Pediatric Acetaminophen Toxicity Treatment & Management

Treatment for acetaminophen (APAP) overdose with antidotal therapy must be managed on an inpatient basis.

Consultations

A medical toxicologist or a regional poison control center may be helpful in treating patients with possible co-ingestions, complicated histories, or atypical presentations.

Consultation with a hospital-based pediatric gastroenterologist affiliated with a transplant center is needed for patients who have signs of clinically significant hepatotoxicity.

If the ingestion is due to an attempt to harm oneself, psychosocial and/or psychiatric evaluation is indicated.

Delayed presentation of an acute single ingestion of APAP

Until recently, the standard of care for acetaminophen (APAP) overdose management in the United States was administration of N- acetylcysteine (NAC) to patients who presented within but not later than 24 hours after ingestion. Data from England suggest that NAC may be beneficial for acetaminophen (APAP)-induced hepatic failure when patients present more than 24 hours after ingestion.

To date, there are no known clinical studies conducted to evaluate the use of NAC in patients who present late with hepatotoxicity but without signs of hepatic failure. However, the approach of the medical community (hepatologists, toxicologists) is that NAC can be initiated at any stage after a toxic acetaminophen exposure if there is evidence of hepatotoxicity. NAC seems to benefit any stage of hepatotoxicity status post ingestion due to its multiple mechanisms of action, namely glutathione regeneration; antioxidant capability; and aiding with hepatic circulation. Studies have shown the maximal effect of NAC is up to 8-10 hours post ingestion; however, due to the benign nature of this antidote as related to adverse effects and the potential for overall greater benefit with minimal risk, its use is not restricted to timing status post ingestion.

Medical toxicologists recommend treatment with NAC in patients who present more than 24 hours after ingestion, if unmetabolized acetaminophen (APAP) is detected in the serum and if hepatic injury is evident. Laboratory findings of hepatic injury or impaired hepatic function include increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, elevated total bilirubin values, and prolonged prothrombin times (PTs).

Continuation of NAC therapy is based on the patient's clinical status, on detectable serum values of acetaminophen (APAP), and liver function (PT and ALT, AST, total bilirubin levels). The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide medical management in these cases.

The beneficial effect of NAC in late treatment when liver damage has occurred suggests that additional repair mechanisms may be present. Proposed mechanisms of NAC in this setting include an antioxidant effect, decreased neutrophil accumulation, and improved microcirculatory blood flow with increased oxygen delivery to hepatic tissue.

Surgical intervention

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include metabolic acidosis, renal failure, coagulopathy, and encephalopathy.

Initial appropriate supportive care is essential in acetaminophen (APAP) poisoning. Immediate assessment of the patient's airway, breathing, and fluid status (ie, ABCs) is critical before treatment for suspected acetaminophen (APAP) overdose is started. In addition, assessing for other potential life-threatening co-ingestions (eg, salicylate) is important.

Admit patients with acetaminophen (APAP) levels above the possible line on the Rumack-Matthew nomogram for treatment with N -acetylcysteine (NAC). Treat patients with evidence of hepatic failure, metabolic acidosis, encephalopathy, or coagulopathy in an intensive care unit (ICU).

Transfer patients with evidence of clinically significant hepatotoxicity to a hospital with intensive care support and organ transplant services.

GI decontamination

Consider gastrointestinal (GI) decontamination with activated charcoal in any patient who presents within 4 hours of ingestion. Consider gastric lavage if ingestion occurred within 1 hour of evaluation. Protecting the patient’s airway is critical with these procedures.

Oral N-acetylcysteine (Mucomyst)

The antidote for acetaminophen (APAP) toxicity is N -acetylcysteine (NAC), which has several mechanisms to prevent hepatotoxicity. The oral formulation is the drug of choice for the treatment of acute, chronic, or late-presenting acetaminophen ingestions.

NAC is converted to cysteine, which replenishes glutathione stores, as well as directly detoxifies N -acetyl-benzoquinoneimine (NAPQI) to nontoxic metabolites. This agent provides a substrate for sulfation, increasing the capacity for nontoxic metabolism, and can directly conjugate to NAPQI to reduce toxicity.

A national multicenter study revealed that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion.^[8] Treatment with oral NAC effectively prevented hepatotoxicity, regardless of the initial plasma acetaminophen level, if it was started within 8 hours of the ingestion. Its effectiveness did not depend on whether NAC was started 0-4 or 4-8 hours after ingestion.^[8]

Intravenous N-acetylcysteine (Acetadote)

In 2004, the US Food and Drug Administration (FDA) approved an intravenous (IV) formulation of N -acetylcysteine(NAC) for use in adults. In February 2006, this FDA approval was modified to include children (patients < 40 kg).

IV administration of NAC is recommended for use in selected patients, including those with an altered mental status, GI bleeding and/or obstruction or a history of caustic ingestion, potential fetal toxicity from maternal toxicity, or an inability to tolerate oral NAC because of refractory emesis despite proper use of antiemetics.

Pharmaceutical guidelines for IV NAC administration differ depending on the patient's body weight and/or on whether the ingestion is acute or chronic. Guidelines for IV dosage and administration are discussed in Medications.

Adverse side effects associated with the IV administration include flushing, pruritus, and a rash (seen in about 15% of patients). These side effects are remedied by stopping the infusion, administering an antihistamine, and restarting this antidote at a slower infusion rate. Bronchospasm and hypotension can occur; however these effects are rare (< 2% of patients).