Acetaminophen toxicity case file
Eugene C. Toy, MD, Barry C. Simon, MD, Terrence H. Liu, MD, MHP, Katrin Y. Takenaka, MD, Adam J. Rosh, MD, MS
Case 40
An 18-year-old woman is brought by a friend to the emergency department (ED) about 30 minutes after she took “a bunch” of Tylenol. The patient states she was upset with her parents who grounded her after she came home late from a party; she swallowed half a bottle of extra-strength Tylenol in order to “make them feel sorry.” She is tearful, says she was “stupid,” and denies any true desire to hurt herself or anyone else. She has no other complaints and denies any past attempts to hurt herself. On examination, her blood pressure is 105/60 mm Hg, heart rate is 100 beats per minute, and respiratory rate is 24 breaths per minute (crying). Her pupils are equal and reactive bilaterally. Her sclera is clear, and her mucous membranes are moist. The lungs are clear and the heart sounds are regular. The abdominal examination is benign with normal bowel sounds. She is awake and alert without any focal neurologic deficits.
⯈ What is the most appropriate next step?
⯈ What are the potential complications of this ingestion?
⯈ What is the mechanism of acetaminophen toxicity?
ANSWER TO CASE: 40
Acetaminophen Toxicity
Summary: This is an 18-year-old woman with an acute acetaminophen overdose 30 minutes prior to arrival in the ED. She is alert and oriented with stable vital signs.
- Most appropriate next step: Obtain IV access; send appropriate laboratory studies; administer activated charcoal; evaluate need for N-acetylcysteine (NAC)
- Potential complications: Hypoglycemia, metabolic acidosis, hepatic failure, and renal failure
- Mechanism: Production of toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI)
ANALYSIS
Objectives
- Learn the general approach to the poisoned patient.
- Recognize the clinical signs and symptoms of acetaminophen toxicity.
- Understand the evaluation and treatment of patients with acetaminophen toxicity.
Considerations
Acetaminophen (APAP) is one of the most commonly used analgesics and antipyretics. It is available in a variety of prescription, over-the-counter, and combination medications labeled for fever, cold, cough, and pain relief. As a result, it is the most common over-the-counter agent reported in accidental and intentional overdoses, leading to more hospitalizations after overdose than any other pharmaceutical agent. A toxic exposure to APAP is suspected when more than 200 mg/kg or more than 10 g is ingested in a single dose or over the course of 24 hours. In addition, an ingestion of more than 150 mg/kg or more than 6 g per day for at least 2 consecutive days is potentially toxic. Hepatotoxicity is the most life-threatening complication, but may be indolent; thus, serum APAP level and a precise time of ingestion are important to plot on a nomogram to assess likelihood of toxicity. This patient was forthcoming about the medication used in the overdose; however, many patients will underreport or deny the use of APAP. Consequently, an APAP level should be drawn on all suspected overdose patients. Although clinical evidence of hepatotoxicity may be delayed for 24 to 72 hours, NAC therapy is most effective if started within 8 hours of ingestion. Because this patient reported the ingestion within 30 minutes, there is time for a serum APAP level, activated charcoal decontamination, and then NAC therapy. If time is an issue, NAC treatment should be initiated without delay. Emesis should not be induced because of the possible delay in therapy. After medical stabilization, assessment of suicide potential is important.
Approach To:
Acetaminophen Toxicity
CLINICAL APPROACH
Although APAP is safe at therapeutic dosages, ingestions more than 200 mg/kg can lead to liver failure and death. Under normal circumstances, most APAP is metabolized in the liver and excreted by the kidneys. Of the remainder, approximately 5% is excreted unchanged in urine. Another 5% is metabolized by the hepatic cytochrome P450 system to form NAPQI. This toxic intermediate is then detoxified by conjugation with glutathione. In acute APAP overdose, glutathione depletion leads to accumulation of NAPQI which then binds to hepatocyte intracellular proteins causing toxicity. APAP toxicity can be divided into four clinical phases (Table 40–1).
Clinical Evaluation
When approaching the poisoned or overdose patient, the clinician’s priorities are to perform a rapid assessment, stabilize the ABCs, decontaminate, minimize absorption, and administer any antidotes. Important historical information includes type, amount, and timing of ingestion; current symptoms; circumstances of the ingestion (accidental or intentional); and possible coingestants. The physical examination should focus on the abdomen (RUQ tenderness) and mental status (signs of encephalopathy). A complete physical examination is important to search for any concomitant toxic syndromes (toxidromes) (Table 40–2). Table 40–3 lists common antidotes. Consulting with the local poison control center is also recommended for any suspected ingestion or overdose.
