Chapter 42. Acetaminophen Overdose

Acetaminophen is the most widely used analgesic and a commonly used antipyretic. It has been available as an over-the-counter formulation for more than 40 years and is exceptionally safe when used according to manufacturer directions. Unfortunately, toxic levels can make it a silent and lethal killer, as overdose may initially present with few, if any, symptoms.1–3 If not promptly discovered and treated, acetaminophen toxicity can lead to liver failure and death (unless a successful liver transplant is performed).4–10

Acetaminophen is packaged under multiple names and is a component of many different medicinal products around the globe. In the United States it is commonly sold as the brand name Tylenol®, while in the United Kingdom it is generally sold under the alternate generic names of paracetamol and N-acetyl-p-aminophenol (APAP).11

In the United States, acetaminophen is available in varied doses and forms. Pill forms are made in 325- and 500-mg immediate release, as well as 650-mg extended release. For both products, the adult dose should not exceed 4 g per day.12 Pediatric formulas vary in both dosing and form, including concentrated drops, liquid suspensions, suppositories, and dissolving or chewable tablets.11,12 Pediatric doses (child and infant) should not exceed 90 mg/kg per day or 15 mg/kg per dose every 4 hours.11

Acetaminophen is found in many over-the-counter and prescription medicines (i.e., Sudafed PE® Severe Cold: acetaminophen, diphenhydramine, and phenylephrine; Percocet®: acetaminophen and oxycodone; Fioricet®: acetaminophen, butalbital, and caffeine). Unintentional overdose may occur with these multidrug products, as the general public is unaware of the multiple names.

Acetaminophen overdose may be acute or chronic (Figure 42-1). An acute overdose is generally defined as a toxic dose (>150 mg/kg) ingested in less than 8 hours. A chronic overdose is generally defined as a toxic dose taken over more than 8 hours. Overdose may be accidental, as is frequently the case with pediatric overdoses, or it may also be intentional, as is the case with suicide attempt.

Overdose is defined as anything over the recommended 4 g per day. However, for the average adult (70 kg), the acetaminophen ingestion necessary for hepatotoxicity is much higher—150 mg/kg, or approximately 10.5 g. Thus, approximately 20 extra strength (500 mg each) pills are potentially lethal for the average patient.1,13 Since acetaminophen is readily available over-the-counter, it is an easy overdose agent for suicide attempts.

Additionally, pediatric dosing (child and infant formulas) is easy to confuse and can often lead to therapeutic error. Pediatric dosing is particularly problematic since the infant's formula (100 mg/mL) is more than three times as concentrated when compared with the children's formula (32 mg/mL).11 Thus, equal volumes contain significantly different milligrams of acetaminophen, creating a high potential for overdose.

The risk of hepatotoxicity after an acute acetaminophen overdose is determined using the Rumack–Matthew nomogram (Figure 42-2).1,3,13–17 This easy-to-use graph allows providers to assess risk based on plasma acetaminophen concentration and time postingestion. The antidote, N-acetylcysteine (NAC), is administered if there is a possible risk of hepatotoxicity.1,3,13–24 This is discussed in detail further in this chapter.

Acetaminophen is a frequently used analgesic throughout the world, particularly in the United States, Canada, and Europe.20,25,26 In the United States, it is the most commonly used prescription and over-the-counter drug, taken either alone or as a multidrug product, with over 50 million people using it every week.26 In the United States it is the most common type of medicine associated with poisoning, and the second most common medicine related to overdose-related deaths (of which half are due to ingestions of a multidrug product that contains acetaminophen).25

In 2009, Poison Control Centers responded to 258,016 calls involving acetaminophen (234,084 in combination with another drug, and 23,932 calls regarding acetaminophen alone.25 Additionally that year, acetaminophen (alone or in combination) was responsible for 410 deaths—nearly 15% of all poison related deaths in the United States.25

Acetaminophen overdose places a large burden on the health care system, as it is responsible for over 70,000 visits to health care facilities.25–27 If untreated within 24 hours, acetaminophen poisoning has significant morbidity and mortality risks. Patients who initially present with hepatic failure have a mortality rate of 20–40%.27

