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Using the 150 rule to prevent hepatotoxicity from acetaminophen

Nicholas, William A., MPAS, PA-C; Moore, Randy, MPAS, PA-C

Journal of the American Academy of PAs: April 2019 - Volume 32 - Issue 4 - p 51–53
doi: 10.1097/01.JAA.0000554235.40113.c5
Special Topics in Pharmacology

ABSTRACT Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in adults and a major cause of acute liver failure in children. Prompt treatment with N-acetylcysteine can mitigate hepatotoxicity and progression to liver failure. This article describes a 16-year-old girl who ingested a large dose of extra-strength acetaminophen, and how the 150 rule was used in her management.

William A. Nicholas practices emergency medicine with EmCare in the Baylor Health System in Dallas, Tex. He also serves as a physician assistant in the Texas Army National Guard. Randy Moore practices at Wellness Pointe Family Health in Longview, Tex. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Roy A. Borchardt, PA-C, PhD; Michael D. Overcash, MPAS, PA-C; Jennifer M. Coombs, PhD, PA-C; Brian K. Yorkgitis, PA-C, DO; and Ellen D. Mandel, DMH, MPA, MS, PA-C, department editors

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A 16-year-old girl was brought to the ED by emergency medical services (EMS) with complaints of decreased mental status and acute ingestion of acetaminophen.

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According to EMS, the patient's sister called for the ambulance with acute concerns, noting that the patient had been acting depressed lately due to the death of their mother. When EMS arrived at the patient's home, she was found lying in bed next to a bottle of extra-strength acetaminophen; about 60 of the 500-mg pills were missing. The patient endorsed suicidality and consuming a large quantity of acetaminophen pills about 4 hours earlier. When questioned by EMS, the patient described a headache and some chest discomfort.

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Physical examination

Vital signs were within normal limits. The patient was slow to respond to questions and appeared lethargic. She had a flat affect and depressed mood. She responded appropriately when asked her name, place, time, and situation. She had no focal neurologic deficits. Her Glasgow Coma Scale (GCS) score was 15 out of 15, and cranial nerves II through XII were intact. Her head was normocephalic, atraumatic, and pupils were equal, round, and reactive to light. She moved all extremities well with equal strength bilaterally, no sensory deficits, and no abnormal movements. Examination of her ears, nose, throat, neck, heart, lung, abdomen, and skin were unremarkable.

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Diagnostic testing

The presumptive diagnosis was acetaminophen overdose with possible coingestion of other toxic substances. The differential diagnosis also included drug or alcohol abuse, hepatotoxicity, hypoglycemia, electrolyte or acid-base imbalance, dysrhythmia, closed head injury, and suicidal ideation or gesture. The patient's laboratory workup included a complete blood cell count; comprehensive metabolic panel; prothrombin time; partial thromboplastin time; lipase; troponin; venous blood gases; ethanol, acetaminophen, and salicylate serum levels; and urinalysis with drug screen and pregnancy test. An ECG was performed, along with a CT scan of the head and a chest radiograph.

Laboratory testing revealed an acetaminophen level of 153 mcg/mL. The patient's urine drug screen was positive for benzodiazepines and cannabinoids. Her liver and renal function tests were within normal limits, and the rest of her workup did not reveal any significant abnormalities.

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ED course

The patient was put on suicide precautions and a cardiac monitor. IV access was established. Poison control was consulted and recommended treatment started with N-acetylcysteine (NAC), 150 mg/kg IV over the first hour, followed by 50 mg/kg over the next 4 hours, then 100 mg/kg over the next 16 hours (Figure 1). During treatment, the patient became nauseated and was given 4 mg of IV ondansetron.



The patient slept for the majority of her stay in the ED, which lasted a little over 2 hours. Her vital signs remained stable. Because of her age, she was transferred to the ICU at a nearby medical center for pediatric specialty care.

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This case report illustrates a classic example of acetaminophen toxicity and the 150 rule (Table 1). Acute acetaminophen toxicity generally occurs at doses of 150 mg/kg or greater, or 7 to 10 g per dose for most children and adults.1,2 On the Rumack-Matthew nomogram, a 4-hour acetaminophen level greater than 150 mcg/mL is an indication to begin treatment with NAC.1 The starting dose of IV NAC is 150 mg/kg over the first hour.3



The Rumack-Matthew nomogram compares acetaminophen concentration with time since ingestion. It is used to determine the potential for hepatotoxicity and also to guide the decision to initiate treatment with NAC. The nomogram should only be used in patients with acute acetaminophen ingestion and does not apply to chronic overdoses. Also note that if acetaminophen levels are obtained before 4 hours or more than 24 hours postingestion, the data cannot be interpreted with the nomogram.2,4

NAC can be administered orally or IV. The loading dose for the oral form is 140 mg/kg, followed by 18 doses of 70 mg/kg every 4 hours for total treatment duration of 72 hours.4 Poor compliance with oral NAC is common due to its foul smell and tendency to cause nausea and vomiting. Coadministration of antiemetics usually is needed.4,5 However, some patients will not tolerate treatment, such as patients with excessive vomiting, pancreatitis, bowel obstruction, or other contraindications to administration of oral medications.6 These patients require treatment with IV NAC.

