AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 accidental 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.

Pathophysiology

The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults. The at-risk dose may be lower in some susceptible patient populations, such as persons with alcohol abuse, malnourishment, or viral illness with dehydration. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic compounds. These water-soluble conjugates are then eliminated in the urine.

In acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugative pathways of metabolism become saturated. Excess APAP is then oxidatively metabolized in the liver via the mixed function oxidase P450 system to a toxic 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 reduced glutathione stores, NAPQI binds to, and interacts with vital cellular proteins and the lipid bilayer of hepatocyte membranes. An ensuing cascade of oxidative and inflammatory damage can result is hepatocellular death and centrilobular (zone III) liver necrosis.

The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and increases the available glutathione to conjugate NAPQI. It may also enhance sulfate conjugation of any unmetabolized APAP. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations, and this vasodilatory effect on microcirculatory blood flow enhances local oxygen delivery to peripheral tissues. These microvascular effects are associated with a decrease in morbidity and mortality even in the setting of established hepatotoxicity.

NAC is most effective when administered within 8 hours of 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 APAP 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 malnutrition, AIDS, chronic ethanol abuse, or anorexia nervosa may be at increased risk for morbidity because of deficient glutathione stores and inadequate detoxification of NAPQI. Patients with enhanced ability to make NAPQI due to induction of the P450 oxidative enzyme system, specifically the subfamilies cyp2E1, cyp1A2, and cyp3A4, may be at increased risk of morbidity. Agents that induce this enzyme activity are numerous but include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or chronic ethanol ingestion.
• Pediatric patients younger than 5 years appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate acetaminophen, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported any alternative pediatric therapy, treatment in children should be the same as in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

• Because antidotal therapy is most effective when initiated within 8 hours postingestion, 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 acetaminophen'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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Vomiting of unclear etiology
Hepatic failure
Hepatorenal syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 recommended NAC therapy. The nomogram is not applicable after multiple or chronic ingestions. It may be less reliable following ingestions that include anticholinergics or opioids or extended-release formulations.
  • The serum APAP concentration should be measured after any intentional overdose because the history of acetaminophen ingestion may not be elicited. Clinical toxicity may not be evident soon after overdose, and the risk of morbidity increases when the initiation of NAC therapy is delayed. (See Special Concerns for information regarding extended-relief acetaminophen.)
• Transaminase levels
• • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours postingestion 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 bilirubin
• Electrolytes and creatinine
• • Lactate
  • Renal failure has been shown to coexist with or, rarely, be independent of liver toxicity in overdose. One study indicated that this is more likely to occur in alcoholic persons. Renal failure usually is not observed acutely but rather within 2-3 days of overdose.
• Human chorionic gonadotropin (HCG) in females of childbearing age
• • 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 (ATN), usually in conjunction with hepatic failure.
• Arterial blood gas: Poor prognosis is associated with an arterial pH less than 7.30 (which fails to correct with fluid administration), serum creatinine greater than 3.4 mg/dL, PT greater than 100s, and elevated lactate greater than 3.5 mmol/L.

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.

Procedures

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 after 1 hour 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.

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.
• If fulminant hepatic failure is present, consult a hepatologist and transplant surgeon.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: 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.

Drug Category: Antidote

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

Drug Category: 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Transfer

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

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 always should 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 alcoholism.
• 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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.
  • Finally, activated charcoal administration may prevent significant acetaminophen absorption 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 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 toxic acetaminophen ingestion is suspected.
  • Oral NAC administration may be staggered with activated charcoal if multiple doses of activated charcoal are necessary for treatment of a co-ingestant. Intravenous NAC administration may be preferable in this instance.
  • For greatest efficacy, administer NAC within 8 hours of ingestion; a later presentation should not preclude its administration if the history or presentation suggests potential toxicity. Failure to administer NAC because of late presentation could be considered medically and legally risky.
  • Failure to consider and evaluate for possible co-ingestants or to consider the effects of decreased GI motility on absorption of APAP; the treatment nomogram does not pertain to these situations. Therefore, in the absence of good data on multidrug or co-ingestions involving APAP, 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 with ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for presence of hepatotoxicity and unmetabolized acetaminophen.
  • Begin NAC therapy if the patient has elevated AST and ALT and a measurable acetaminophen concentration.
  • Consult the regional poison control center for guidance on a treatment regimen.
• Late presentation
• • If a patient presents 8-24 hours or longer postingestion, evaluate for ongoing hepatotoxicity and initiate NAC therapy if indicated.
  • NAC administration in cases of hepatic failure has been associated with 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 ability of the Rumack-Matthew nomogram to guide treatment. Several studies show that eliminations of extended and immediate-release acetaminophen are 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 the stomach or co-ingestants that delay gastric emptying. Consult the regional poison control center for guidance in evaluation and treatment regimen.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Amato CS, Wang RY, Wright RO, Linakis JG. Evaluation of promotility agents to limit the gut bioavailability of extended-release acetaminophen. J Toxicol Clin Toxicol. 2004;42(1):73-7. [Medline].
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• Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. Jun 1998;31(6):710-5. [Medline].
• Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med. Nov 1996;28(5):549-51. [Medline].
• Brent J. Are activated charcoal-N-acetylcysteine interactions of clinical significance?. Ann Emerg Med. Dec 1993;22(12):1860-2. [Medline].
• Burkhart KK. The acetaminophen nomogram: will it withstand the test of the extended relief formulation?. Acad Emerg Med. Aug 1996;3(8):738-9. [Medline].
• Cetaruk EW, Dart RC, Hurlbut KM, Horowitz RS, Shih R. Tylenol Extended Relief overdose. Ann Emerg Med. Jul 1997;30(1):104-8. [Medline].
• Chamberlain JM, Gorman RL, Oderda GM, Klein-Schwartz W, Klein BL. Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?. Ann Emerg Med. Sep 1993;22(9):1398-402. [Medline].
• Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). Acad Emerg Med. Aug 1996;3(8):740-4. [Medline].
• Ekins BR, Ford DC, Thompson MI, Bridges RR, Rollins DE, Jenkins RD. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med. Nov 1987;5(6):483-7. [Medline].
• FDA. Acetadote (R) IV N-Acetylcysteine prescribing information. Food and Drug Administration MedWatch Web site. Available at: http://www.fda.gov/medwatch/SAFETY/2004/apr_PI/Acetadote_PI.pdf. 2004. [Full Text].
• Gardner CR, Heck DE, Yang CS, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology. Mar 1998;27(3):748-54. [Medline].
• Perry H, Shannon MW. Acetaminophen. In: Haddad LM, Shannon MW, Winchester J, Fletcher J, eds. Clinical Management of Poisoning and Drug Overdose. 3^rd ed. WB Saunders Co; 1998:664-74.
• Smilkstein MJ. A new loading dose for N-acetylcysteine? The answer is no. Ann Emerg Med. Sep 1994;24(3):538-9. [Medline].
• Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med. Mar 1994;23(3):519-23. [Medline].
• Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. Jan 2006;30(1):1-5. [Medline].
• Stork CM, Rees S, Howland MA, Kaplan L, Goldfrank L, Hoffman RS. Pharmacokinetics of extended relief vs regular release Tylenol in simulated human overdose. J Toxicol Clin Toxicol. 1996;34(2):157-62. [Medline].
• Vassallo S, Khan AN, Howland MA. Use of the Rumack-Matthew nomogram in cases of extended-release acetaminophen toxicity. Ann Intern Med. Dec 1 1996;125(11):940. [Medline].

Article Last Updated: Oct 3, 2007