Acetaminophen overdose is now the number one cause of acute liver failure in the United States.28–32 This morbidity and mortality can be avoided when promptly treated.27,33,34 As discussed below, the antidote, NAC, is nearly 100% effective if given within 8 hours, is often useful up to 12–24 hours, and occasionally may even prove useful after 24 hours.17–24

Acetaminophen is rapidly absorbed in the gastrointestinal tract. Peak serum levels occur within 4 hours, and possibly as soon as 2 hours, after ingestion. The drug is primarily metabolized by the liver.1,3,5–10,29

The drug itself does not directly damage the liver. Rather, damage is caused by acetaminophen metabolism when N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite, is produced (Figure 42-3).1,3,5–10,29

Therapeutic acetaminophen doses create approximately 5% of the metabolite NAPQI. These small amounts of NAPQI are rapidly detoxified by glutathione into cysteine and mercapturic acid conjugates.1,3,5–10,29 However, in the setting of acetaminophen overdose, glutathione stores are depleted and there is an accumulation of NAPQI that causes hepatic injury and cell death.

The American College of Emergency Physicians (ACEP) defines hepatotoxicity after acetaminophen overdose as any increase in the aspartate aminotransferase (AST) level.34 Severe hepatotoxicity is generally defined as an AST level >1,000 IU/L.34 Acute liver failure is defined as severe hepatotoxicity with hepatic encephalopathy (Figures 42-4 and 42-5).34

If glutathione can be replenished, then NAPQI can be metabolized into a nontoxic form that is then excreted via the kidneys. Cysteine is the rate-limiting substrate necessary for the creation of glutathione (which is formed via the synthesis of cysteine, glutamate, and glycine). NAC is a substance that provides an absorbable form of cysteine that can then be hydrolyzed to synthesize glutathione. This additional glutathione is then used to detoxify the enormous levels of NAPQI created during acetaminophen overdose.

There are several factors that appear to lessen hepatotoxicity. Acute ethanol ingestion is reported to reduce the hepatotoxic effects of acetaminophen by nearly 50%, although this protective effect is without clear mechanism.35 Others suggest that coingestion of opioid analgesics is a protective factor in the development of hepatic encephalopathy (OR 0.26; CI 0.07, 0.96).36 Phenytoin, initially thought to cause hepatotoxicity, is now suggested to be hepatoprotective by increasing glucuronidation that facilitates the metabolism of acetaminophen into nontoxic metabolites.37 These studies are clinically limited; thus, further research is necessary to fully understand the above relationships and the underlying mechanisms of action.

Multiple factors appear to worsen hepatotoxicity during acetaminophen overdose. These include cirrhosis, chronic alcohol abuse, coingestions, certain preventable conditions, other medications, and dehydration and/or malnutrition.31,38

Nearly one third of all patients who overdose on acetaminophen ingest other substances (often alcohol and/or opiates). Certain coingestions appear to be independent risk factors for the development of hepatic encephalopathy, renal dysfunction, and death or liver transplantation.36 Preventable conditions also appear to increase mortality among patients found to be hepatotoxic secondary to acetaminophen overdose. These include attempted suicide, substance abuse, and trauma.30,31

The relation between chronic, heavy alcohol abuse and acetaminophen use has been debated for decades. While alcoholics are likely to be at a greater risk for hepatotoxicity following acetaminophen overdose, there is little to no evidence to suggest such toxicity when taking therapeutic doses of acetaminophen.37 Dehydration and/or malnutrition may compound the relationship between alcoholism and acetaminophen toxicity during acute ingestions; however, further research is needed to better understand these potential risk factors.31,37

Any patient presenting to the Emergency Department receives a primary survey: airway, breathing, circulation, disability/dextrose, and exposure. In a poisoned patient, the resuscitation and diagnosis occur simultaneously by utilizing all members of the health care team. It is imperative to receive a thorough history from emergency medical services (EMS) personnel, as well as family, friends, and/or bystanders.