Diagnostic studies include serum electrolytes, blood urea nitrogen (BUN)/creatinine, glucose, liver enzyme levels, coagulation studies, and urinalysis (as well as pregnancy test if appropriate). Because coingestion is common, a toxicology screen and salicylate level should be obtained. An ECG should be obtained to evaluate for dysrhythmias associated with other ingestants and electrolyte abnormalities.
If the patient’s mental status is altered, a computed tomography (CT) scan of the head is also recommended. However, the single best predictor of the risk of hepatotoxicity is a serum APAP level. This should be drawn 4 hours postingestion, or immediately if the time of ingestion is unknown. Using the APAP level and the Rumack-Matthew nomogram, the clinician can then predict the severity of
toxicity and determine the need for NAC therapy (Figure 40–1). The APAP level between 4 and 24 hours is plotted; if the level falls above the lower line, known as the treatment line, NAC should be initiated. This nomogram is not applicable for chronic ingestions, delayed ingestions, unknown time or duration of ingestion, extended release APAP, or coingestions.
Treatment
Initial treatment of the patient with an APAP overdose consists of stabilizing the ABCs, obtaining IV access, and placing the patient on cardiac and oxygen saturation monitors. Gastric lavage is rarely necessary due to the rapid gastrointestinal absorption of APAP. Activated charcoal can reduce gastric absorption of the drug but may also adsorb oral NAC. Thus, if activated charcoal is given, separating the first dose of NAC and activated charcoal by 1 to 2 hours may be preferable. NAC, the antidote for APAP toxicity, acts by replenishing glutathione stores and combining with NAPQI as a glutathione substitute. It is most effective when given within 8 hours of ingestion. The indications for NAC include a toxic level as determined using the Rumack-Matthew nomogram or evidence of hepatic failure. NAC can be empirically started if an APAP overdose is suspected and an APAP level will not be available within 8 hours of the ingestion; the NAC can then be discontinued if the APAP level is nontoxic and the patient is asymptomatic. Any patient who requires NAC treatment should be admitted to the hospital. Although the nomogram is not applicable for ingestions greater than 24 hours prior to ED arrival, NAC therapy may still be helpful.
aThis is an approximation. Doses should be titrated to ethanol level of 100-150 mg/dL.
The standard 72-hour NAC regimen is an oral loading dose of 140 mg/kg followed by maintenance doses of 70 mg/kg every 4 hours for 17 additional doses. Because of its acrid smell and taste, oral NAC often induces nausea and vomiting. Dilution in fruit juice or a chilled drink and the administration of antiemetics can be helpful.
Figure 40–1. Acetaminophen toxicity nomogram based on serum acetaminophen concentration versus time after ingestion.
If the patient has intractable vomiting or fulminant hepatic failure, intravenous NAC may be indicated (150 mg/kg loading dose, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours). Intravenous NAC should be used cautiously as rate-related anaphylactoid reactions can occur.
A small fraction of patients will develop fulminant hepatic failure, associated with a 60% to 80% mortality rate. Most deaths associated with liver failure occur 3 to 5 days postingestion, attributed to cerebral edema, sepsis, hemorrhage, multiorgan failure, or acute respiratory distress syndrome.
COMPREHENSION QUESTIONS
40.1 A 16-year-old adolescent girl is brought to the ED after taking a number of pills from her parents’ medicine cabinet. The parents have brought in all the medication bottles. Which of the following is most concerning for toxicity?
A. Ampicillin
B. Diphenhydramine
C. Fluoxetine
D. Theophylline
40.2 A 34-year-old man admits taking “the whole bottle” of acetaminophen over the course of 36 hours because of a severe headache. Which of the following is the best guide to determine whether to initiate NAC therapy?
A. Initiate NAC due to potentially toxic exposure
B. Serum APAP level and liver enzymes
C. Plotting the serum APAP level on the nomogram
D. If over 24 hours have elapsed, NAC therapy is not efficacious
40.3 A 25-year-old man is brought into the ED 1 hour after a witnessed overdose of 20 to 25 pills of acetaminophen tablets. At what time would be the best time to draw the APAP level?
