Pediatric Acetaminophen Toxicity Workup

Chronic acetaminophen (APAP) toxicity has been recognized in pediatric patients. This condition occurrs in young, febrile children with reduced oral intake who were treated with repeated doses of acetaminophen (APAP).

In chronic acetaminophen (APAP) toxicity, the importance of fasting, reduced glutathione stores, and enhanced metabolism is unclear. Risk factors for chronic acetaminophen (APAP) toxicity include sustained administration of high doses, fever, poor oral intake, and young age. The daily dose of acetaminophen (APAP) for children should not exceed 80 mg/kg/d.

The Rumack-Matthew nomogram was developed for single acute exposures for acetaminophen (APAP) and should not be used to evaluate chronic exposures. Elevated values on liver function testing are better than nomographic measures as predictors of toxicity.

Diagnosing chronic acetaminophen (APAP) toxicity can be difficult, because the patient's presentation may appear to reflect the initial illness. In these situations, consider consulting a poison control center or a medical toxicologist in regard to management strategies.

Laboratory tests to consider

If mental status changes or clinical signs of encephalopathy are noted, obtain serum ammonia levels (an arterial sample is best).

Assess for pancreatic injury by obtaining lipase and amylase levels, especially if the patient has evidence of clinically significant hepatotoxicity and complaints of severe abdominal pain.

Hepatic injury can cause coagulopathy; hence, blood products may be needed. Typing, cross-matching, and antibody screening should be performed.

Order a quantitative pregnancy test (serum level of human chorionic gonadotropin) in all women of childbearing age. Acetaminophen (APAP) crosses the placental barrier. Delayed antidotal treatment in pregnant women has been associated with fetal loss.

Check the salicylate serum level to address concern for co-ingestants and the potential need to initiate medical care for salicylate poisoning.

Radiologic studies

In some circumstances, imaging studies may be helpful.

Computed tomography (CT) scanning of the head is indicated for patients who present with or who develop altered mental status or encephalopathy. Encephalopathy due to cerebral edema occurs in the late clinical presentation of acetaminophen overdose (stage 3 or 4) and is detectable on CT scanning. Additional neuroimaging with MRI may be indicated to further define cerebral changes.

Ultrasonography is helpful in defining hepatic and/or renal abnormalities as well as in assessing for involvement of other abdominal organs.

The modified Rumack-Matthew nomogram, or the acetaminophen (APAP) toxicity nomogram, is used to interpret acetaminophen (APAP) values to assess hepatotoxicity risk in patients. It was initially developed for single, acute ingestions of acetaminophen (APAP) and is based on observational data from patients who overdosed and who did not receive antidote therapy.

The nomogram predicts the risk of hepatotoxicity at a single level in time. It does not predict fulminant hepatic failure or death.

Nomogram tracking begins 4 hours after ingestion and ends 24 hours after ingestion.

The upper line of the nomogram is the probable line. About 60% of patients with values above this line develop hepatotoxicity. The lower line is the possible line, which was added to the nomogram to give a 25% margin of error to allow for variations in measurements of the acetaminophen (APAP) level or for uncertainty regarding the time of ingestion.

The nomogram cannot be used if the patient has a delayed presentation of more than 24 hours after ingestion or a history of multiple N -acetyl-p -aminophenol (APAP) ingestions. Its reliability also decreases for ingestions involving extended-release acetaminophen (APAP) tablets or for co-ingestions of acetaminophen (APAP) with anticholinergics or opioids.

Obtain a plasma acetaminophen (APAP) level in patients who have a history of a potentially toxic ingestion, who ingested an unknown amount of acetaminophen (APAP), who have altered mental status, or who have attempted suicide.

Routine assessment of acetaminophen (APAP) levels is controversial, but it is recommended because deaths from occult overdoses with this drug have occurred.

Negligible acetaminophen (APAP) values from an ingestion occurring within 4 hours can be used to rule out hepatotoxicity.

Any serum concentration based on a sample drawn 4 hours or longer after a single ingestion may be plotted on an acetaminophen (APAP) toxicity nomogram (Rumack-Matthew nomogram) to estimate the risk of hepatotoxicity.

Hepatic transaminase levels start to rise within 24 hours after ingestion (stage 1) and peak 48-72 hours after ingestion (stage 2). In severe overdose, transaminase elevation can be detected as early as 12-16 hours after ingestion.

Evidence of hepatic injury due to acetaminophen (APAP) overdose is defined by elevation of the plasma transaminase values of more than 1000 IU/L. A rapid progression of transaminase values to 3000 IU/L or higher reflects worsening hepatotoxicity.

Additional serum measurements of hepatic function include glucose, prothrombin time (PT) and bilirubin may be useful.

Renal function tests of electrolyte, blood urea nitrogen (BUN), and creatinine levels can reveal evidence of renal failure, which often occurs with hepatic failure. Urinalysis to check for proteinuria and hematuria helps in diagnosing acute tubular necrosis (ATN) that can also occur in this clinical setting. Renal injury becomes apparent 2-3 days after an acute acetaminophen (APAP) ingestion (stage 2). Although renal failure is rare, it can occur independent of hepatic failure.

Patients who reach stage 4 hepatotoxicity have hepatic histiologic changes. These changes can range from cytolysis to centrilobular necrosis. Centrilobular involvement is seen due to the increased concentration of CYP2E1 enzymes in these cells, a site of maximal N -acetyl-benzoquinoneimine (NAPQI) production. Improvement and recovery of these histiologic changes takes longer than clinical recovery (about 3 mo).