of hepatotoxicity in cases of acetaminophen ingestion that also include anticholinergic agents or opioids, or in the case of extended-release acetaminophen formulations. (See Special Concerns for information regarding extended-relief acetaminophen.)
  • A serum acetaminophen concentration should be measured after any intentional overdose because the history of acetaminophen ingestion may not be elicited and the onset of clinical toxicity is delayed after overdose. The risk of morbidity increases when the initiation of NAC therapy is delayed.
• Transaminase levels
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours post ingestion and peak at about 72 hours.
  • Toxicity is defined as serum AST or ALT levels greater than 1000 IU/L.
• Measures of hepatic function
  • Serum glucose
  • Prothrombin time (PT) and international normalized ratio (INR) are laboratory components predictive of mortality. Elevated PT and INR indicate impaired synthetic liver function.
• Other serum measures of hepatic damage
  • Serum concentrations of NAPQI-protein adducts have been measured as evidence of acetaminophen-induced hepatotoxicity.³ The peak serum concentrations of NAPQI-adducts correlate with peak AST and ALT concentrations, and they may be diagnostic of acetaminophen-induced hepatotoxicity in late-presenting patients with acute liver failure of unknown etiology. NAPQI-protein adducts are not available in real-time clinical practice and could be obtained only through specialized laboratories.
• Electrolytes and creatinine
  • Lactate is a laboratory component predictive of mortality.
  • Acute tubular necrosis and renal failure have been shown to coexist with or, rarely, be independent of hepatotoxicity in acetaminophen overdose. One study indicated that this is more likely to occur in persons with a history of ethanol abuse. Renal failure, when it occurs, usually occurs within 2-3 days of overdose.
  • Serum creatinine is a laboratory component predictive of mortality.
  • It is suggested that serum phosphate can be used as an early predictor of outcome in severe acetaminophen-induced hepatotoxicity .⁴
• Human chorionic gonadotropin (HCG) in females of childbearing age⁵
  • Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation.
  • Delay in treating pregnant patients with antidotal therapy is associated with fetal demise.
• A type and crossmatch should be drawn for the treatment of active bleeding in the face of coagulopathy.
• Urinalysis: Proteinuria and hematuria may be seen with acute tubular necrosis, usually in conjunction with hepatic failure.
• Arterial blood gas: pH <7.3 is a laboratory component predictive of mortality.

Imaging Studies

• CT scan of the head
  • CT scan may reveal cerebral edema in patients with late presentation and encephalopathy.
  • Consider in patients with altered mental status.
• Ultrasound
  • Ultrasound may reveal mild hepatic enlargement in late presentation.
  • If clinically indicated, this is usually an inpatient procedure.

Other Tests

• Obtain ECG in order to exclude the presence of cardioactive substances/coingestants

Procedures

• Gastric lavage: Gastric lavage has no proven efficacy in isolated acetaminophen overdose.

Treatment

Prehospital Care

Stabilize immediate life-threatening conditions and initiate supportive care.

Emergency Department Care

• Supportive therapy, including IV fluids, oxygen, and cardiac monitor
• Gastric decontamination
  • Oral activated charcoal (AC) avidly adsorbs acetaminophen and should be administered if the patient presents within 1 hour of ingestion.
  • Oral AC may be of benefit greater that 1 hour after the ingestion if the ingestion involves an agent that delays gastric emptying or slows GI motility. Oral activated charcoal administered with NAC greater than 4 hours after ingestion has been shown in one case series to be effective in reducing the incidence of transaminitis after toxic acetaminophen ingestion.
• Administer N -acetylcysteine, if indicated. Early administration of NAC, within 8 hours of ingestion, is nearly 100% hepatoprotective. NAC should be administered while awaiting a serum acetaminophen level if the patient presents close to or later than 8 hours postingestion, or if the patient is pregnant.
• Assess for evidence of other life-threatening co-ingestions.
• For further information, see the American College of Emergency Physicians treatment guidelines for acetaminophen poisoning.⁶

Consultations

• Medical toxicologist, available through consultation with a regional poison control center
  • 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.
• Hepatologist, in the setting of hepatic dysfunction. 
• Transplant surgeon, in the setting of clinical and laboratory indicators that are highly predictive of death unless urgent transplantation is undertaken. The King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen-induced fulminant hepatic failure include the following:
• Arterial pH <7.3 (regardless of grade of encephalopathy) OR
• Grade III or IV encephalopathy AND
• PT >100s AND
• Serum creatinine >3.4 mg/dL

Medication

Agents used in the treatment of acetaminophen poisoning include activated charcoal, N -acetylcysteine, and antiemetics.

