Managing Acetaminophen Toxicity Materials

PARACETAMOL PERIL: MANAGING ACETAMINOPHEN TOXICITY

Faculty:

L. Austin Fredrickson, MD, FACP

L. Austin Fredrickson, MD, FACP, is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care.

Kristina (Tia) Neu, RN

Kristina (Tia) Neu is a licensed Registered Nurse and author currently developing in-service training for healthcare professionals. She is a National Board-Certified Health & Wellness and Lifestyle Medicine Coach. Her work experience includes work in several areas of the healthcare profession, including psychiatric nursing, medical nursing, motivational health coaching, chronic case management, dental hygiene, cardiac technician, and surgical technician.

Jennifer Salvon, RPh

Jennifer Salvon is a clinical pharmacist at Mercy Medical Center in Springfield, Massachusetts, and a freelance medical writer at Salvon Scientific.

Pamela Sardo, PharmD, BS

Pamela Sardo is a freelance medical writer, pharmacist licensed in 3 states, and the founder/principal at Sardo Solutions. She received her BS from the University of Connecticut and a PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, pharmaceutical manufacturing, and managed healthcare across broad therapeutic classes and disease states.

Topic Overview

Acetaminophen (APAP) poisoning is the most common cause of acute liver failure in the United States and other countries. Liver damage often occurs after an APAP overdose, but liver failure and death are rare. N-acetylcysteine (NAC) is a highly effective antidote for an APAP overdose. If a patient with APAP poisoning is treated with the NAC protocol promptly, the patient is almost sure to recover and survive the event. Pharmacists and pharmacy technicians should know the potential risks associated with this commonly used over-the-counter medication. They should also learn what they can do to minimize APAP overdoses and implement these strategies in their daily practices.

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Type of Activity: Knowledge

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Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Course Test and course evaluation

Release Date: February 28, 2025 Expiration Date: February 28, 2028

Target Audience: This educational activity is for pharmacists and pharmacy technicians.

Secondary Audiences: Other healthcare professionals, such as nurses, physicians, or others who may be part of a healthcare team, may be interested in this educational topic. The healthcare team's approaches to patient care are discussed in this activity. No state board or professional organization has evaluated this activity to determine whether it meets the continuing education requirements of nurses, physicians, or other professions not listed under the “Target Audience” described above. Always verify with individual employers or supervisors whether they will accept this educational activity upon completion.

How to Earn Credit: From February 28, 2025, through February 28, 2028, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the pharmacologic profile of acetaminophen

Explain the pathophysiology of acetaminophen toxicity

Describe the approach to the management of acetaminophen toxicity

Discuss the role of healthcare professionals in the management and prevention of acetaminophen toxicity

Disclosures

The following individuals were involved in developing this activity: L. Austin Fredrickson, MD, FACP, Kristina (Tia) Neu, RN, Jennifer Salvon, RPh, Pamela Sardo, PharmD, BS. L. Austin Fredrickson, Kristina (Tia) Neu, Jennifer Salvon, and Pamela Sardo have no conflicts of interest or financial relationships regarding the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2025: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

Paracetamol Peril: Managing Acetaminophen Toxicity Introduction

Acetaminophen (APAP), also known as paracetamol in Europe and many other countries, is an over-the-counter analgesic for mild to moderate pain and fever. Acetaminophen toxicity is the leading cause of acute liver failure in the United States and other developed nations. This toxicity not only leads to liver damage but, in some instances, may also affect the kidneys and other organ systems. Healthcare teams equipped with the knowledge and skills to recognize APAP toxicity can implement diagnostic and treatment protocols, potentially preventing significant physical harm to patients. The toxicity of APAP following chronic overdose is contingent on the duration of usage and the presence of risk factors. In cases of chronic use, measuring serum levels is critical to determine the need for treatment. The Rumack-Matthew nomogram is a valuable tool for assessing the toxicity of acute APAP ingestion. N-acetylcysteine is the standard treatment for APAP toxicity, and when administered promptly and appropriately, it results in positive patient outcomes. In severe cases, hemodialysis or liver transplantation may be necessary.

