Acetaminophen
Perspective
Acetaminophen is one of the most commonly used antipyretic and analgesic agents throughout the world. Acetaminophen is found as an isolated product or in combination medications for the treatment of cold symptoms, pain, and headache. In 2010, an intravenous (IV) formulation was approved in the United States (an IV formulation was available in Europe and Australia previously) for the treatment of pain1–3 and as an antipyretic.4 Given the widespread use and availability of acetaminophen, toxicity is a concern in all intentional ingestions as well as with repeated supratherapeutic dosing and drug abuse. Acetaminophen toxicity is one of the leading causes of hospital admission, antidote use, and fatalities from oral poisonings in the United States.5
Principles of Disease
Acetaminophen is absorbed rapidly, with peak plasma concentrations generally occurring within 1 hour and complete absorption within 4 hours. Once it is absorbed, acetaminophen inhibits prostaglandin E2 (PGE2) synthesis, leading to antipyresis and analgesia. Inhibition of PGE2 synthesis is by either direct cyclooxygenase-2 inhibition or inhibition of membrane-associated prostaglandin synthase.6,7
In therapeutic doses, acetaminophen is primarily metabolized by conjugation with glucuronide (40-67%) and sulfate (20-46%) into nontoxic metabolites that are excreted in the urine8 (Fig. 148-1). A small percentage (<5%) is oxidized by cytochrome P450 2E1 (CYP2E1) (and to a lesser extent 1A4 and 3A4) to a highly cytotoxic metabolic intermediary, N-acetyl-p-benzoquinone imine (NAPQI).9,10 In therapeutic doses, NAPQI is short-lived, combining rapidly with glutathione and other thiol-containing compounds to form nontoxic metabolites that are excreted in the urine. With typical therapeutic acetaminophen dosing, glutathione stores and the ability to regenerate glutathione easily keep up with NAPQI production.
After large ingestions or repeated supratherapeutic ingestions, the amount of NAPQI produced begins to outstrip glutathione stores and the liver’s ability to regenerate glutathione, leading to unbound NAPQI. The highly reactive electrophile NAPQI covalently binds to cell proteins in the liver, which initiates a cascade of events that lead to hepatic cell death. Renal injury may also occur with or without liver injury11 and may be mediated by renal CYP enzymes or activation of prostaglandin synthase.
Acetaminophen-induced liver damage initially occurs in hepatic zone III (centrilobular) because oxidative metabolism is concentrated in this area. With severe toxicity, necrosis of the entire liver parenchyma may occur. The clinical effects of severe acetaminophen toxicity are the result of severe fulminant liver failure rather than a direct acetaminophen effect. These effects include multiorgan failure, systemic inflammatory response syndrome, hypotension, cerebral edema, and death.12
The principal therapy for acetaminophen toxicity is N-acetylcysteine (NAC), which is effective by two separate mechanisms. Soon after overdose, NAC serves as a glutathione precursor and a sulfur-containing glutathione substitute (see Fig. 148-1), binding to and thereby detoxifying NAPQI and avoiding subsequent hepatotoxicity. In addition, NAC may decrease NAPQI formation by enhancing acetaminophen conjugation with sulfate to nontoxic metabolites.
Even after acetaminophen hepatotoxicity is evident, NAC acts as a free radical scavenger and an antioxidant and alters hepatic microcirculation and oxygen delivery.13 In patients with acetaminophen-induced hepatic failure, IV administration of NAC decreases the rates of cerebral edema, hypotension, and death even when no acetaminophen remains.12
Clinical Features
Early after acute acetaminophen ingestion, patients may be asymptomatic or have mild nonspecific symptoms (e.g., nausea, vomiting, anorexia, malaise, diaphoresis) (Table 148-1). Liver injury becomes evident after a period of 8 to 36 hours as an elevation in aspartate transaminase (AST).14 Once liver injury has begun, patients may have right upper quadrant pain or tenderness, vomiting, and jaundice. AST concentrations continue to rise rapidly14 and usually peak in 2 to 4 days, corresponding to maximal liver injury. Alanine transaminase (ALT), prothrombin time, and bilirubin typically begin to rise and peak shortly after AST values. With severe toxicity, AST, ALT, and the prothrombin time may all be elevated within 24 hours (Fig. 148-2).14 With maximal liver injury, patients have signs and symptoms consistent with fulminant liver failure, including metabolic acidosis, coagulopathy, and hepatic encephalopathy. Death may occur from hemorrhage, adult respiratory distress syndrome, sepsis, multiorgan failure, or cerebral edema. The risk of renal injury increases with the severity of hepatic injury; renal injury occurs in less than 2% of patients without hepatotoxicity and in 25% of patients with severe hepatotoxicity.