GI decontaminants

Emergency treatment in poisoning caused by drugs and chemicals. The network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

Activated charcoal (Actidose, CharcoAid, Charcodote, Liqui-Char)

Drug of choice for gastric decontamination in patients presenting within 1 h post-ingestion, or in cases where co-ingestants may delay gastric emptying or gut motility.

Dosing

Adult

1 g/kg PO or 10 times the amount of drug ingested

Pediatric

Administer as in adults

Interactions

Effectiveness of other medications decreases with coadministration: may inactivate ipecac syrup if used concomitantly; do not mix with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity to activated charcoal; unprotected airway with absent gag reflex; poisoning or overdose of mineral acids or alkalis; relative contraindication includes ingestion of hydrocarbons

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 very effective in poisonings due to alcohols, lithium, and iron salts; adverse effects include nausea and vomiting; risk of aspiration if the airway is not secure; monitor for bowel sounds to minimize risk of charcoal ileus and potential bowel obstruction (only if multiple doses administered)

Antidote

May provide substrate for conjugation with the toxic metabolite of acetaminophen. Administer all doses, even if acetaminophen level has dropped below toxic range.

N-acetylcysteine (Mucomyst, Acetadote)

Drug of choice for the prevention and treatment of acetaminophen-induced hepatotoxicity. Approved by the FDA for both PO and IV administration. For maximum hepatoprotective effect, administer within 8 h of acetaminophen ingestion. When given PO, dilute in chilled juice or cola to a 5% solution. May be administered via nasogastric tube if severe nausea threatens administration. Repeat dose if vomiting occurs within 1 h of oral administration. When administered IV, dilute in 5% dextrose solution, infuse per recommended IV protocol.

Dosing

Adult

Three recognized and acceptable protocols for the administration of NAC are as follows:

PO
Loading dose: 140 mg/kg PO once; follow with maintenance dose
Maintenance dose: (start 4 h after loading dose): 70 mg/kg PO q4h for 17 additional doses (ie, 18 doses totaling 1330 mg/kg administered over 72 h)

Continuous IV administration (total treatment time 21 h)
Acute (8-10 h after ingestion) in patients >40 kg:
Loading dose: 150 mg/kg IV infused over 15 min (dilute in 200 mL D5W) follow with maintenance doses
First maintenance dose: 50 mg/kg IV infused over 4 h (dilute in 500 mL D5W), followed with second maintenance dose
Second maintenance dose: 100 mg/kg IV infused over 16 h (dilute in 1000 mL D5W)

Intermittent IV administration (total treatment time 48 h)
Late presenting or chronic (>10 h after ingestion) in patients >40 kg:
Loading dose: 140 mg/kg IV infused over 1 h (dilute in 500 mL D5W), followed with maintenance dose
Maintenance dose: 70 mg/kg IV q4h for at least 12 doses (dilute each dose in 250 mL of D5W and infuse over minimum 1 h)
Decrease total volume of D5W if fluid restriction required

Shortened courses of NAC (20-48 h) have been shown to be safe and effective in a subset of patients who have undetectable serum acetaminophen levels, and normal AST, ALT, and INR after 20 h of NAC treatment (consult a medical toxicologist or poison control center if considering shortened NAC therapy).⁷

Pediatric

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

Interactions

NAC decreases carbamazepine levels; NAC enhances hypotension of nitroglycerin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

Adverse effects associated with PO NAC include nausea and vomiting; only 1 case of an anaphylactoid reaction following PO NAC has been reported; IV NAC may cause various degrees of infusion rate-dependent erythema at infusion site or flushing (these are generally self-limited); anaphylactoid reactions, including urticaria, fever, bronchospasm, and hypotension respond to antihistamines and stopping the infusion (they may be limited by slowing infusion rate and may be more common in patients with asthma); adjust total fluid volume for IV in patients <40 kg or fluid restricted patients

Antiemetics

Emesis frequently is associated with acetaminophen toxicity and is a common consequence of activated charcoal and PO NAC administration. For these reasons, antiemetic therapy often is necessary to facilitate the successful administration of PO NAC.

