Acute Care

Guest Editor: H. Ralph Schumacher, Jr, MD
Professor of Medicine University of Pennsylvania School of Medicine, Philadelphia

Case Presentation
An 8-year-old boy was brought by his father to the emergency department at 6 am. The boy was complaining of abdominal pain, which had woken him from sleep at 3 am. The pain was reported as 8 on a scale of 1 to 10. It originated at the umbilicus and radiated to the right-lower quadrant. The boy had not had nausea, diarrhea, or emesis, but he did have constipation associated with tenesmus for about 1 week.

Review of systems revealed that he had been having oral pain for the past 9 days since a bicycle accident, in which he had fractured his maxilla and several teeth. Because of the pain, he had been eating only mashed potatoes and grits. His father said that the boy had not required narcotics for analgesia. In addition, he had not needed acetaminophen for several days, because the pain had been decreasing. The boy had been mildly constipated for several months and had a hard bowel movement every few days. His medical history was significant only for mild intermittent asthma. He was using albuterol on an as-needed basis.

Physical examination revealed an afebrile, well-hydrated child who was curled up into a fetal position, moaning in pain. His weight was 28.6 kg. Examination of the head, eyes, ears, nose, and throat was remarkable only for an upper dental fixator. His abdomen was distended and extremely tender, particularly on the right. Bowel sounds were present. The rest of the examination was unremarkable. He was transferred to a pediatric hospital for surgical consultation.

In the pediatric emergency department, an abdominal radiograph, computed tomography (CT) scan, and blood tests were ordered. The radiograph revealed a large amount of stool in the colon. After an enema, he had a bowel movement, and the pain resolved. He then had 3 more bowel movements, after which he and his father left the hospital, against medical advice, before the CT scan could be performed.

Laboratory test results revealed elevated serum transaminase levels (Table 1: 6:45 am). The father was contacted and asked to bring the boy back to the hospital.

Upon returning to the hospital the boy had no complaints. Repeat physical examination revealed only mild right subcostal tenderness, with no rebound tenderness. Results of repeat liver function tests showed increased elevation of transaminase levels (Table 1: 5:30 pm). The child was admitted to the hospital for observation and was started on intravenous fluids at half-maintenance levels. He was given a clear liquid diet and polyethylene glycol (PEG) solution.

The discrepancy between the boy’s clinical recovery and his worsening liver function generated significant discussion. Viral hepatitis seemed quite unlikely, given the lack of nausea and the rapid recovery. Pancreatitis was excluded by normal pancreatic enzyme levels and biliary obstruction by normal serum bilirubin levels. One of the treating physicians had seen adults with severe postoperative constipation and moderately elevated serum transaminase levels, but this seemed an unlikely cause of such severe transaminase elevations, particularly as the constipation and abdominal pain had resolved while the transaminase levels continued to rise.

The history and physical examination were repeated. Physical examination results remained benign; he still had mild right subcostal tenderness but a normal liver span of 11.5 cm. The child said that he had not taken any medications on his own, and there did not seem to be any available to him in the home. His father was quite certain that he had given the last dose of acetaminophen 2 days earlier, and he described an appropriate dose and frequency. The child was not taking any other medications that might contain acetaminophen. A determination of serum acetaminophen level was ordered.

The serum transaminase levels had somewhat decreased compared with those from a sample taken at 5:30 pm, but the serum acetaminophen level was 11.3 µg/mL (Table 2: Day 1, 9:38 pm). The father was interviewed again and continued to insist that he had not given his son acetaminophen for at least 2 days. The boy’s mother was then called. Although each parent was adamant about not giving the child acetaminophen for at least 2 days, it seemed that they had each been giving him acetaminophen before that, without consideration of the last dose given by the other parent. It was not possible to determine the dose.

The experts at the local poison control center were consulted. They opined that since the child’s transaminase levels were decreasing, the prothrombin time was normal, and the last dose of acetaminophen was given 2 days ago, N-acetylcysteine (NAC) was not immediately required, although they left the final decision up to the treating physicians. Because the transaminase levels were improving at the time the high serum acetaminophen level was discovered, the decision was made not to administer NAC.

The next morning the boy still felt and appeared well, the results of an examination were normal, his transaminase levels were further decreased, and his acetaminophen level was negligible (Table 2: Day 2, 7:30 am). Hepatitis serology results were negative. The boy was discharged, his parents were told to give him PEG powder (MiraLax) twice daily, and repeat liver function tests were scheduled in 3 days.

