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Acute acetaminophen toxicity in adults

Saccomano, Scott J. PhD, RN, GNP-BC

doi: 10.1097/01.NPR.0000586020.15798.c6
Feature: ACETAMINOPHEN TOXICITY
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Abstract: When taken in the recommended dosage, acetaminophen is a safe and effective analgesic and antipyretic agent. Its wide availability and easy accessibility make accidental or intentional overdose, leading to hepatotoxicity, a common occurrence. To prevent morbidity and mortality, prompt recognition of acetaminophen toxicity is essential. This article covers the stages of acetaminophen toxicity, recommended treatments, and NP considerations, including patient education recommendations.

When taken in the recommended dosage, acetaminophen is a safe and effective analgesic and antipyretic agent. Its wide availability and easy accessibility make accidental or intentional overdose, leading to hepatotoxicity, a common occurrence. To prevent morbidity and mortality, prompt recognition of acetaminophen toxicity is essential. This article covers the stages of acetaminophen toxicity, recommended treatments, and NP considerations, including patient education recommendations.

Scott J. Saccomano is an assistant professor at the University of North Carolina, Wilmington, N.C., as well as a member of The Nurse Practitioner Editorial Advisory Board.

The author has disclosed no financial relationships related to this article.

This article was originally published in Saccomano SJ. Acute acetaminophen toxicity in adults. Nursing Crit Care. 2019;14(5):10-17.

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One of the most widely used pharmaceutical analgesic and antipyretic agents available today is acetaminophen, also known as N-acetyl-p-aminophenol (APAP) and paracetamol. Acetaminophen is a component of hundreds of over-the-counter (OTC) and prescription medications used worldwide and is frequently associated with accidental and intentional overdose. Acetaminophen toxicity has medical, social, and economic negative effects.1,2

Prompt recognition of acetaminophen toxicity is necessary to decrease morbidity and mortality. Unfortunately, there are only nonspecific clinical findings associated with early-stage acetaminophen toxicity, making early recognition and treatment difficult. This article reviews the stages of acetaminophen toxicity, recommended treatments, and nursing considerations, including patient education.

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Background

Acetaminophen is used in many pharmaceutical preparations because of its easy accessibility and low cost. It is available in both prescription and OTC formulations and is commonly found in three strengths: regular strength, extra strength, and extended release. Several forms of acetaminophen are available, including tablets, caplets, capsules, oral-disintegrating tablets, chewable tablets, oral syrup, liquid, solution and suspension, as well as rectal suppositories.3 In 2011, the FDA approved an acetaminophen I.V. formulation to be used in an inpatient setting to treat fever and pain in children 2 years of age and older, and adults. It should be noted that this article concentrates on acute single oral consumption of acetaminophen; however, hepatotoxicity has been found as a result of medication errors with I.V. acetaminophen.2 Additionally, acetaminophen is used in many combination products, such as combined with an opioid, including codeine and oxycodone.

When used in the recommended therapeutic doses, acetaminophen has an excellent safety profile; however, with misuse and overdose, hepatotoxicity can occur. As an OTC medication, acetaminophen continues to be perceived as a benign medication. It should be noted that acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute liver failure in the US.2 This misconception helps to explain the high rate of acetaminophen toxicity.1 (See Acetaminophen toxicity statistics.) Acetaminophen toxicity is a major cause of acute liver injury. Perhaps more significantly, acetaminophen toxicity is the most common cause of acute liver failure (ALF) and is reported as the primary reason for emergency liver transplantation in the US. It is estimated that almost half of the patients with ALF are related to accidental acetaminophen overdose, with 63% of these involving acetaminophen combination products.6

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Pharmacokinetics

An active metabolite of phenacetin and phenazopyridine HCl, acetaminophen exhibits substantial antipyretic activity and some analgesic activity. In comparison to nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen exhibits minimal anti-inflammatory activity. Acetaminophen is available in both immediate-release and sustained-release formulations. Historically, the maximum daily adult dose of acetaminophen was 4 g. In 2012, the FDA suggested, but did not mandate, a maximum daily dose for adults of 3 g.