Back to Basics: Acetaminophen Essentials

Acetaminophen exerts analgesic and antipyretic effects through several mechanisms. Acetaminophen inhibits cyclooxygenase (COX) enzymes, particularly COX-2, in the central nervous system, leading to decreased prostaglandin synthesis and alleviating pain and fever.1

Unlike non-steroidal anti-inflammatory drugs (NSAIDs), APAP's COX inhibition is more pronounced in the central nervous system, explaining its limited anti-inflammatory effects. Acetaminophen also blocks pain signals peripherally and affects the heat-regulating center of the hypothalamus, producing an antipyretic effect.2

Acetaminophen may be administered in a variety of ways, including orally, rectally, and intravenously. It is rapidly and completely absorbed in the gastrointestinal tract after oral administration. Peak serum concentrations are achieved in one hour, with therapeutic concentrations ranging from 10 to 20 mcg/ml.2

Acetaminophen has a narrow safety margin compared to other OTC analgesics.3 The toxic dose of APAP is 10 times the therapeutic dose, while the toxic dose of ibuprofen is 60 times its therapeutic dose.3 Drugs with a narrow therapeutic index pose significant risks, as small variations in dosage or blood concentration can lead to severe, potentially life-threatening adverse reactions.

Three liver pathways metabolize APAP: glucuronidation, sulfate conjugation, and oxidation by CYP2E1. Approximately 88% of APAP is metabolized by glucuronidation and sulfate conjugation. The resulting compounds are harmless and are eliminated in the urine.4 A small portion of APAP is metabolized via CYP2E1, forming a hepatotoxic metabolite N-acetyl- benzoquinone imine (NAPQI). Less than 5% of the drug is eliminated unchanged in the urine.4 When APAP is consumed at therapeutic doses, NAPQI binds with glutathione (GSH), creating a NAPQI-GSH complex that is converted into non-toxic mercapturic acid or cysteine, both of which are removed from the body via urine and bile.4,5

The saturation of this metabolic pathway leads to the accumulation of NAPQI, causing hepatotoxicity. The toxicity of APAP following chronic overdose is contingent on the duration of usage and the presence of risk factors. Supratherapeutic doses of APAP, fasting, and alcoholism deplete glutathione stores and contribute to increased concentrations of NAPQI.5

In cases of chronic use, measuring serum levels is critical to determine the need for treatment. N-acetylcysteine is the standard treatment for APAP toxicity, and when administered promptly and appropriately, results in positive patient outcomes.

Acetaminophen is available in several dosages and formulations, outlined in Table 1 below.

Table 1

Available Acetaminophen Dosage Formulations6

Recommended oral dosing of APAP:5

Adults and children > 12 years:5

325-650 mg every 4-6 hours

1000 mg every 6 hours

Maximum daily dose = 4,000 mg

Children < 12 years:5,7

10-15 mg/kg every 4-6 hours

Maximum daily dose = 75 mg/kg/day OR 4000 mg

The dosing interval should be longer in neonates; suggested doses are 10 to 15 mg/kg every 6 to 8 hours; the maximum dose is 60 mg/kg/day, not to exceed 40 mg/kg/day in preterm neonates less than 33 weeks of gestational age

Maximum dosing is controversial due to the risk of liver injury. Some healthcare professionals feel the recommended maximum daily dose of 4000 mg of APAP is excessive and potentially harmful.8-11 In 2011, the Food and Drug Administration (FDA) requested that manufacturers limit APAP in prescription products to 325 mg by January 2014. No recommendation was made to lower the 4000 mg daily limit.12 Unfortunately, data from before and after the implementation of this change found no significant variation in the incidence of APAP toxicity.3 As this issue persists, some clinicians recommend lowering the maximum daily dose to 3000 mg in 24 hours, which prescribers may also recommend to their patients, especially higher-risk groups.13

At present, no combination prescription drugs in the U.S. contain more than 325 mg of APAP. However, over-the-counter (OTC) formulations of APAP can include up to 500 mg per tablet or capsule.14 While the US places no sales restrictions on APAP, many European countries limit APAP sales to pharmacies and restrict them to small pack sizes.3

Acetaminophen is contraindicated in patients who have hypersensitivity to the drug or if the patient has severe hepatic impairment or severe active liver disease. It should be used cautiously if the patient has glucose-6- phosphate dehydrogenase (G6PD) deficiency (a genetic condition associated

with hemolytic anemia that may be exacerbated by APAP use), consumes ≥

three alcoholic drinks per day, or has renal impairment.5

Oral formulations of APAP are considered safe to use during pregnancy.15 However, before 2015, studies were published showing a possible association between APAP use in pregnancy and ADHD in children.16-