Antiemetics that do not decrease gastric motility or significantly alter mental status are the DOC; anticholinergic drugs, such as prochlorperazine (Compazine) are not considered beneficial, in part because of their propensity to cause both of these effects. Phenothiazines also may add to the toxicity associated with other anticholinergic drugs, which may be in combination with APAP-containing formulations.

Metoclopramide (Reglan)

Functions as an antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS. Is generally considered an initial drug of choice due to low cost.

Dosing

Adult

10-20 mg IV, not to exceed 1 mg/kg; not to exceed 3 mg/kg/d divided prn

Pediatric

1-2 mg/kg IV total dose

Interactions

Opiate analgesics may increase metoclopramide toxicity in CNS

Contraindications

Documented hypersensitivity to metoclopramide

Precautions

Pregnancy

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

Precautions

Caution in patients with a history of mental illness or Parkinson disease; adverse effects include drowsiness, hypotension, and acute dystonia, especially at high doses; may increase the frequency of seizures in patients with epilepsy

Ondansetron (Zofran)

Selective 5-HT3–receptor antagonist that blocks serotonin both peripherally and centrally. Considered a potentially more effective antiemetic, with less common adverse effects than metoclopramide.

Dosing

Adult

1 mg, or 0.15 mg/kg, up to 8 mg IV q8h, not to exceed 3 doses in 24 hours

Pediatric

0.15 mg/kg IV q 8h, not to exceed 3 doses in 24 hours

Interactions

Although cytochrome CYP enzyme inducers (barbiturates, rifampin, carbamazepine, and phenytoin) may potentially change the half-life and clearance of ondansetron, dosage adjustment is not usually required

Contraindications

Documented hypersensitivity to ondansetron

Precautions

Pregnancy

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

Precautions

Medication is to be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

Follow-up

Further Inpatient Care

• Admit patients for NAC therapy if they have an acetaminophen level associated with potential toxicity, as suggested by the Rumack-Matthew treatment nomogram.
• Unless coexisting toxicologic, medical, or psychiatric issues are present, patients with acetaminophen toxicity may be admitted and treated on a general medical floor.
• Admit patients to an ICU setting if they show signs of significant hepatotoxicity; hepatic failure; or other potentially life-threatening, coexisting, toxicologic, or medical issues.

Further Outpatient Care

• Patients who do not have an acetaminophen level associated with potential toxicity, as determined by the Rumack-Matthew nomogram, may be discharged or transferred for psychiatric evaluation if indicated, when they are otherwise medically clear.
• Out-of-hospital treatment guidelines are available from the American Association of Poison Control Centers.⁸

Transfer

• Transfer patients with fulminant hepatic failure to a facility capable of intensive care monitoring and evaluation for potential transplantation.

Prognosis

• With aggressive supportive care, the mortality rate for acetaminophen hepatotoxicity is less than 2%. Patients who survive should be expected to have a return of normal hepatic function.

