Chapter 113: Acetaminophen

• Widely available in both prescription and OTC products, acetaminophen is a common pediatric overdose.

• Acetylcysteine is the antidote for acetaminophen overdose and can be given orally or intravenously.

• Treatment with acetylcysteine is rarely indicated in children less than 6 years of age.

• Acetylcysteine is nearly 100% effective when started within 8 hours of acetaminophen ingestion.

• A child less than 6 years can be safely discharged following an acetaminophen exposure if the maximum ingested dose is less than 200 mg/kg or if acetaminophen is not detected in the serum at any time at least 1 hour after ingestion.

Being ubiquitous, acetaminophen is a leading pharmaceutical taken in overdose, whether accidentally by young children or for self-harm by adolescents and adults. Despite this high incidence of overdose, a large margin of safety and a highly effective antidote ensure that death caused by acute acetaminophen ingestion is unheard of in young children.¹ Fatalities are also unlikely when treatment is started within 20 hours of acute overdose, and hepatic injury rare when started within 8 hours. Young children are frequently suspected of ingesting liquid acetaminophen preparations formulated for children. These are absorbed more rapidly than pills but in most instances not enough has been ingested (200 mg/kg)1to warrant concern. Because these patients typically present asymptomatic shortly after the exposure, most of these unintentional exposures in young children do not need empirical therapy with antidote when a serum acetaminophen concentration can be readily measured. Dosing errors with the antidote are not infrequent especially in young children. Therefore, the indications and dosing calculations as well as total fluid volume administered should be verified meticulously. Adolescents often are not aware that acetaminophen ingestion can be lethal, or that many different products contain acetaminophen, and may unknowingly take a life-threatening amount as a suicidal gesture.²

Acetaminophen (APAP, or paracetamol) is a synthetic analgesic and antipyretic. The therapeutic dose in children is 10 to 15 mg/kg (maximum 650 mg) given every 4 to 6 hours, with a maximum recommended total of five doses per day. Therapeutic serum concentrations are 10 to 20 μg/mL. Acetaminophen is well absorbed after an oral therapeutic dose, with peak levels generally occurring at 30 to 60 minutes. Even after overdose absorption is only minimally delayed in most cases, with peak concentrations seen within 4 hours of acute ingestion. Co-ingested opioids and antimuscarinic agents, solids, and sustained-release formulations of acetaminophen have only a minor effect on this absorption. Absorption of liquid formulations is more rapid than that of tablets or caplets. Following gastrointestinal absorption, APAP is taken up and metabolized by the liver, which is the primary target organ of toxicity. The normal serum elimination half-life is 2 to 3 hours but may be prolonged significantly following massive overdose or if liver injury has occurred. Indeed, an elimination half-life greater than 4 hours is one of the first manifestations of serious liver injury.

After a therapeutic dose, 90% of the drug is inactivated by conjugation with sulfate and glucuronide. In young children, the sulfate conjugate predominates. Less than 5% is excreted unchanged in the urine. The remainder is metabolized by cytochrome P450 primarily CYP2E1 to the toxic electrophile NAPQI. In the presence of adequate hepatic glutathione, NAPQI is rapidly inactivated. In overdose, the sulfate and glucuronide pathways become saturated, glutathione becomes depleted and free NAPQI attacks macromolecules in hepatocytes, eventually causing fulminant liver failure.

Acute ingestion of more than 200 mg/kg or 10 g (whichever is less) is potentially toxic and requires emergent evaluation. It is important to remember that acetaminophen is found in many combination products, and that many patients are unaware of the acetaminophen content of such products.

Patients are frequently asymptomatic shortly after acute acetaminophen ingestion, although vomiting may occur. Co-ingestants present in combination products such as codeine and antihistamines may provide early symptoms of overdose. Rarely, massive ingestion of at least 1000 mg/kg acetaminophen can, by itself, cause lethargy, coma, anion-gap metabolic acidosis, hypothermia, and hyperglycemia. Even in such cases, consideration should still be given to the possibility of co-ingestants.

As serum acetaminophen concentrations fall, and in the absence of treatment, the aspartate and alanine aminotransferases (AST and ALT) will begin to rise. Severe hepatic failure is demonstrated by encephalopathy, coagulopathy, jaundice, hypoglycemia, and markedly elevated aminotransferases (>1000 IU/L). While the degree of aminotransferase elevation may be impressive, at times exceeding 20,000 or 30,000 IU/L, the degree of elevation is not by itself prognostic, and patients with isolated rises in aminotransferases without other signs of liver dysfunction invariably recover.