18 The FDA reviewed these studies and determined that the evidence was inconclusive.16

Acetaminophen is found in very small levels in breast milk.5 However, studies have shown no adverse effects on infants who were breastfed after their mothers took APAP or its prodrug phenacetin.19 Nevertheless, the drug should be used cautiously by nursing mothers.5

The adverse effects of APAP are generally minimal if taken appropriately. Common side effects are mild and temporary gastrointestinal distress and rash.5

Some drug interactions between APAP and commonly used medications include the following:

Barbiturates5 and Rifampin:20 The metabolism of APAP may be increased (along with increased levels of the toxic metabolite NAPQI), decreasing the effectiveness of APAP and increasing the risk of liver damage.

Carbamazepine:5 The metabolism of APAP may be increased, decreasing its effectiveness and potentially increasing the percentage of NAPQI generated.

Isoniazid5 and Phenytoin:21 Induce CYP2E1, which may enhance the hepatotoxic effects of APAP.

Prilocaine:5 Taking APAP and prilocaine together can increase the risk of developing methemoglobinemia.

Warfarin:5 APAP may enhance the anticoagulant effect of warfarin and increase the patient’s international normalized ratio (INR). Frequent assessment of INR may be appropriate in patients initiating, adjusting, or terminating therapy with APAP while on warfarin.

Certain disease states, such as infectious hepatitis, alcoholism, malnourishment, starvation, and liver injury from other causes, may increase the risk of APAP overdose.10,22

Toxic Threshold: Understanding Acetaminophen Toxicity

When the liver's ability to detoxify the harmful metabolite NAPQI is overwhelmed, APAP toxicity occurs, leading to hepatocellular necrosis and potential damage to other organs. Acetaminophen toxicity is prevalent primarily due to its widespread availability and the general belief that it is safe. Over 60 million Americans consume APAP every week, and more than 600 prescriptions and OTC products contain APAP.23

Acetaminophen toxicity can result from acute accidental or intentional overdose or from repeated ingestion of supratherapeutic doses. Acute intentional overdose results from the consumption of a toxic amount of APAP within 8 hours, often due to deliberate suicide attempts. An unintentional overdose occurs when a person ingests multiple products containing APAP, resulting in an excessive cumulative dose of the medication. Chronic overuse results from repeated doses at or above the recommended limit over an extended period.3,24

Unintentional acetaminophen overdose is particularly common in young children due to dosing errors, incorrect formulation use, and caregiver confusion over using multiple acetaminophen-containing products.7 In contrast, intentional overdose is more common in adolescents and adults.7

Chronic alcohol use can increase susceptibility to APAP toxicity by inducing CYP2E1 activity, increasing the formation of the toxic metabolite NAPQI. Conditions that reduce glutathione in the body, including older age and malnutrition, can enhance susceptibility to APAP toxicity. Pre-existing liver damage may increase the risk of toxicity due to a reduced ability to metabolize APAP properly.25 The clinical presentation of APAP poisoning is described as having four phases or stages.26-28

Table 2 describes the stages of APAP toxicity.

Table 2

Stages of Acetaminophen Toxicity26-28

Acetaminophen toxicity is the leading cause of acute liver failure in the United States, Europe, and Australia.9 The American Association of Poison Control Centers (AAPCC) publishes annual reports documenting the number and nature of drug overdoses, including APAP, that may be accessed at the AAPCC website and on PubMed. More than 80,000 cases of APAP toxicity were reported to US Poison Centers in 2021.23 Acetaminophen toxicity results in 56,000 to 75,000 emergency department visits annually.23

In the US, 30% of drug-induced liver injury (DILI) is caused by APAP toxicity. Acetaminophen toxicity accounts for over 6% of all poisonings and 11% of all intentional poisonings.24 Annual deaths from APAP overdose are estimated to be 0.4% of overall overdose patients.26

Acetaminophen toxicity has been reported as the second most common cause of liver transplantation worldwide and the most common in the U.S.5 When diagnosed and treated promptly, APAP toxicity mortality is less than 2%.10

Clinicians need to be aware that if the patient has ingested a massive amount of APAP, the patient may not present with a normal progression through the phases. These patients will rapidly become comatose and acidotic and may require liver transplantation.26-28