IV administration of NAC avoids the problems associated with the oral route and has the additional advantage of a shorter duration of treatment.2,4,5 The IV protocol, described above, delivers a total dose of 300 mg/kg over 21 hours, compared with 72 hours for the oral regimen.3 Hypersensitivity reactions to IV NAC, such as urticaria, angioedema, bronchospasm, and hypotension, have been seen in 10% to 20% of patients.7 In these situations, the infusion should be stopped and symptoms treated appropriately with medications such as diphenhydramine, famotidine, methylprednisolone, albuterol, or epinephrine as needed.6,7 In many patients, the NAC infusion can be restarted at a slower rate while the patient is closely monitored.7 However, in patients with persistent systemic anaphylaxis, IV NAC must be discontinued, and the oral regimen should be administered as an alternative.6 Fortunately, discontinuing IV NAC therapy because of adverse reactions rarely is necessary because recipients are less likely to experience vomiting and anaphylactoid reactions with the IV route than the oral route.8

Consider gastrointestinal (GI) decontamination with 1g/kg of activated charcoal for patients presenting after an acute overdose of acetaminophen, especially if the patient presents within 1 hour of ingestion.4 Some authors have suggested that activated charcoal may be beneficial for up to 4 hours, or even as many as 16 hours after ingestion.4 Activated charcoal should not be administered to patients who are sedated or unable to protect their airway unless they are intubated.9

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Acetaminophen is absorbed in the GI tract rapidly, with concentrations peaking within 90 minutes.7 However, its half-life in the blood can be prolonged to more than 4 hours in patients with liver impairment.7 Conversely, acute alcohol ingestion competes with acetaminophen for CYP2E1, which actually lowers the risk of hepatotoxicity in patients with acute acetaminophen overdose.7

About 90% of acetaminophen is metabolized into sulfate and glucuronide conjugates.7 These metabolites are nontoxic and water-soluble, so they are excreted safely by the kidneys.1,2,10 About 2% of the drug is excreted unchanged in the urine.7 The remaining drug is metabolized by the cytochrome P450 pathway, mainly by CYP2E1, which produces the hepatotoxic compound N-acetyl-p-benzoquinoneimine (NAPQI).7 NAPQI normally is broken down into nontoxic metabolites by the antioxidant glutathione.1,2,10

Large amounts of NAPQI are produced in patients with acute acetaminophen overdose, and these increased amounts deplete glutathione. When 70% to 80% of glutathione becomes depleted, NAPQI begins reacting with cellular proteins and killing liver cells.7 NAC, a precursor to glutathione, replenishes glutathione stores to allow detoxification of reactive metabolites.7,11 Therefore, when given early enough, NAC prevents liver damage caused by overproduction of NAPQI.1,2,10,12 In fact, if administered within 8 hours after an acute ingestion, NAC can reduce a patient's risk for developing hepatotoxicity to less than 5%.4

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Acetaminophen toxicity occurs in four distinct stages:

  • During the first 24 hours, the patient may have no symptoms or experience nonspecific symptoms, such as nausea, vomiting, malaise, or diaphoresis.
  • At 24 to 72 hours, signs and symptoms may include right upper quadrant pain or elevated transaminase and bilirubin levels.
  • Signs of liver failure begin at 72 to 96 hours after ingestion (the hepatic stage), and include lethargy, jaundice, hepatic encephalopathy, and renal failure.
  • In the final stage, starting at the 96th hour, the patient will either recover over the next 2 weeks or die.2
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Adults who take high therapeutic doses of 3 g to less than 4 g a day for 2 or more consecutive days may develop chronic acetaminophen overdose.2 Several risk factors decrease glutathione storages and put patients at increased risk of acetaminophen-induced hepatotoxicity; these include chronic alcohol ingestion, malnutrition, and fasting states.7 Patients with these risk factors who are taking high doses of acetaminophen should be evaluated for possible toxicity.4 Consider treatment and consult a poison control center for guidance if the patient has signs of liver damage, such as liver tenderness, jaundice, or elevations of AST, ALT, and international normalized ratio, even if the patient's acetaminophen level is well below the treatment threshold on the Rumack-Matthew nomogram.4

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Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in adults and also is a major cause of acute liver failure in children.1 More than 50% of acute liver failure cases are caused by unintentional and chronic overdoses of acetaminophen; about 44% are caused by intentional overdoses.2,12 NAC may prevent hepatotoxicity and progression to liver failure if administered expeditiously.4,12,13

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1. Ogilvie JD, Rieder MJ, Lim R. Acetaminophen overdose in children. CMAJ. 2012;184(13):1492–1496.
2. Qual MT, Boyer EW. Acetaminophen toxicity. J Legal Nurse Consulting. 2013;24(2):22–30.
3. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol. 2012;50(2):91–98.
4. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin. 2012;28(4):499–516.
5. Smilkstein MJ, Bronstein AC, Linden C, et al Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20(10):1058–1063.
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8. Bateman DN, Dear JW, Thanacoody HK, et al Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383(9918):697–704.
9. Chyka PA, Seger D, Krenzelok EP, et al Position paper: single-dose activated charcoal. Clin Toxicol. 2005;43(2):61–87.
10. Qual MT, Boyer EW. Acetylcysteine (N-acety-L-cysteine): antidote and toxic agent. J Legal Nurse Consulting. 2014;25(1):14–30.
11. Xie Y, McGill MR, Dorko K, et al Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol. 2014;297(3):266–274.
12. Lancaster EM, Hiatt JR, Zarrinpar A. Acetaminophen hepatotoxicity: an updated review. Arch Toxicol. 2015;89(2):193–199.
13. Green JL, Heard KJ, Reynolds KM, Albert D. Oral and intravenous acetylcysteine for treatment of acetaminophen toxicity: a systematic review and meta-analysis. West J Emerg Med. 2013;14(3):218–226.

acetaminophen; acute liver failure; hepatotoxicity; Rumack-Matthew nomogram; N-acetylcysteine; 150 rule

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