Patient Education

• Advise patients of the potential risk associated with the inappropriate use of acetaminophen, which commonly is considered an innocuous over-the-counter drug.
• Educate parents of the proper acetaminophen dosing for children and the danger associated with misusing various acetaminophen preparations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Because the infant suspension (drops) is a more concentrated formulation than the elixir (100 mg/mL vs 32 mg/mL), this can be a potential source of therapeutic error. Parents should always be given clear dose and formulation instructions. They should also be instructed to carefully examine over-the-counter medications that may contain acetaminophen in combination formulations.
• Educate patients of the increased potential for renal toxicity associated with concurrent acetaminophen and NSAID analgesic use, or chronic ethanol use.
• For excellent patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Acetaminophen (Tylenol) Poisoning, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• NAC-activated charcoal interaction
  • In vitro studies have shown that NAC is adsorbed to activated charcoal and the administration of activated charcoal reduced total NAC absorption by 39% in human volunteers, as measured by serum NAC levels. Prospective evaluation of patients treated with activated charcoal and NAC, however, indicated no adverse outcome associated with this treatment.
  • Despite binding to NAC, activated charcoal adsorbs acetaminophen more avidly. Therefore, although charcoal may decrease the bioavailability of NAC, this decrease is clinically inconsequential.
  • Importantly, activated charcoal administration may prevent significant acetaminophen absorption from the GI tract and obviate the need for NAC.
  • Super-loading doses of NAC have not been shown to be of greater clinical benefit than the current recommended loading dose.
  • Administer activated charcoal and draw a 4-hour serum acetaminophen concentration if the patient presents within 1-2 hours of ingestion.
  • Draw an acetaminophen level if the patient presents later than 4 hours after ingestion. Administer NAC if the presentation is close to 8 hours postingestion, or if the acetaminophen level will not be available within 8 hours postingestion, and if the history is unclear but a potentially toxic acetaminophen ingestion is suspected.
  • Oral NAC administration may be staggered with activated charcoal if multiple doses of activated charcoal are necessary for the treatment of a co-ingestant. Intravenous NAC administration may be preferable in this instance.
  • For greatest hepatoprotective efficacy, administer NAC within 8 hours of ingestion; a later presentation should not preclude NAC administration if the history or presentation suggests potential toxicity. The failure to administer NAC because of late presentation could be considered medically and legally inappropriate.
  • Consider and evaluate for possible co-ingestants and consider the possible effects of decreased GI motility on the absorption of acetaminophen; the predictive value of the treatment nomogram may not pertain to these situations. Therefore, in the absence of good data on multi-drug ingestions or co-ingestions involving acetaminophen, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

Special Concerns

• Chronic ingestion
  • If a patient presents after the ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for the presence of a persistent serum acetaminophen concentration and hepatotoxicity.
  • Begin NAC therapy if the patient has elevated AST and ALT and a measurable acetaminophen concentration.
  • Consult a regional poison control center for guidance on a treatment regimen.
• Late presentation
  • If a patient presents 8-24 hours or later post ingestion, initiate NAC therapy and evaluate for ongoing 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.
• Extended-relief acetaminophen (Tylenol ER)
  • The Tylenol ER preparation became available in 1995. The tablet is composed of acetaminophen 325 mg in immediate release form with 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. Several studies show that the elimination of extended and immediate-release acetaminophen preparations is nearly identical after 4 hours. However, some case reports have documented acetaminophen levels falling above the treatment nomogram line as late as 11-14 hours postingestion of the extended-release preparation.
  • Check 4-, 6-, and 8-hour acetaminophen concentration levels. 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 levels may be necessary if the patient has food in their stomach or co-ingestants that delay gastric emptying. Consult a regional poison control center for guidance in evaluation and the optimal treatment regimen.

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Keywords

acetaminophen toxicity, paracetamol, N-acetyl-p-aminophenol, APAP, analgesic agent, antipyretic agent, N-acetyl-p-benzoquinone-imine, NAPQI, hepatocellular death, hepatocellular necrosis, centrilobular liver necrosis, N -acetylcysteine, NAC, fulminant hepaticfailure, hepatic encephalopathy, renal failure, coagulopathy, diaphoresis, acetaminophen toxicity, acetaminophen overdose, APAP toxicity, APAP overdose, hepatotoxicity, acetaminophen poisoning, APAP poisoning

Contributor Information and Disclosures

Author

Susan E Farrell, MD, Assistant Professor of Medicine, Harvard Medical School; Education Consultant, Office for Graduate Medical Education, Partners HealthCare Systems; Attending Physician, Department of Emergency Medicine, Brigham and Women's Hospital
Susan E Farrell, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Miguel C Fernández, MD, FAAEM, FACEP, FACMT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio
Miguel C Fernández, MD, FAAEM, FACEP, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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