Acetaminophen toxicity can also impact other organs. Acute renal failure occurs in <2% of all cases of APAP poisoning.29 Most cases of renal impairment caused by APAP poisoning occur along with acute hepatic injury.29 The onset of renal failure caused by APAP overdose typically begins after liver damage and liver failure. It does not appear that there is a reliable way to predict which patients with an APAP overdose will develop renal failure, and the peak serum creatinine levels may not be seen until two to seven days after the ingestion.29

Cardiotoxicity and acute pancreatitis have been reported after APAP overdose.30 Elevated serum amylase is also common after APAP overdose. Cardiac damage, dysrhythmias, and acute pancreatitis are rare, and these

conditions are unlikely to be directly caused by APAP. They are likely sequelae of hepatic failure, an idiosyncratic response unrelated to the overdose, or due to an exacerbation of pre-existing medical problems from APAP-induced hepatic failure.30

Antidotes in Action: Navigating Acetaminophen Toxicity

Until 2023, there were no standardized guidelines for managing APAP toxicity in the U.S. and Canada. This absence of authoritative clinical guidelines led to varying management strategies in different healthcare settings, such as poison control centers and emergency departments. In 2023, new consensus guidelines were introduced to unify the treatment of APAP poisoning.24

Assessing Acetaminophen Toxicity

Initial Assessment

The initial evaluation of a patient with known or suspected APAP toxicity includes several steps. First, assessing the patient’s airway, breathing, and circulation is essential to confirm their stability.26,27 A physical examination should evaluate vital signs,26,27 and assess for signs of liver injury: right upper quadrant tenderness or hepatomegaly, jaundice or scleral icterus, and signs of hepatic encephalopathy (altered mental status). Signs of fluid overload (ascites, edema) and coagulopathy (ecchymosis, petechiae) may also be present in acute liver injury.16,31 Evaluating acetaminophen poisoning in a pregnant patient is the same.24

A complete and accurate history is important, though not always possible. When conducting a history, it is essential to collect the following information:24

Patient demographics

Ingestion details

Amount of APAP ingested

Time of ingestion

Type of formulation

Concurrent medications

Ingestion of combination products

Was the ingestion a single ingestion or repeated supratherapeutic doses

Intent:

Accidental or intentional

Any history of self-harm or psychiatric conditions

Symptoms:

Presence of nausea, vomiting, abdominal pain, or confusion

Onset and progression of symptoms

Medical history:

Pre-existing liver disease

Alcohol consumption

History of substance abuse Laboratory Testing

Several laboratory tests are important in assessing APAP toxicity. A serum APAP concentration is the primary test used to diagnose and evaluate the severity of APAP toxicity.24 The optimal timing for obtaining this level is four hours after ingestion.24 If the time of ingestion is unknown or has exceeded four hours, it should be obtained as soon as possible.26,32,33

The Rumack-Matthew nomogram was developed in the 1970s to help estimate the risk of liver toxicity in acute APAP toxicity.34 Serum levels of APAP are plotted on the graph against the elapsed time of drug ingestion to guide toxicity treatment, as shown in Figure 1 below. The original treatment line, derived from patient data, started at 200 mcg/ml at 4 hours post-ingestion. A

recently published guideline adjusts this treatment line to 150 mcg/ml at four hours.24

Figure 135

Rumack-Matthew Nomogram

Treatment is indicated when a serum APAP level is above the treatment line. When the time of ingestion is unknown but falls within the last 24 hours, the earliest possible time of ingestion should be estimated and plotted on the nomogram. The nomogram should not be utilized until at least four hours after ingestion, as the levels may be unreliable.24,28 Nomogram failures are rare and represent incorrect use of the nomogram, inaccurate ingestion histories, or outliers regarding unidentified risk factors.27 It is important to note that the Rumack-Matthew nomogram is used to treat acute APAP toxicity. Acute ingestion is any ingestion period of less than 24 hours, regardless of ingestion pattern.24

Tests to evaluate liver function include alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Normal levels of ALT range from 7-56 units/liter, and for AST, 8-33 units/liter. AST and ALT levels typically rise between 8 and 24 hours after an acute ingestion.3 Levels may become significantly elevated, exceeding 1000 units/liter.36