The history should be obtained from both the patient and a corroborator. Questions should address the time of ingestion, the specific substances, the route of ingestion (PO, IV, PR, inhaled), and the exact amounts. Regardless of historical source, it is imperative to count pills if the bottles (prescription or OTC) are available. Specific to acetaminophen overdose:

• Were there coingestions?
• Were extended-release tablets involved?
• Did the patient intend to hurt himself or herself or was the ingestion accidental?
• Was the ingestion acute (i.e., all at once) or was it chronic (generally >8 hours)?

The history and physical exam must focus on coingestions, self-harm, homicidal intent, and psychiatric illness. Keep in mind that any attempted suicide must consider acetaminophen overdose among possible coingestions.

The clinical presentation and progression of acetaminophen overdose are generally categorized into four stages (Figure 42-4):

• Stage 1 (0–24 hours): Preclinical toxic effects with minimal signs and symptoms, possibly asymptomatic, and often normal liver function tests. The vague, nonspecific symptoms of this stage might include nausea and vomiting, diffuse abdominal pain, and general malaise.
• Stage 2 (24–72 hours): Hepatic injury (hepatotoxicity). Patients may begin to develop RUQ pain, although sometimes they are clinically asymptomatic. AST and ALT begin to rise, and possibly bilirubin. If injury is severe, then coagulopathy studies (PT, PTT, INR) may increase.
• Stage 3 (72–96 hours): Hepatic failure with encephalopathy. Liver function tests peak, and clinical signs and symptoms of liver failure are evident, including jaundice, vomiting and gastrointestinal pain, coagulopathy, encephalopathy, metabolic acidosis, and possibly acute renal failure and/or pancreatitis.
• Stage 4 (>96 hours): Survival or death. Either there is full resolution of hepatotoxicity or fulminant liver failure progresses to multiorgan failure and death.

Patients presenting with acetaminophen overdose must be completely undressed and examined from head to toe. It is useful to use security and/or police at the bedside for staff safety and the collection of patient belongings. This includes a thorough inspection of substances or objects that might be in pockets or hidden in/on the patient's body. Providers should be extremely cautious for dirty needles, sharp objects, and/or other contaminants.

As part of the primary survey, a blood glucose check is essential, as is an inspection of the oropharynx. It may be useful to inspect the rectal cavity for any retained substances (i.e., tablets, drug balloons, or other paraphernalia) and/or gastrointestinal bleeding.

An acute acetaminophen overdose will generally have few, if any, symptoms. Those symptoms that do exist may be vague and nonspecific, and may include mild abdominal pain or cramping, nausea and vomiting, and general malaise. Massive, acute overdose may, on occasion, present initially with metabolic acidosis and coma, even before the development of hepatotoxicity. Usually such presentation is caused by coingestions, frequently alcohol and/or opiates.

Coingestions often create additional signs and symptoms elicited during the physical exam of an acetaminophen overdose. Classic toxidromes may be encountered when additional substances are ingested: opioid, sympathomimetic, cholinergic, anticholinergic, or others.

Delayed presentation of acute acetaminophen overdose may present with more severe symptoms of hepatotoxicity, such as jaundice, RUQ pain and tenderness, and possibly altered mental status.

Applicable laboratory data and related studies should be ordered as listed in Figure 42-6. The Rumack–Matthew nomogram is the most important tool used to guide clinical decisions about the treatment of acute acetaminophen overdose up to 24 hours after ingestion. It has potential use for the ingestion of extended-release preparation, as discussed later in the chapter. The nomogram may not be used under the following circumstances34:

• Unknown time or duration of ingestion;
• Chronic ingestion (repeated supratherapeutic);
• Delayed presentation (>24 hours after ingestion).

The following serum acetaminophen levels are toxic according to the nomogram (Figure 42-2):

• 4-hour level >150 mcg/mL.
• 6-hour level >110 mcg/mL;
• 8-hour level >75 mcg/mL;
• 24-hour level >4.5 mcg/mL.

There are four general treatment modalities for acetaminophen overdose: (1) decrease absorption, (2) increase elimination, (3) antidote, and (4) liver transplantation.20,39

In the Emergency Department, one must first complete a primary survey and ensure that airway, breathing, and circulation are appropriately established. Oxygen, IV access, cardiac monitor, and pulse oximetry are ordered as needed.

