Death caused solely by acetaminophen ingestion is rare in the pediatric population. In 2006, only seven deaths associated with acetaminophen in patients younger than 19 years were reported to poison control centers in the United States.1 All of these cases involved teenagers, the majority of whom had also ingested other drugs. The small number of fatalities in this population can be explained by the availability of a very effective antidote, NAC, as well as the fact that young children are relatively resistant to acetaminophen-induced hepatotoxicity.
Young children are more likely to be administered liquid acetaminophen preparations, which are absorbed more rapidly than pills, or rectal suppositories, which have prolonged and unpredictable absorption. Adolescents often are not aware that acetaminophen ingestion can be lethal, and may unknowingly take a life-threatening amount as a suicidal gesture.2
Acetaminophen (also called APAP or paracetamol) is a synthetic analgesic and antipyretic that lacks the anti-inflammatory effects found in salicylates and nonsteroidal agents. The therapeutic dose of APAP in children is 15 mg/kg given every 4 to 6 hours, with a maximum recommended total daily dose of 75 mg/kg (or five doses). Therapeutic serum levels are 10 to 20 μg/mL.3 Acetaminophen is well absorbed after an oral therapeutic dose, with peak levels generally occurring at 30 to 60 minutes. However, after overdose, the peak level may be delayed for up to 4 hours. Absorption of liquid elixir is more rapid than that of tablets or caplets. Following gastrointestinal absorption, APAP is taken up by the liver, where tissue concentrations are high. Normal serum half-life is 1 to 3 hours after a therapeutic dose, but may be prolonged significantly following toxic ingestion.
Acetaminophen is eliminated primarily by hepatic pathways. After a therapeutic dose, 90% of the drug is metabolized to inactive sulfate and glucuronide conjugates. In young children, unlike in adults and adolescents, the sulfate conjugate predominates. Less than 5% is excreted unchanged in the urine. The remaining 2% to 4% is metabolized by the cytochrome P450 mixed-function oxidase (MFO) system to the toxic intermediate NAPQI. In the presence of adequate hepatic stores of glutathione, NAPQI is rapidly converted to nontoxic conjugates. In overdose, the sulfate and glucuronide pathways become saturated, and increased amounts of acetaminophen are shunted through the MFO system. Glutathione becomes depleted and free NAPQI attacks hepatocytes, causing acute liver failure. Drugs that induce activity of the MFO system (for example, isoniazid) may increase the risk of toxicity after acetaminophen overdose.4
Acute ingestion of more than 140 mg/kg of acetaminophen is potentially toxic and requires emergent evaluation. It is important to remember that acetaminophen is found in many combination products. For example, if a patient presents to the emergency departmant comatose after taking an oxycodone-acetaminophen preparation, the clinician should not neglect to measure an acetaminophen level, and begin treatment if indicated. It is essential not to overlook this aspect of the case while dealing with the more evident and dramatic opioid effects.
Stage I (0–24 Hours after Ingestion): Gastrointestinal Irritation
Although patients in this initial stage may be asymptomatic, young children frequently vomit after acetaminophen overdose. Hepatic enzymes are in the normal ranges. Atypical findings such as lethargy, coma, or acidosis should prompt consideration of possible coingestants.
Stage II (24–48 Hours after Ingestion): Latent Period
As nausea and vomiting resolve, patients appear to improve, but rising transaminase levels reveal evidence of hepatic necrosis. On physical examination, hepatic tenderness and enlargement may be apparent. Increased aspartate aminotransferase (AST) is the most sensitive indicator of liver toxicity.3
Stage III (72–96 Hours after Ingestion): Hepatic Failure
Severe hepatotoxicity presents with jaundice, hypoglycemia, renewed nausea and vomiting, right upper quadrant pain, coagulopathy, encephalopathy, hyperbilirubinemia, and markedly elevated transaminase levels. In this stage, acetaminophen-induced hepatotoxicity is usually accompanied by an AST >1000 IU/L. In fulminant hepatic failure, AST can rise to levels of 20 000 or 30 000 IU/L. It is very unusual, but not unprecedented, for children younger than 6 years to develop fulminant effects from acute APAP ingestion.