The rate of increase in these levels is significant, with initial ALT/AST levels being highest in patients who develop severe hepatotoxicity.3 AST and ALT levels usually peak between 72-96 hours after ingestion, during stage III of APAP toxicity.36 In non-fatal cases, AST and ALT levels typically begin to normalize after 5 days as the liver recovers.36 It is important to note that normal AST and ALT levels in the early stages of APAP toxicity do not exclude the possibility of significant hepatotoxicity, as these enzymes may take time to rise after ingestion.3

A salicylate level should also be measured as patients occasionally confuse aspirin and APAP and may use products interchangeably.37 Opioids and anticholinergics decrease gastrointestinal mobility.28 If a patient has co- ingested APAP with either of these, a post-ingestion level should be checked at 4 hours post-ingestion and repeated at 6 hours post-ingestion.28

Initial laboratory testing in acute liver failure may reveal a prolonged prothrombin time, INR greater than 1.5, elevated AST, ALT, and bilirubin levels, thrombocytopenia, electrolyte abnormalities, elevated ammonia levels,

and acid-base disturbances.28 Normal laboratory values may indicate that toxic ingestion has not occurred but may also reflect recent ingestion.27 If the AST, ALT, or INR are above the normal range, if the patient has (or may have taken) an overdose of APAP, and there is no other reason for the laboratory abnormalities, this is a strong indication of a need for treatment.26,27,38

Managing Acetaminophen Toxicity

Treating or managing APAP toxicity may include gastric decontamination, N-acetylcysteine (NAC), or urgent liver transplantation. The management of acetaminophen poisoning is the same in pregnant patients.24

Gastric Decontamination

Single-dose activated charcoal is the preferred method of gastric decontamination and is believed to be most beneficial if administered within the first 4 hours post-ingestion.24,28 Activated charcoal binds to APAP in the GI tract, and prompt administration of activated charcoal can prevent APAP from being absorbed and converted to NAPQI and reduce the need for antidotal therapy.3,26,27 A single dose of activated charcoal should be administered for the following reasons:27

Ingestion of a toxic amount of APAP

Normal ABCs.

The patient is awake, alert, and has a normal gag reflex

The patient has co-ingested a substance that may rapidly cause depressed consciousness

The patient has a functioning gastrointestinal tract

The recommended dose is 50 to 100 gm for adults and 25 to 50 gm for children.24 Activated charcoal is not recommended in patients who have consumed liquid APAP formulations due to their rapid absorption. It is also not recommended for use after repeated supratherapeutic ingestions.3

N-acetylcysteine

N-acetylcysteine is a highly effective antidotal treatment for APAP poisoning. It is the mainstay in APAP toxicity management. N-acetylcysteine restores glutathione by replenishing cysteine and provides thiol groups that react directly with NAPQI, allowing its removal from the body.28

N-acetylcysteine can be administered orally (PO) and intravenously

Both options are effective for preventing and treating APAP toxicity.24 Intravenous administration is more common and advantageous in clinical situations where PO administration may be compromised, such as in cases of vomiting, gastrointestinal conditions, or evidence of hepatic failure.3

N-acetylcysteine administration is most effective when given within eight hours of an APAP overdose.26,27 N-acetylcysteine should be administered as soon as possible after a patient is diagnosed with an APAP overdose.26,27 Administering NAC several hours or even days after an APAP overdose may still be beneficial; however, effectiveness begins to decline 8-10 hours post- ingestion, making prompt identification of at-risk patients important.39 Indeed, despite the decrease in effectiveness, administration of NAC even 24 hours after ingestion is advised, particularly if signs of ongoing liver injury persist.16

When the serum APAP level and the laboratory test results are known, and the history and physical examination are completed, a treatment decision can be made. A patient is at risk and should receive antidotal therapy for the following findings:24,40,41

APAP level is above the treatment line on the Rumack-Matthew nomogram

It has been confirmed that the patient has taken a toxic amount of APAP

It is suspected or possible that the patient has taken a toxic amount of APAP, and there is a measurable APAP level

There is a measurable APAP level, but the ingestion time is unknown

There is a measurable level of APAP, but no one witnessed the person ingesting the drug. There is no other report of APAP ingestion

It is suspected or possible that the patient has taken a toxic amount of APAP, and there is laboratory or clinical evidence of liver damage

N-acetylcysteine is not contraindicated in pregnant patients, as acetylcysteine appears safe and efficacious for treating APAP overdose in this population.24 Some clinicians prefer administering NAC intravenously, but no studies are available to demonstrate that oral administration is less effective in pregnant patients.24