When ingested, acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Thirty to sixty minutes post ingestion, acetaminophen reaches peak concentration with a half-life of 2 to 3 hours. Therapeutic levels of extended-release acetaminophen are maintained at 10 mcg/mL to 20 mcg/mL for approximately 6 to 8 hours.7 Acetaminophen is not strongly bound to plasma proteins.8,9

At therapeutic doses, 90% of acetaminophen is metabolized in the liver and is converted into nontoxic glucuronide and sulfate conjugates that are subsequently excreted by the kidneys. A smaller amount—less than 4%—of acetaminophen is excreted in the urine unchanged. Similar amounts of acetaminophen are also excreted in urine through a complex conversion process; the cytochrome P-450 enzyme metabolizes a small amount of acetaminophen producing a toxic compound, N-acetyl-p-benzoquinone imine (NAPQI).7 NAPQI has a short half-life and conjugates with hepatic glutathione, which converts it to APAP-cysteine and APAP-mercapturate, both of which are readily excreted in urine.

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Toxicity

Acetaminophen toxicity occurs during a period of up to 8 hours after ingestion.10 Toxicity in an adult is unlikely to result from a single dose of 7.5 to 10 g. Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period. Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peak aspartate aminotransferase [AST] or alanine aminotransferase [ALT] levels greater than 1,000 IU/L) unless appropriately treated.7

Ingestion of toxic amounts of acetaminophen overloads the normal glucuronide and sulfate metabolic pathways. Increased glucuronide rapidly depletes any available glutathione resulting in unbound NAPQI binding to hepatocytes and causing cellular necrosis.10–12 (See Acetaminophen toxicity metabolic pathways.)

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Clinical manifestations

Nonspecific signs and symptoms in the early stages of acetaminophen toxicity make early recognition challenging. This accounts for a possible delay in treatment and high morbidity and mortality statistics. Most patients who overdose on acetaminophen will initially be asymptomatic, as clinical signs and symptoms of end-organ toxicity do not usually manifest until 24 to 48 hours after an acute ingestion. As a result, to identify a patient who may be at risk for hepatotoxicity, NPs need to determine the time(s) of ingestion, the quantity, and the formulation of acetaminophen ingested.2

Acetaminophen toxicity is characterized by four stages, defined in time after ingestion:13

  • Stage I: the first 24 hours post ingestion. This is the most critical stage and is characterized by vague findings of nausea, malaise, vomiting, pallor, lethargy, anorexia, and diaphoresis.13,14 Some patients remain asymptomatic during this stage and lab studies are typically normal.7
  • Stage II: 24 to 72 hours post ingestion. Initially, stage I signs and symptoms resolve and patients appear to improve clinically while hepatic aminotransferases (AST, ALT) increase. As stage II progresses, patients develop right upper quadrant pain, with hepatomegaly and liver tenderness. Elevations of serum prothrombin time (PT) and total bilirubin levels, and renal function abnormalities may develop.7
  • Stage III: 72 to 96 hours post ingestion. During this stage, signs and symptoms become more pronounced. Systemic findings, including malaise, nausea, and vomiting, return and can be accompanied by central nervous system involvement, such as confusion, somnolence, and possible coma. Jaundice as well as pancreatic, renal, and cardiac damage may be present.9,15 Peak abnormalities of serum AST, ALT, bilirubin, and PT are often detected, with AST levels elevated to 1,000 U/L and may rise as high as 30,000 U/L (normal, 10 to 40 U/L) in severe acetaminophen toxicity. Serum PT levels greater than 2.2 times control (normal, 11.0 to 13.0 seconds), and total bilirubin levels greater than 4 mg/dL (normal, 0.3 to 1.0 mg/dL) indicate severe hepatotoxicity.16,17
  • Stage IV: 4 days to 2 weeks post ingestion (recovery phase). Stage IV represents the period of hepatic damage resolution. During this stage, clinical signs, symptoms, and lab values return to near baseline or baseline and permanent damage occurs infrequently; this suggests that the patient has received treatment at some point during Stage II.13
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Diagnosis

Screening should include the overall doses of acetaminophen per day that are greater than 4 g per dose or 10 g per day. Screening should also include hepatotoxicity risk factors such as alcoholism; drug therapies such as isoniazid; fever; hepatitis (viral or toxic); vascular insult; chronic liver diseases; and reduced glutathione stores.1,6,18,19 A patient history is very important for diagnosis. The preliminary step in patients with suspected acetaminophen toxicity is to obtain a history of drug ingestion and use. Ask questions such as: Is there a history or pattern of acetaminophen use? (single or repeated doses) What was the time of ingestion? What was the intent of ingestion? (suicide or not) Are there any coingestants administered with acetaminophen? Finally, evaluate for any comorbidities such as alcohol use, Gilbert syndrome, recent fasting, or anticonvulsant therapy as these can predispose one to hepatic injury.7 In all four stages, key diagnostic studies include:2,13,16,20