A review of the records of the boy’s trauma admission obtained after his discharge revealed he had sustained fractures of the left maxilla, right nasal bone, and teeth. His discharge medications had been oral clindamycin (Cleocin), 360 mg every 8 hours (37.5 mg/kg daily); acetaminophen, 540 mg every 4 hours as needed (113 mg/kg daily); and ibuprofen, 300 mg every 6 hours as needed (42 mg/kg daily).

Discussion
Acetaminophen toxicity can result from a single excessive dose or long-term overdosing. In 2003, the deaths of 11 children under the age of 18 years were attributed, at least in part, to acetaminophen.¹ Three of these were intentional suicides by teenagers.¹ The remaining 8 all involved children aged 5 years or younger; 5 were determined to be therapeutic errors, and the reasons for the other 3 were not known.¹ Accidental overdosage in children has been associated with an age of less than 10 years and unintentional multiple dosing, both of which were features of this case. Other factors associated with accidental acetaminophen overdosage in children include use of multiple acetaminophen-containing preparations, lack of adult supervision of medication administration, and the use of adult rather than pediatric preparations.^2,3

When acetaminophen toxicity is suspected after a single dose, the Rumack-Matthew nomogram may be used to determine the risk of hepatotoxicity.⁴ Generally, a single dose of 120 to 150 mg/kg is considered hepatotoxic in children.⁵ The nomogram, however, does not apply to long-term overdosing, as was suspected in this case. Many authors feel that the hepatic metabolism of acetaminophen decreases with progressive hepatotoxicity, thus resulting in higher serum acetamin­­ophen levels from multiple doses than would be expected from a single large dose.^2,6,7 One study showed that the Rumack-Matthew nomogram only applied to 17% of patients with significant hepatic injury caused by acetaminophen, not to the 83% who had taken multiple doses.⁸

In the case reported here, for example, roughly extrapolating from a standard nomogram4 and pharmacokinetic data,⁹ the acetaminophen level of 11.3 µg/mL correlated with a single dose of 9000 mg/kg 2 days earlier, which was clearly unrealistic.

Exactly how much acetaminophen the boy had received and when could not be determined. He apparently received generous doses of acetaminophen (19 mg/kg each dose, which at appropriate dosing intervals would correspond to 113 mg/kg daily) at perhaps as much as twice the recommended frequency for several days. He had also been prescribed clindamycin, which could occasionally cause jaundice and elevated liver function test results.¹⁰ Although there are no literature suggesting that clindamycin prolongs the half-life of acetaminophen, as it is generally believed that hepatotoxicity reduces the clearance of acetaminophen, this is also a theoretical possibility.

The ultimate natural history of acetaminophen hepatotoxicity is either fulminant hepatic failure or complete recovery. Fulminant failure is associated with extremely high transaminase levels, frequently more than 10,000 U/L.^3,11 Despite a relatively high acetaminophen level, because our patient’s transaminase levels were not extremely high and were in fact decreasing with the third set of laboratory reports, it was decided to follow his transaminase and acetaminophen levels and not administer NAC.

In 2003, more than 120,000 calls were made to poison control centers regarding acetaminophen exposure in children aged 19 years or younger, of whom more than 65,000 were admitted to the hospital.¹

Of note, this child’s constipation, which had originally brought him to the emergency department, turned out to be a red herring. More than 97% of acetaminophen is absorbed within 2 hours in healthy individuals⁹; constipation has not been associated in the medical literature with acetaminophen toxicity. In this case, the association was incidental. Exacerbation of the boy’s chronic constipation seemed to be the result of his soft diet, and both the soft diet and acetaminophen ingestion were thought to be caused by his mouth pain.

Conclusion
This case highlights the particular vulnerability of young children to accidental overdosage and emphasizes the inapplicability of the Rumack-Matthew nomogram to long-term overdosage. In addition, this case demonstrates that acetaminophen toxicity must be suspected whenever elevated transaminase levels cannot be entirely explained by some other cause. In fact, even if some other pathology—such as, in this case, constipation so severe that it presented as an acute abdomen—partially explains the clinical scenario, a check of the serum acetaminophen level is warranted. Whereas this boy did well with observation only, if his transaminase levels had risen, he would have required NAC to prevent hepatic failure. And if his elevated transaminase levels had been dismissed, he could have had a far worse outcome.

References
1. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004;22:335-404.

2. Rivera Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr. 1997;130: 300-304.

3. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children. J Pediatr. 1998;132: 22-27.

4. Rumack BH, Peterson RC, Koch GC, et al. Acetaminophen overdose. 662 cases with oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385.