Although studies are limited on the use of NAC during breastfeeding, existing evidence suggests oral and IV NAC is generally low risk; however, if there are specific clinical concerns for certain patients, a conservative “pump and discard” strategy may be employed.42

Oral NAC Administration

When using NAC orally, the patient is given a loading dose of 140 mg/kg followed by 17 doses of 70 mg/kg at 4-hour intervals. To dilute a 10% solution, mix 1 mL of diluent with every 1 mL of the solution. To dilute a 20% solution, mix 3 mL of diluent with every 1 mL of the solution. Use the diluted solutions within 1 hour of preparation.43

If the patient vomits within an hour of administration of the dose, the dose should be repeated, or the patient should be switched to the IV formulation.43 Patient monitoring during treatment includes daily laboratory testing of the AST, ALT, INR, BUN, SCr, and serum APAP levels.43

The adverse effects of oral NAC are primarily nausea and vomiting. Oral NAC smells like rotten eggs and has an unpleasant taste, so nausea and vomiting are common, reported in at least 20% of patients.27,30 To minimize these side effects, dilute oral NAC with juice or soda, serve it cold in a covered cup, and advise the patient to sip it slowly. If needed, oral NAC can be given through a nasogastric tube.44

Contraindications to oral NAC include sensitivity to NAC, the inability to use the GI tract, or persistent vomiting.43,44 Oral NAC cannot be administered to patients without a functioning GI tract, and it cannot be easily (or at times safely) administered to patients with altered mental status. Disruption of treatment because of nausea and vomiting is common, and patients often refuse to drink oral NAC.43,44

Intravenous NAC Administration

The initial dose should be administered as soon as the need for treatment becomes evident. Over 15 different regimens exist, making dosing decisions difficult. The 2023 guideline recommends a regimen that delivers at least 300 mg/kg orally or intravenously during the first 24 hours of treatment.43 N-acetylcysteine administered intravenously is preferred if the patient is pregnant, has hepatic failure, or cannot take the oral form (for instance, in cases of intractable vomiting or non-functioning gastrointestinal tract).27,30

Many IV NAC regimens exist. The 2023 consensus recommends using a regimen that delivers at least 300 mg/kg of PO or IV NAC during the first 20 to 24 hours of treatment.24 The most common method involves IV administration via the 3-bag method. Patients weighing between 40 and 100 kg are given three doses as follows:3,24

150 mg/kg of NAC, diluted in 200 mL of 5% dextrose in water (D5W), infused over 60 minutes, followed immediately by

50 mg/kg of NAC, diluted in 500 mL of D5W, infused over four hours, and followed immediately by

100 mg/kg of NAC, diluted in 1000 mL of D5W, infused over 16 hours.

The maximum doses of IV NAC are 15,000 mg, 5,000 mg, and 10,000 mg for the three respective infusions, corresponding to a body weight of 100 kg. In patients weighing more than 100 kg, the calculation of the acetylcysteine dose is capped at 100 kg.3,24

Dilution of IV NAC adjusted in patients weighing under 41 kg. The above dosing regimen provides too much free fluid and can cause hyponatremia and seizures.24 Therefore, NAC administration may require weight-based adjustments to avoid these effects. The loading dose should be diluted in 100 mL diluent, the second in 250 mL diluent, and the third in 500 mL diluent.24

An alternative administration technique uses IV administration of NAC in a two-bag method, delivering a total dose of 300 mg/kg. Administration via a two-bag regimen reduces adverse reactions while maintaining similar efficacy. The most straightforward modification involves administering a 200 mg/kg dose over 4 hours, followed by a 100 mg/kg dose over 16 hours.3,45

Allergic reactions, including anaphylaxis, have been reported in up to 18% of patients receiving intravenous NAC treatment. These reactions are generally mild to moderate, presenting as flushing, itching, and rash. Severe reactions, such as angioedema, bronchospasm, and hypotension, can occur but are infrequent. Anaphylactoid reactions are more likely during the initial one-hour infusion in patients with lower APAP levels (<300 mcg/mL), females, individuals previously treated with NAC, and those with asthma.26,43,45

Patients with minor allergic reactions (such as erythema and flushing) may continue the intravenous NAC infusion and should be closely monitored.46,47 If the patient has urticaria, IV diphenhydramine may be administered. If a patient is experiencing a severe allergic reaction, the NAC infusion should be stopped, and emergency measures should be initiated as needed.46,47