Nasogastric tubes (NGT) are of limited clinical benefit, if any, in the setting of acetaminophen overdose.20,39,40 Some facilities continue to use this practice, although it is not supported by evidence-based guidelines. Given the risk for inducing vomiting, and potentially compromising the airway, most physicians have abandoned the use of an NGT. There is a limited argument for the continued use of an NGT if the ingestion occurs less than 1 hour prior to arrival or if dangerous coingestants were consumed. Under these circumstances, it is argued that gastric lavage may remove some of the pill fragments remaining in the stomach, thereby preventing further absorption.

The medications used to treat acetaminophen overdose consist of activated charcoal (decreases adsorption and enhances elimination) and NAC (antidote to increase elimination), with antiemetics used as clinically indicated.

Gastrointestinal decontamination is primarily achieved with activated charcoal. There is moderate evidence that significant benefit occurs if this is given within 1 hour of the ingestion.20,40 Super activated charcoal may offer some detoxification benefit when given within 3 hours postingestion; however, this is not typically stocked in many Emergency Departments.41 There is no clinical benefit to the use of syrup of ipecac and it should no longer be used in acetaminophen overdose.39 Antiemetics are used symptomatically to prevent aspiration and airway compromise.

The most important treatment in acetaminophen overdose is the antidote NAC—manufactured under the brand names Mucomyst® and Acetadote®.17,20,22,24,33 It works via the pathways discussed above (Figure 42-3).

When given within 8–10 hours postingestion, there is no difference in the efficacy between the oral and IV preparations.18,22 Historically, the oral preparation was used; however, the IV preparation was approved by the Food and Drug Administration (FDA) in 2004, and has subsequently become the primary preparation.42 Many institutions now use the IV form because of decreased treatment time, a decreased likelihood of complications secondary to vomiting, and a decreased hospital stay and associated costs.20 IV NAC should also be used if treatment is more than 10 hours postingestion or if underlying conditions prevent oral use.18,19 There is some evidence that patients with asthma or atopic dermatitis should receive oral therapy because of the decreased risk of anaphylactoid reaction; however, this is not necessarily the current standard of care.18,42,43

Over the past decade, a significant change in treatment has occurred as the IV form of NAC has become the standard over PO. This decreases total time of treatment and also reduces risk of aspiration from vomiting (Figures 42-7, 42-8, 42-9).

The IV dosing for adults (patients >40 kg) consists of the following protocol: Acute ingestions (8–10 hours after ingestion) receive an IV loading dose of 150 mg/kg (body weight) diluted in 250 mL of D5W infused over 1 hour. Two maintenance doses are then initiated as follows: The first maintenance dose (started immediately after the loading dose) is 50 mg/kg diluted in 500 mL of D5W infused IV over 4 hours. The second maintenance dose (started immediately after the first maintenance dose) is 100 mg/kg diluted in 1,000 mL of D5W infused IV over 16 hours. The total of the three doses administered is 300 mg/kg over 21 hours.

The oral (PO) loading dose for adults is 140 mg/kg (body weight) once, and then maintenance doses (start 4 hours after loading dose) of 70 mg/kg repeated every 4 hours for a total of 17 additional doses. Total of 18 doses administered equaling 1,330 mg/kg over 72 hours.33,44–45

The IV dosing for adult chronic ingestion, or late presentation (>8 hours after ingestion), is an IV loading dose of 140 mg/kg (body weight) diluted in 500 mL D5W infused over 1 hour. Maintenance doses are then initiated as follows: 70 mg/kg diluted in 250 mL of D5W infused IV over at least 1 hour. This maintenance dose is repeated every 4 hours for at least 12 doses. Total treatment time is at least 48 hours.46 If fluid restriction is required, then the total volume of D5W may be decreased.

The IV dosing for pediatrics (patients <40 kg) is the same as the adult protocol, except the volume of D5W is decreased (Figure 42-7). The oral (PO) dosing protocol for pediatrics is the same as the adult protocol above.

All patients treated with NAC must be admitted to the hospital for further treatment and evaluation. Any patient presenting with an overdose secondary to a suicide attempt must be evaluated by Psychiatry.