Patients who ultimately recover have a complete recovery with essentially normal hepatic function and architecture on histology several weeks later. The presence of a persistent metabolic acidosis despite fluid resuscitation, or the combination of progressive encephalopathy, worsening coagulopathy and renal failure are strongly indicative of a poor prognosis unless liver transplantation is performed. Deaths in children under the age of 6 years are due to repeated supratherapeutic dosing over days in the context of an intercurrent illness with minimal oral intake.³ There is no well-documented case of death in a child less than 6 years of age attributed to a single acute overdose of acetaminophen.¹

A serum acetaminophen concentration should be drawn at 4 hours after the ingestion of greater than 200 mg/kg or 10 g (whichever is less) or immediately if the patient presents greater than 4 hours after ingestion. The Rumack–Matthew nomogram (Fig. 113-1) reliably identifies those patients who do not require antidotal therapy after acute acetaminophen ingestion. The nomogram is predicated upon a reasonably accurate estimate of the time of ingestion and a serum acetaminophen concentration drawn between 4 and 20 hours after ingestion. This concentration is plotted on the nomogram. If the point falls above the treatment line administration of the antidote acetylcysteine (NAC) is indicated. Levels drawn earlier than 4 hours cannot be interpreted using the nomogram. However, an undetectable serum concentration at any time after 1 hour of ingestion excludes even a therapeutic ingestion and is useful especially in young children following unintentional exposures as it allows immediate discharge. It is important to realize that this nomogram cannot be used in cases of chronic or staggered dosing, when the time of ingestion is not well established, or when the serum acetaminophen concentration will only be available more than 8 hours after ingestion. In such cases, NAC should be initiated empirically in all patients who have ingested a potentially toxic amount and continued until “stopping criteria” for NAC (discussed below) are satisfied.

When treatment with NAC is indicated, AST, ALT, acetaminophen, electrolytes, creatinine, and coagulation profile should be obtained approximately every 12 hours. Risk stratification and decisions regarding NAC dosing are best made using such serial testing.

A single dose of activated charcoal given within 1 hour of acetaminophen ingestion can reduce absorption and the need for antidotal therapy.

Acetylcysteine (NAC) helps replenish glutathione and restores the liver's ability to detoxify NAPQI. Its use prevents hepatic injury and death. There are several protocols for NAC therapy with the most prevalent being 20-hour intravenous and 72-hour oral protocols.⁴ It is most effective if started within 8 hours after an acute overdose⁴ but remains beneficial even if started very late when hepatotoxicity is evident.⁵ The efficacy of NAC therapy after 8 hours is highly time-sensitive.⁶ However, current recommendations favor individualizing treatment duration, and continuing treatment until specific clinical and biochemical end-points have been satisfied.⁷ This particularly important for patients with massive acetaminophen overdose.

The oral NAC protocol long used in the United States for treating APAP toxicity consisted of a loading dose of 140 mg/kg followed by 17 additional doses of 70 mg/kg given at 4-hour intervals. The 20% solution is unpalatable and should be diluted with three parts fruit juice or soda. Vomiting is common, and when it occurs within 1 hour of treatment, the dose is repeated with metoclopramide (0.25 mg/kg IV over 5 minutes) or ondansetron (0.15 mg/kg over 5 minutes). If necessary, NAC can be given via a nasogastric tube. If activated charcoal has been administered, the usual dose of NAC does not need to be increased.

Intravenous NAC had been used for decades in the rest of the world, and in 2004 the Food and Drug Administration approved an intravenous formulation for use in the United States. Unlike the oral route, intravenous administration is not limited by vomiting and patient cooperation. The Edinburgh protocol is most widely used and is shown with slight modification in Table 113-1. Originally crafted as a 20-hour protocol, treatment should be continued in cases with hepatic failure (Table 113-2).

Anaphylactoid reactions with urticaria, flushing and mild wheezing can occur especially during the initial intravenous load, and are easily treated by halting the infusion temporarily and administering antihistamines. Because such reactions are more common in patients with lower serum acetaminophen concentrations, they represent another reason to avoid empirically administering antidote in small children believed to have ingested acetaminophen but who ultimately have low or undetectable serum concentrations. Following an anaphylactoid reaction, it is prudent to verify the indication for antidote, its dilution and infusion rate. However, it is essential to resume the antidote if clinically indicated. Withholding the antidote when indicated because of an anaphylactoid reaction, or history of prior reaction, is unwarranted.

Children under the age of 6 years rarely require NAC therapy. Most of them are brought to the hospital shortly after the discovery of possible ingestion. Thus, there is sufficient time to wait for the result of a serum acetaminophen concentration. Measurement is indicated if the potential for ingestion of greater than 200 mg/kg exists. If the result is above the treatment line, NAC dosing and dilution should be verified carefully. Ten-fold NAC dosing errors can be fatal. Care should be given to the volume of fluid administered to young children. Guidelines for dilution of NAC are found in Table 113-1.

An asymptomatic patient whose APAP level is below the treatment line on the Rumack–Matthew nomogram after acute overdose does not need antidote or further testing. Patients should not be discharged home until appropriate psychiatric assessment in the case of intentional overdose for self-harm or without counseling caregivers about poison prevention following accidental exposures. If the APAP level is above the treatment line, the patient should be admitted for treatment with NAC.

Asymptomatic patients with suspected chronic APAP overdose can be medically cleared if they already satisfy the same stopping criteria for NAC at presentation (Table 113-2). If the serum acetaminophen is measurable, or they fail to satisfy other criteria, a course of NAC is indicated but may be quite brief in these patients. Repeat testing can be performed when the serum acetaminophen is expected to be no longer detectable, which may be less than 12 hours later. Any patient with fulminant hepatic failure (encephalopathy, hypoglycemia, coagulopathy, or acidosis) should be admitted to a critical care unit with experience managing liver failure and evaluated for transplant candidacy.