Duration of NAC Administration

Experts recommend continuing NAC administration until stopping criteria are met. A common clinical error is administering NAC for 21-24 hours and then stopping without reassessing the patient. Some patients may require longer treatment.24 Biomarkers such as AST, ALT, INR, and APAP levels guide the duration of treatment. Extended NAC infusions should be administered to

high-risk patients with persistently elevated APAP levels or established hepatotoxicity.3

Stopping criteria include the following:24

APAP concentration < 10 mcg/ml

INR < 2.0

AST/ALT normal for the patient or, if elevated, decreased from the peak by 25-50%

The patient is clinically well

If the stopping criteria are not met at the end of the 24-hour IV NAC treatment, additional treatment with NAC is warranted.24 A fourth bag is initiated, dosed at 100 mg/kg in 1000 mL of D5W, and infused at a rate of

6.25 mg/kg/hr.24 Acetaminophen concentration, AST, ALT, PT, and INR should be drawn every 12-24 hours, and the patient should be assessed for stopping criteria.24 The need for IV NAC beyond the standard three-bag protocol is not uncommon.

Hemodialysis

Hemodialysis removes APAP from the blood. It is an extracorporeal treatment that may be used if a patient’s APAP level is extremely high and may be combined with NAC administration in severe cases. However, hemodialysis is rarely needed since, in most cases, NAC is effective and sufficient.26,27

Special Situations

Acute APAP ingestion is the most common instance of APAP toxicity. Other circumstances require a slightly different approach. Table 3 summarizes some of these situations.

Table 3

Management of APAP Toxicity in Special Situations24

Ingestion of at least 30 gm APAP OR

SDAC may be warranted longer than 4 hours post-ingestion

Additional laboratory testing if pt has developed signs of mitochondrial dysfunction (altered consciousness, metabolic acidosis, or hyperprolactinemia)

Increased dose of NAC may be warranted in consultation with

Multiple ingestions for a period greater than

Based on presentation

If APAP > 20 mcg/ml or AST or ALT abnormal: Administer NAC until stopping criteria are met

Extended- release = products labeled for use every 8 hours

Activated charcoal may be useful longer than 4 hours after ingestion

NAC admin if APAP conc drawn 4-24 hours after ingestion is above nomogram treatment line

Concern that APAP absorption may be delayed or prolonged

Management with NAC at the same dose and duration except:

If APAP at 4-24 h post- ingestion is 10 mcg/ml or less, additional levels and NAC are not needed

If APAP at 4-24 h post- ingestion > 10 mcg/ml but less than the treatment line and pt has anticholinergic or opioid effects, another measure

Emergency Physicians and Advanced Practice Providers

Initial Assessment and Diagnosis: Evaluate the patient’s history, symptoms, and timing of ingestion. Use the Rumack-Matthew nomogram to assess the risk of hepatotoxicity based on serum APAP levels.

Treatment Initiation: Order and administer antidotes (SDAC or NAC) promptly. Stabilize patients with unstable vital signs.

Management of Complications: Address complications such as acute liver failure or co-ingestions, such as opioids or anticholinergics.

Pharmacists

Medication Reconciliation: Identify potential drug interactions and assess the patient’s medication history to detect hidden sources of APAP.

Antidote Preparation: Ensure NAC is prepared and administered promptly.

Education: Inform patients and families about safe APAP use and overdose prevention.

Nurses

Monitoring and Support: Monitor vital signs and laboratory tests to assess for signs of liver injury.

Administration of Treatments: Administer NAC infusions or activated charcoal as prescribed and ensure patient compliance with therapy.

Education: Teach patients and caregivers about the risks of APAP toxicity and strategies for prevention.

Poison Control Centers

Guidance for Healthcare Teams: Provide real-time recommendations on diagnosis, risk stratification, and treatment protocols based on evidence-based guidelines.

Education: Offer resources to the public on safe medication practices to prevent overdoses.

Clinical Toxicologists

Specialized Consultation: Provide expertise in complex cases, such as massive overdoses, delayed presentations, or patients with comorbidities.

Treatment Adjustments: Recommend advanced interventions like prolonged NAC therapy, activated charcoal use, or extracorporeal elimination (e.g., dialysis) when indicated.

Surgeons/Transplant Specialists

In severe cases of acute liver failure unresponsive to medical therapy, evaluate the patient for potential liver transplantation.