5. American Academy of Pediatrics. Committee on Drugs. Acetaminophen toxicity in children. Pediatrics. 2001;108:1020-1024.

6. Anderson BJ, Holford NH, Armishaw JC, et al. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr. 1999;135:290-295.

7. Schiødt FV, Ott P, Christensen E, et al. The value of plasma acetaminophen half life in antidote treated acetaminophen overdosage. Clin Pharmacol Ther. 2002;71:221-225.

8. Bond GR, Hite LK. Population based incidence and outcome of acetaminophen poisoning by type of ingestion. Acad Emerg Med. 1999;6:1115-1120.

9. Rose SR, Gorman RL, Oderda GM, et al. Simulated acetaminophen overdose: pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med. 1991;20:1064-1068.

10. PDR.net. Cleocin phosphate. Available at www.pdr.net.

11. Schiødt FV, Lee WM. Fulminant liver disease. Clin Liver Dis. 2003;7:331-349, vi.

Commentary

Acetaminophen (N-acetyl-p-aminophenol) is the most common cause of pharmaceutical poisoning each year, both in children and in adults.¹ While single acute overdoses with suicidal intent are common in adults and adolescents, the scenario of repeated therapeutic dosing because of parental error is unfortunately common in young children.¹

Acetaminophen is remarkably free of toxicity when dosed appropriately and is therefore one of the safest drugs available. Excess intake, however, overwhelms the normal metabolism of acetaminophen. Under typical conditions, acetaminophen is metabolized to nontoxic excretable metabolites. In overdose, however, the cytochrome (CY) P450 enzyme system predominates, generating the toxic metabolite N-acetyl-p-benzoquinoneamine (NAPQI), which leads to free-radical–mediated tissue damage in the liver, as well as in other organ systems. Cellular glutathione, one of the body’s endogenous antioxidant systems, detoxifies NAPQI somewhat but is soon outstripped, so further tissue damage ensues.²

N-acetylcysteine (NAC) therapy acts at a number of points along this metabolic cascade. Early in the course, NAC inhibits CYP450-mediated generation of NAPQI. It donates a sulfur moiety to replete cellular glutathione, thus restoring the body’s own antioxidant stores. It detoxifies NAPQI directly to excretable metabolites. Finally, NAC has general antioxidant properties, which can not only prevent hepatic and other tissue injury but can also repair an already damaged tissue. For this reason, NAC can be beneficial not only in various stages of acetaminophen toxicity but also in other free-radical–mediated disease states, such as hepatic failure from other causes.²

In this case report, NAC therapy was not instituted because of the falling hepatic transaminase levels. This highlights a highly complex issue in the management of acetaminophen poisoning. NAC is of undisputed benefit in acute overdoses of over 150 mg/kg, when a 4-hour serum acetaminophen level is 150 µg/mL or greater; this is referred to as the “rule of 150s” for acetaminophen toxicity. As discussed, the Rumack-Matthew nomogram is a highly sensitive tool for predicting hepatotoxicity in an acute single overdose.³ However, the complex toxicodynamics and heterogenous exposure history of repeated supratherapeutic dosing are not so easily evaluated by the nomogram.

In patients for whom the nomogram is not applicable, it is helpful to establish whether there is either (1) remaining acetaminophen that may be further metabolized with toxic effect or (2) potentially serious liver injury (indicated by elevated transaminase levels). NAC therapy has been shown to be effective even in the late stages of acetaminophen toxicity. A safe practice in these complex situations is to institute NAC, a relatively benign therapy, until the transaminase values have returned to normal, the acetaminophen level has fallen to nondetectable levels, and 36 hours have passed since the last dose.

In many cases, as in this one, patients with mild transaminase level elevations will recover without therapy. However, the current recommendation is to institute NAC in these patients if (1) there are symptoms with any elevation in aspartate aminotransferase (AST); (2) the AST level is greater than twice normal; or (3) the AST level is elevated, and the acetaminophen level is greater than 10 µg/mL.² The patient in this case meets at least 2 of these criteria.

Because these are complex situations requiring individualized management, consultation with the local poison control center or a toxicologist is recommended.

Editor’s note: In this particular case, the local poison control center was contacted, and it recommended against NAC administration.

References
1. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004;22:335-404.

2. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Goldfrank LG, Flomenbaum NE, Lewin NA, et al, eds. Goldfrank’s Toxicologic Emergencies. 7th ed. New York, NY: McGraw-Hill; 2002: 480-506.

3. Rumack BH, Peterson RG. Acetaminophen overdose: incidence, diagnosis and management in 416 patients. Pediatrics. 1978;62:898-903.