Stage IV (4–14 Days after Ingestion): Recovery or Death
Patients who ultimately recover show improvement in laboratory parameters of hepatic function starting on about day 5, and eventually recover completely. Follow-up histology is normal. Less fortunate patients develop progressive encephalopathy, renal failure, coagulopathy, and hyperammonemia. The prognosis is poor for patients with these findings unless liver transplantation is performed.
The Rumack-Matthew nomogram (Fig. 108–1) allows the clinician to predict the probability that hepatic toxicity will occur after single acute acetaminophen ingestion. A blood acetaminophen level is drawn 4 hours after the acute ingestion, or immediately if more than 4 hours have elapsed since the time of ingestion. Levels drawn earlier than 4 hours may not represent the peak serum concentration and thus may be misleadingly low. This level is plotted on the nomogram against hours postingestion. If the point falls above the potential toxicity line, treatment with the antidote NAC is indicated. It is important to realize that this nomogram cannot be used in cases of chronic toxicity or when the time of ingestion is not well established. If treatment with NAC is indicated, additional laboratory values that may influence management include liver enzymes, bilirubin, electrolytes, creatinine, and coagulation profile.
The Rumack-Matthew nomogram predicts the probability that hepatic toxicity will occur after a single acute acetaminophen ingestion.
Induction of emesis with syrup of ipecac is contraindicated. Gastric lavage is generally not indicated but can be considered if the patient presents within 1 hour of ingestion and has taken a life-threatening overdose of another drug in addition to acetaminophen. Standard doses of activated charcoal can be given if the patient arrives within 1 hour of ingesting APAP alone, or if other toxic substances are also involved.
NAC helps restore the liver's ability to detoxify NAPQI and can prevent hepatonecrosis. It is most effective if started within 8 hours after an acute overdose.5 However, there is now good evidence that NAC has some benefit even if started very late, possibly even up to days after ingestion when hepatic failure is evident.6 NAC should not be withheld on the basis of an arbitrary time limit.
The Rumack-Matthew nomogram indicates which patients require treatment following a single, acute APAP ingestion occurring at a known time (Fig. 108–1). It was devised using data from a relatively small number of adult patients, but is also applied to children. The original studies indicated that 60% of patients whose levels are above the probable toxicity line after a single acute APAP overdose would go on to develop severe hepatotoxicity (serum AST >1000 IU/L). The lower “possible toxicity” line was added to give a margin of safety. It is current practice to treat any patient who has an APAP level that falls in the range of possible or probable hepatotoxicity. In cases where the patient has not taken a single acute overdose, but rather has taken multiple doses or overdoses of APAP, or has ingested APAP chronically, the nomogram cannot be used to predict hepatotoxicity or need for treatment with NAC.
The oral NAC protocol long used in the United States for treating APAP toxicity consists of a loading dose of 140 mg/kg followed by 17 additional doses of 70 mg/kg given at 4-hour intervals. The commercial 20% solution (Mucomyst, Mead Johnson & Company) is unpalatable and should be diluted with three parts fruit juice or soda. If vomiting occurs within 1 hour of treatment, the dose is repeated. Persistent vomiting that interferes with therapy can be suppressed with metoclopromide (0.25 mg/kg IV over 5 minutes) or ondansetron (0.15 mg/kg over 5 minutes). If necessary, NAC can be infused slowly through a nasogastric tube. If activated charcoal has been administered, the usual dose of NAC does not need to be increased, but is best given at least 30 to 60 minutes after the charcoal.
In a review of APAP toxicity over the first 35 years of the drug's use, Rumack describes how the NAC treatment regimen was originally derived from theoretical calculations, with individual doses and length of treatment tripled to provide a margin of safety.7 Rumack states “The 72-hour oral NAC protocol is probably unnecessary in many cases where the drug has a shorter half-life [than 4 hours] and disappears before the full dosage is completed.” Based on a retrospective chart review of 75 mostly adult patients, Woo and coworkers suggested that, because evidence of APAP-induced hepatotoxicity is apparent within 36 hours of acute ingestion, treatment could be stopped at that time if liver enzymes were normal and APAP levels undetectable.8 Some poison centers have been using this guideline for years.