A common theme for all healthcare providers is patient education. Here are some key counseling points to help patients guard against APAP toxicity:

Always check the labels of medications to ensure you are not taking more than one product containing APAP at the same time.

Follow the recommended dosage instructions, and do not exceed the maximum daily dose of 4,000 mg. For most adults, the safest

maximum daily dose is 4,000 mg, but it is advisable to stay below 3,000 mg if possible, especially with frequent use or in high-risk patients.

Be aware that APAP is often abbreviated as APAP in prescription medications, especially when combined with other drugs like codeine or hydrocodone.

The Institute for Safe Medication Practices recommends writing the full word APAP and to avoid writing the abbreviation APAP in prescriptions.50

Recognize that APAP is present in many OTC and prescription medications, including pain relievers and cold medicines.

Consult a healthcare provider if you need to take high doses for chronic pain.

Limit alcohol consumption as alcohol can increase the risk of liver damage when taking APAP.

Keep all medications, including APAP, out of reach of children to prevent accidental ingestion.

Seek medical attention promptly if you suspect an overdose or have taken too much APAP, seek medical help immediately. Early treatment can prevent severe liver damage.

Inform your doctor or pharmacist about all medications you are taking to avoid an unintentional APAP overdose.

Figure 2 provides helpful resources on APAP poisoning to review.

Figure 2

Resources for APAP Poisoning

Summary

Understanding APAP toxicity is crucial for healthcare professionals because it is a leading cause of acute liver failure. Managing APAP toxicity requires recognizing early symptoms, such as abdominal pain and nausea, and promptly administering NAC as an antidote. However, NAC can pose risks if not given correctly, highlighting the importance of precise dosing and monitoring. The development of standardized guidelines in 2023 represents a significant advancement in ensuring consistent and effective treatment protocols for APAP toxicity. By adhering to these guidelines and staying informed about the latest clinical practices, healthcare providers can enhance patient outcomes and reduce the risk of liver injury associated with APAP toxicity. Additionally, ongoing education and awareness regarding the safe use of APAP are essential to prevent accidental overdoses and mitigate the risk of hepatotoxicity.

Course Test

Which option below describes the pharmacologic profile of acetaminophen?

It is an analgesic for mild to moderate pain and fever

It is frequently used to decrease the metabolism of phenytoin

It is often used as a gargle for sore throat

It is only intended for veterinary oral and rectal use

Acetaminophen is metabolized and converted to a toxic metabolite by

conjugation.

CYP2E1.

inhibiting the synthesis of prostaglandins.

absorption.

The maximum recommended daily dose of acetaminophen for adults is

4000 mg.

6000 mg.

7500 mg.

10,000 mg.

When acetaminophen is taken in toxic doses, it produces N- acetyl-benzoquinone imine (NAPQI), which depletes the liver’s production and storage of

cytochrome P-450 enzymes.

eicosanoids.

glutathione.

arachidonic acid.

A massive overdose of acetaminophen can cause a rapid onset of

metabolic acidosis and coma.

splenitis.

hypertension.

glutathione production and hepatic encephalopathy.

In patients with suspected acetaminophen poisoning, a serum acetaminophen level must be measured

immediately after ingestion.

4 hours after ingestion.

2 hours after ingestion.

one hour after ingestion.

The antidotal therapy for acetaminophen poisoning is

glucagon.

methylene blue.

sodium thiosulfate.

N-acetylcysteine (NAC).

Acetaminophen is contraindicated if a patient has

consumed any amount of alcohol.

is pregnant.

has severe hepatic impairment.

is under the age of 12.

A patient who has been prescribed emergency administration of N-acetylcysteine (NAC) but who does not have a functioning gastrointestinal tract would benefit most from

a liquid form of NAC.

intravenous NAC.

oral NAC, crushed.

sublingual NAC.

Which option below most accurately describes healthcare professionals and their roles likely to be involved with addressing acetaminophen toxicity?

Nurses who provide expertise in complex cases, such as massive overdoses, delayed presentations, or patients with comorbidities.

Poison control center staff who evaluate the patient for potential liver transplantation

Clinical toxicologists who prepare antidotes and ensure NAC is prepared and administered promptly

Emergency physicians who evaluate the patient’s symptoms, timing of ingestion, and use the Rumack-Matthew nomogram

References

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