Dose-dependent hypokalemia has been observed, although it tends to be more profound at higher levels of acetaminophen toxicity.47,48 It is unclear if this is related to acetaminophen or other confounding factors. One study suggests a renal effect (of unclear etiology) that causes kaliuresis within the first 24 hours after ingestion.48 This occurs regardless of NAC treatment and is independent of vomiting. The treatment is to replace potassium accordingly.

Renal insufficiency occurs in 1–2% of patients, generally among the more severe ingestions.49 One study suggests nephrotoxicity is higher in adolescents, possibly as high as 9%, although further research is indicated.50

Fulminant liver failure may lead to significant acidosis, coagulopathy, cerebral edema, and/or multiorgan system failure.51 Each of these findings must be addressed accordingly, and is frequently resolved in the Intensive Care Unit (ICU) setting. Referral to a liver transplant center is required.

Pediatric patients are treated similarly to adults, except the D5W is decreased during the administration of IV NAC.

Pregnant patients are treated similarly to nonpregnant patients.19,20,52 There is no increased risk of adverse pregnancy unless there is severe maternal toxicity.19

Extended-release tablets (650-mg pill) are composed of half immediate-release acetaminophen (325 mg/pill) and half extended-release acetaminophen (325 mg/pill). Therefore, there may be a delayed rise in serum acetaminophen levels.20,53,54 If the initial 4-hour serum acetaminophen level is above the nontoxic range on the Rumack–Matthew nomogram, then treatment with NAC should be immediately initiated. However, if the initial 4-hour serum acetaminophen level is below the nontoxic range on the Rumack–Matthew nomogram, then research suggests that a second serum acetaminophen level and AST/ALT should be repeated 4–6 hours after the first (8–10 hours postingestion) and treated accordingly based on results.20,53,54 Treatment with NAC should be initiated if the serum acetaminophen level is >10 mcg/mL or if serum AST or ALT is elevated.

Delayed presentation (ingestion >24 hours prior to presentation) requires the immediate initiation of NAC. Laboratory tests should be ordered as listed above, including acetaminophen level and liver function tests Figure 42-6. Treatment with NAC should be continued if the serum acetaminophen level is >10 mcg/mL or if serum AST or ALT is elevated (Figure 42-8).

Chronic ingestion (toxic overdose taken over >8 hours) requires laboratory tests as above, including liver function tests Figure 42-6. The Rumack–Matthew nomogram may not be used in this scenario. NAC should be initiated if the serum acetaminophen level is >10 mcg/mL or if serum AST or ALT is >50 IU/L. It should be continued for 12 hours or until evidence of clinical and laboratory improvement substantiates cessation. Treatment with NAC should be considered if the patient has a history of chronic overdose or exhibits signs and symptoms consistent with toxicity (Figure 42-9).46

Safe discharge from the Emergency Department may occur (on rare occasion) if the following criteria are met:

• No coingestions;
• No significant medical problems;
• Observation for 4–6 hours with a normal reevaluation;
• Safe acetaminophen levels based on the Rumack–Matthew nomogram;
• Psychiatry evaluation and clearance, if suggestion of intentional overdose.

Patients are often unaware that acetaminophen is commonly present in other medicine they are taking—either prescribed or over-the-counter.55 There is evidence to suggest that the removal of acetaminophen from multidrug products (e.g, percocet, vicodin, etc.) may reduce unintentional overdose. Also, multiple studies suggest that limiting the quantity of acetaminophen available in a single purchase generally reduces associated morbidity and mortality from acute and chronic toxicity.56,57 Presently, the FDA and Congress are considering both of these strategies.

Acetaminophen is the most widely used analgesic, and a commonly used antipyretic, that is a potentially silent and lethal killer. If not promptly discovered and treated, acetaminophen overdose may lead to liver failure and death. However, if treated early with the antidote NAC, then survival is nearly 100%. IV NAC is now the preferred route of treatment for both adults and pediatrics. Given the high morbidity and mortality associated with acetaminophen overdose, it is essential that the Emergency Medicine physician have a high index of suspicion for any potentially lethal overdose.