Diagnostic Strategies
Risk Assessment with Acute Acetaminophen Ingestion
The initial diagnostic strategy of an acute ingestion is well established. The first step is to determine the patient’s risk of acute acetaminophen exposure. Patients who report an acute intentional ingestion of acetaminophen should have laboratory risk stratification regardless of the reported amount ingested. It is likely that significantly more than 150 mg/kg must be acutely ingested before significant liver toxicity occurs; however, history alone may not be reliable. A serum acetaminophen concentration should be considered in all intentional overdoses because approximately 1.4 to 8.4% of patients with intentional ingestions who deny acetaminophen ingestion actually have a detectable but usually subtoxic concentration.15–17
Once a patient is determined to be at risk and a time of ingestion has been established or estimated, the next step is to determine a serum acetaminophen concentration 4 hours after ingestion or as soon as possible after 4 hours. The serum acetaminophen concentration and the time of ingestion determine the need for antidotal therapy by plotting of the serum acetaminophen concentration against the time since ingestion on the treatment nomogram (Fig. 148-3), an adaptation of the Rumack-Matthew nomogram. If the serum acetaminophen concentration is on or above the treatment line (that starts at 150 µg/mL (990 µmol/L) at 4 hours and decreases to 4.7 µg/mL (31 µmol/L) at 24 hours), treatment with NAC should be initiated. If the serum acetaminophen concentration is below the treatment line and the most severe possible scenario has been taken for the time of ingestion, the patient requires no antidote.18 The treatment nomogram is a highly sensitive approach and may be used for all acute ingestions. Alternative approaches in patients with alcoholism,19 in patients with coingestions of antimuscarinic agents,20,21 in patients with unknown ingestion times,22 and after the administration of IV formulations23 have been suggested, but these remain controversial and unvalidated. Strict adherence to the approach described here is recommended.
Measurement of serum acetaminophen concentration before 4 hours is typically not necessary. It is likely that a serum acetaminophen concentration less than 10 µg/mL (66 µmol/L) between 1 and 4 hours after ingestion excludes significant ingestion of acetaminophen; however, there are few data on which to base this conclusion. Absorption of acetaminophen may not be complete before 4 hours, and any serum acetaminophen concentration greater than 10 µg/mL (66 µmol/L) is difficult to interpret. Finally, serum acetaminophen concentrations measured before 4 hours cannot be plotted on the treatment nomogram. Fortunately, there is little need to treat patients before 6 to 8 hours after ingestion; patients treated with NAC up to 6 hours after ingestion, even after very large doses, have no increased risk of hepatotoxicity regardless of their serum acetaminophen concentration.24 For most overdose patients, the risk of hepatotoxicity does not significantly increase unless NAC is delayed for 8 hours or longer after ingestion.24 This is generally enough time for a serum acetaminophen concentration to be determined at 4 hours and the laboratory evaluation to be completed. For patients at risk whose serum acetaminophen concentration cannot be obtained before 8 hours after ingestion, a loading dose of NAC should be considered.
There are few data for development of a strategy of risk assessment after a large IV acetaminophen overdose. Several pharmacokinetic factors suggest that some alteration of the typical nomogram-based assessment may be necessary. After infusion, IV acetaminophen generates serum concentrations that are significantly higher than an equivalent oral dose. In addition, the nomogram that is used for acute ingestions takes into account an absorptive period that is not necessary for an IV infusion. These and other factors suggest that an alternative approach may be necessary, but experience is limited. We adhere to a conservative approach, which suggests that patients be treated with NAC if they either (1) are treated with more than 60 mg/kg IV acetaminophen in one dose or (2) they have a serum acetaminophen concentration that is above 50 µg/mL (330 µmol/L) at 4 hours after the infusion stops.25