  • serum acetaminophen concentration
  • baseline liver function tests (AST, ALT, total bilirubin)
  • basic chemistry panel (electrolytes, blood urea nitrogen, creatinine)
  • complete blood cell count
  • PT/international normalized ratio
  • serum amylase
  • urinalysis.
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Rumack-Matthew nomogram

When acute acetaminophen ingestion has been confirmed, the Rumack-Matthew nomogram is the primary treatment guide. (See Rumack-Matthew nomogram for acetaminophen poisoning.) The Rumack-Matthew nomogram summarizes the relationship between plasma acetaminophen concentration (in microgram/mL or micromole/L), the time after drug ingestion, and the risk of hepatotoxicity. The thick diagonal line of possible hepatotoxicity represents a 25% likelihood of hepatotoxicity. A relatively low level (such as 10 microgram/mL) is safe soon after ingestion but associated with appreciable risk at 24 hours since it reflects a high initial load that has now distributed into the tissues.21

The nomogram should only be used after a single acute acetaminophen ingestion. The line indicates the level at which toxicity is possible after acetaminophen overdose. The serum acetaminophen concentration is the basis for diagnosis and treatment. A serum acetaminophen level should be obtained 4 or more hours after an ingestion to ensure that a peak level has occurred. Patients who ingest extended-release preparations should have a second level drawn 4 hours after the first level to assess for an additional rise in serum concentration. The level should be plotted in relationship to the time of ingestion to determine the likelihood of toxicity and the need for treatment. Use caution in assessing the reliability of the time of ingestion. This nomogram cannot be used for ingestions that occurred more than 24 hours prior to presentation, repeated supratherapeutic oral ingestions, or iatrogenic I.V. overdose.21

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Treatment

The goals of treatment include:

  • supporting airway, breathing, and circulation as necessary
  • preventing absorption of ingested acetaminophen from the gastrointestinal tract
  • administering the antidote N-acetylcysteine (NAC).

The treatment of choice for acetaminophen overdose is the administration of the antidote NAC, which is given to all patients at significant risk for hepatotoxicity. NAC prevents the formation of and the buildup of NAPQI through multiple routes. It prevents binding of NAPQI to hepatic macromolecules, acts as a substitute for glutathione, is a precursor for sulfate, and reduces NAPQI back to acetaminophen. Because of the conjugation process of NAC and NAPQI, cysteine and mercapturic acid are produced, which are nontoxic equivalents excreted in the urine.1,16,22

In addition to its effects for acetaminophen toxicity, NAC possesses anti-inflammatory, antioxidant, and vasodilating properties that will improve microcirculatory blood flow and oxygen delivery to tissues.23 Because of its vasodilating effects, NAC is the selected treatment when hepatotoxicity is present, as its actions can potentially decrease morbidity and mortality. NAC therapy can also be initiated well past the 8- to 10-hour initial window recommended because the therapy remains effective for a maximum of 36 hours after ingestion. NAC therapy is not recommended if acetaminophen levels are not at the toxic level.13,24

In the US, both oral and I.V. forms of NAC are available. When treated with NAC, approximately 1% of patients will develop nausea and vomiting. Useful antiemetics are 5-HT3 receptor antagonists, such as ondansetron, that can be administered to relieve nausea and vomiting. If vomiting occurs within 1 hour of the initial oral loading dose, the route of administration should be changed to I.V.25 (See Acetaminophen safety resources.)

Adverse reactions of oral NAC include stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Clinically overt acetylcysteine-induced bronchospasm occurs infrequently and unpredictably even in patients with asthmatic bronchitis or bronchitis complicating bronchial asthma.26 The most frequently reported adverse reactions to I.V. acetylcysteine include rash, urticaria, and pruritus, and they most commonly occur during the initial loading dose of acetylcysteine.27 After stopping the infusion and administering an antihistamine, the infusion can usually be resumed at a slower rate.13,25 Patients treated with I.V. NAC can develop allergic or anaphylactic reactions. Treatment of these adverse reactions depends on the severity of the symptoms. Approximately 10% to 20% of patients can develop severe reactions, such as respiratory difficulty; the infusion should be stopped and the clinician should contact a medical toxicologist or the poison control center.21

Other approaches to treatment include gastric decontamination using activated charcoal (AC). AC absorbs toxic substances (acetaminophen) on its surface, rendering it nonabsorbable from the gastrointestinal tract. AC should be administered orally within 1 to 2 hours of ingestion, unless contraindicated, as its effectiveness diminishes over time, especially with a toxic dose.2,16