Expanding on this idea of abbreviated therapy, Dart and Rumack recently proposed the concept of “Patient-Tailored Acetylcysteine Administration.”9 They suggested that treatment with NAC should be continued, not for an arbitrary period of time or number of doses, but until a specific clinical endpoint is reached. They reported that their practice at the Rocky Mountain Poison Center was to start treatment with the loading dose of NAC, and then continue maintenance doses until three criteria were met: (1) acetaminophen level was zero or near zero (usually this means <10 μg/mL), (2) alanine aminotransferase (ALT) level was normal or clearly improving, and (3) the patient was clinically well. They point out that an advantage of this goal-oriented therapy is that it can be used in all situations: acute overdose, repeated (chronic) supratherapeutic ingestion, unknown time of ingestion, and cases where the pattern of ingestion is not known. Although this protocol has not been tested in a large prospective controlled study, there is no reason to think it would not be safe and effective, and every reason to believe it would drastically simplify the approach to these cases. Recently, Betten et al. reported good outcomes in a series of more than 200 patients with potentially toxic acute APAP ingestions treated with oral NAC for at least 20 hours.10 After this time, treatment was stopped if serum APAP was less than 10 μg/mL and liver enzymes and coagulation studies were normal. However, only five of these patients were ≤5 years of age.
Intravenous NAC had been used for decades in Europe and Canada to treat APAP toxicity. Finally, in 2004, the Food and Drug Administration approved IV NAC for use in the United States. (Acetadote, Cumberland Pharmaceuticals). After Acetadote was marketed in the United States, it became apparent that the recommended procedure for administering the product had two problems. First, the suggested interval for infusing the loading dose (15 minutes) caused an increased risk for anaphylactoid reactions. Second, the suggested method for diluting the supplied 20% NAC resulted in small children receiving excessive free water, risking hyponatremia and seizures. In February 2006, the package insert was revised to minimize these risks (Table 108–1).
Table 108-1. Acetylcysteine Dosage Guidelines Pediatric (Weight <40 kg) |Favorite Table|Download (.pdf)
Table 108-1. Acetylcysteine Dosage Guidelines Pediatric (Weight <40 kg)
Indications for the use of IV NAC include inability to tolerate oral NAC, intractable vomiting that does not respond to antiemetics, intestinal pathology (such as bowel obstruction or GI bleeding), encephalopathy, and neonatal acetaminophen toxicity secondary to maternal overdose. Some physicians prefer the IV preparation in almost all circumstances. With the 21-hour IV protocol, abbreviated treatment options are not necessary. However, in some cases treatment with NAC may have to be extended beyond 21 hours. White and Liebelt proposed a reasonable protocol for treating acute APAP overdose with IV NAC:
Draw acetaminophen level and plot on Rumack-Matthew nomogram.
If APAP level falls above the “possible toxicity” line, begin therapy with NAC.
Draw AST/ALT, PT/INR, electrolytes, BUN, creatinine, and CBC.
At the end of the infusion, draw PT/INR, AST/ALT, BUN/ creatinine. If any of laboratory results are abnormal, infusion should be continued at a rate of 6.3 mg/kg/h until liver function improves (Note: this is equivalent to 100 mg/kg over 16 hours).
Consult with medical toxicologist regarding duration of therapy.
If the patient develops hepatic injury/failure secondary to acetaminophen, NAC therapy should be continued until liver function and/or clinical status improves.11
Adverse reactions to IV NAC—which usually occur during administration of the loading dose—are generally anaphylactoid and include rash, itching, and wheezing. These will often resolve if the infusion is temporarily suspended and the patient treated with an antihistamine. Very rarely life-threatening reactions have been reported in children with preexisting asthma. When considering the use of IV NAC, it is good practice to seek toxicology consultation through the local poison center.
An asymptomatic patient whose APAP level falls below the “possible toxicity” line on the Rumack-Matthew nomogram can be medically cleared, but should not be discharged home until appropriate interventions have been accomplished. These may include psychiatric assessment in the case of suicidal gesture or attempt, social service consultation for suspected abuse, or counseling of parents or caregivers about the principles of poison prevention. If the APAP level is above the “possible toxicity” line, the patient should be admitted for treatment with NAC.
Asymptomatic patients with suspected chronic APAP overdose can be medically cleared if their liver enzymes are normal and APAP levels essentially undetectable. Any patient with evidence of fulminant hepatic failure (encephalopathy, hypoglycemia, coagulopathy, or acidosis) is admitted to intensive care. All patients whose exposure results from an attempt at self-harm need psychiatric evaluation and adequate suicide precautions.