A. As soon as the patient arrives in the ED
B. At 2 hours postingestion
C. At 4 hours postingestion
D. At 8 hours postingestion
40.4 A 38-year-old school teacher took a “large number of Tylenol tablets” and is found to have an APAP level of 200 μg/mL. The estimated time postingestion is 8 hours. The first dose of NAC is given. Which of the following is the next step to guide therapy?
A. Check APAP level 4 hours after the first NAC dose and if below the toxicity line, no further NAC needed.
B. Check the APAP level 12 hours after the first NAC dose and if below the toxicity line, no further NAC needed.
C. Check the APAP level and liver function tests at the 8 hour after the first NAC dose and if in the normal/nontoxic range, then no further NAC needed.
D. Give the entire course of NAC and no further APAP levels are necessary.
Match the following antidotes (A to H) to the clinical situations (Questions 40.5 to 40.8):
A. Calcium gluconateB. DeferoxamineC. Digoxin FabD. GlucagonE. N-acetylcysteineF. NaloxoneG. PhysostigmineH. Vitamin K
40.5 A 45-year-old man takes too many of his antihypertensive pills and is noted to have a heart rate of 40 beats per minute.
40.6 A 22-year-old pregnant woman with preeclampsia receiving intravenous medication to prevent seizures develops weakness and difficulty breathing.
40.7 A 24-year-old man is brought into the ED with somnolence, pinpoint pupils, and track marks on his arm.
40.8 A 56-year-old woman taking tablets to “thin her blood” is noted to be bleeding from her gums and has multiple bruises on her arms and legs. Life-threatening bleeding can be addressed with transfusion with clotting factors.
ANSWERS
40.1 D. Theophylline has a very narrow therapeutic index, with toxic effects of tachycardia, nausea, vomiting, and seizures.
40.2 A. At 24 hours postingestion, NAC therapy may still be useful. Due to the historically toxic exposure, NAC should be started while a serum APAP level and liver enzymes are checked. If the APAP level is undetectable and the liver enzymes are normal, subsequent doses of NAC can be discontinued. The Rumack-Matthew nomogram is not applicable for ingestions more than 24 hours prior to evaluation.
40.3 C. A serum APAP should be drawn 4 hours postingestion; the nomogram has relevance between 4 hours and 24 hours postingestion.
40.4 D. Once it is determined by the nomogram that the APAP dose is potentially toxic, the entire NAC regimen is given. No further APAP levels need to be drawn.
40.5 D. Glucagon is effective in treating calcium-channel blocker or β-blocker overdose.
40.6 A. This patient is likely receiving magnesium sulfate for seizure prophylaxis, and the antidote for hypermagnesemia is calcium gluconate.
40.7 F. Naloxone is the treatment of choice for opiate overdose. This individual likely is a heroin abuser.
40.8 H. This patient likely has warfarin overdose, which is treated by vitamin K.
CLINICAL PEARLS
⯈ Because the devastating effects of APAP toxicity may be delayed for 24 to 72 hours and antidotal therapy is most effective if started within 8 hours of ingestion, the clinician must have a high level of suspicion of APAP toxicity in any poisoned patient.
⯈ APAP toxicity is caused by the formation of a toxic metabolite, N-acetyl p-benzoquinoneimine (NAPQI).
⯈ N-acetylcysteine (NAC) is the antidote for APAP toxicity and should be given if a toxic ingestion is suspected (based on ingested dose or APAP level and Rumack-Matthew nomogram).
⯈ The priorities when dealing with a patient with an APAP overdose are to perform a rapid assessment, stabilize the ABCs, decontaminate, minimize absorption, and administer NAC if appropriate.
⯈ In general, an APAP level should be drawn on any patient with an overdose history even when APAP ingestion is denied.
References
Aghababian RV, Allison EJ Jr, Boyer EW, et al, eds. Essentials of Emergency Medicine. Sudbury, MA: Jones and Bartlett; 2006:792-794.
Bizovi KE, Hendrickson R. Acetaminophen. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 7th ed. Philadelphia, PA: Mosby Elsevier; 2009.
Heard KJ. Acetylcysteine for Acetaminophen Poisoning. N Engl J Med. 2008;359:285-292.
Schaider J, Hayden SR, Wolfe R, Barkin R, Rosen P, eds. Rosen and Barkin’s 5-Minute Emergency Medicine Consult. 3rd ed. Philadelphia, PA: Lippinott Williams & Wilkins; 2007:22-23.
Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency Medicine: A Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill; 2011.
Wolf SJ, Heard KH, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med; 2007;50:292-313.
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