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NP considerations

NPs play an important role in preventing morbidity and mortality caused by acetaminophen toxicity. Obtaining a comprehensive health history with a focus on medication reconciliation is extremely important. It is also important to obtain an accurate history of the time(s) of acetaminophen ingestion, the quantity, and the formulation of acetaminophen ingested. The history should also include any coingestants, such as salicylates or medications that may delay gastric emptying and acetaminophen absorption (anticholinergic drugs or opioids).2 Be alert to any medications that contain acetaminophen, especially in combination with opioids. The history should also include ethanol ingestion, tobacco use, and any conditions that reduce glutathione stores and increase hepatotoxicity risk, such as older age, alcohol use disorder, underlying hepatic or renal disease, or compromised nutritional status.2

Toxic levels of acetaminophen can also impair renal function; monitor renal function results, as well as accurate intake and output.2 Acetaminophen effects can mask infection and can cause drug-induced antibody-mediated thrombocytopenia; it is essential to monitor for signs and symptoms of infection as well as the patient's platelet count.28,29 Acetaminophen is known to decrease insulin needs, but it is necessary to monitor blood glucose because acetaminophen can falsely elevate glucose monitor readings by a large margin.2,30

Patient education should include how to read medication labels, including OTC product labels, and follow dosing recommendations. Patients can unknowingly ingest acetaminophen from various sources without proper knowledge, including various combination prescription analgesics. The patient should be instructed on the various names of acetaminophen, such as: APAP, paracetamol, acetyl-para-aminophenol, and acetaminophen; all these products should be recognizable as containing acetaminophen. Patients should also be taught about nonpharmacologic measures of pain relief such as relaxation therapy, distraction, physical therapy, and topical heat/cold applications.

Initially, most patients are asymptomatic; however, it is important to teach patients to recognize the signs and symptoms of acetaminophen overdose and emergency procedures to follow if they are having an overdose reaction. Additionally, patients should be instructed when using NSAID therapy in combination with acetaminophen, as this can increase the risk of renal toxicity.31 Patients with a history of alcohol use should consult with their provider prior to using acetaminophen. Patients who consume more than 24 oz of alcohol per day should not mix acetaminophen or products containing acetaminophen with alcohol; as alcohol consumption increases, so does the risk of hepatotoxicity.13

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Conclusion

When used properly, acetaminophen is a safe, effective analgesic and antipyretic. However, acetaminophen toxicity can lead to hepatotoxicity, liver failure, and death. NPs play an important role in decreasing morbidity and mortality in these patients.

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Acetaminophen toxicity statistics

  • In 2017, the American Association of Poison Control Centers reported more than 69,000 individual exposures involving acetaminophen alone, and over 39,000 individual exposures to acetaminophen in combination with other drugs.4
  • In the US, acetaminophen toxicity accounts for approximately 82,000 ED visits annually and almost 30% of these admissions can be attributed to acute acetaminophen overdose. Additionally, approximately 50% of acute liver failure/injury cases are related to acetaminophen toxicity.5
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Acetaminophen safety resources

For more information on the use and safe administration of acetaminophen, visit:

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REFERENCES

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23. Chertoff J. N-acetylcysteine's role in sepsis and potential benefit in patients with microcirculatory derangements. J Intensive Care Med. 2018;33(2):87–96.
24. Teriaky A. The role of N-acetylcysteine in the treatment of non-acetaminophen acute liver failure. Saudi J Gastroenterol. 2017;23(3):131–132.
25. Buckley NA, Dawson AH, Isbister GK. Treatments for paracetamol poisoning. BMJ. 2016;353:i2579.
26. Acetylcysteine Solution USP. Roxane Laboratories, Inc. 2007. https://docs.boehringeringelheim.com/Prescribing%20Information/PIs/Roxane/Acetylcysteine/Acetylcysteine%20 Solution%20USP.pdf.
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29. George JN, Arnold DM. Drug-induced immune thrombocytopenia. UpToDate. 2019. http://www.uptodate.com.
30. Tucker ME. Acetaminophen falsely raises glucose sensor readings by wide margin. eMedicine Journal. 2015. http://www.medscape.com/viewarticle/849650.
Keywords:

acetaminophen; hepatotoxicity; N-acetylcysteine (NAC); N-acetyl-p-aminophenol (APAP); N-acetyl-p-benzoquinone imine (NAPQI); paracetamol; Rumack-Matthew nomogram

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