Case Commentary

An Acetaminophen Dosing Error in A Child  - Commentary

Barry H. Rumack, M.D.
University of Colorado School of Medicine and the Rocky Mountain Poison and Drug Center 
Daniel A. Spyker Ph.D., M.D.
Director of Clinical Pharmacology, Genentech South
San Francisco, CA.

Int J Med Toxicol 2003; 6(2):8


The only plasma level sought in this case was late in the course and was less than the lower limit of quantitation (10 mcg/mL). This value is therefore of little help in assessing exposure. However, we can calculate and plot the plasma level profile from the dose, patient characteristics and basic acetaminophen pharmacokinetics. The following graphs represents the two doses in this patient assuming a Vd of 1 L/kg, an absorption half-life of 0.5 hours and an elimination half-life of 2 hours.

Acetaminophen Kinetics, 700 mg @ 0 hr + 500 mg @ 7 hr, 14 kg patient

Peak plasma level (Cmax) would be about 31 mcg/mL following the first dose and 26 mcg/mL following the second dose. The green lines represent the nomogram utilized for acute overdose evaluation.1 The upper graph is linear and the lower graph is the more common log-linear.

Acetaminophen Pharmacology and Toxicity in the Pediatric Age Group:

Absorption:

Acetaminophen is available in various forms for administration to children, but in all forms the drug is rapidly and almost completely absorbed following oral administration. The absorption half-life ranges from 5 minutes for the elixir to 10 minutes for tablets.2,3 Peak plasma concentrations occur in approximately 3 absorption half-lives (30 to 60 minutes.4,5 One study demonstrated that the mean maximum plasma concentration following 5, 10 or 20 mg/kg all occurred at 30 minutes.6 Thus the absorption half-life has been generally accepted as no longer than 30 minutes.

Volume of distribution:

Volume of distribution has been measured in children and ranges from 0.86 L/kg to 1.0 L/kg in normal children. 7,8 Although the volume of distribution was reported to be as high as 1.34 L/kg in children with liver disease 9, it has generally been accepted as approximately 1 L/kg and this figure is used in most calculations.4

Elimination Half-life:

A wide range of disappearance half-lives of acetaminophen in children has been reported but recent studies have indicated a range of 111 minutes to 148 minutes.5,7,8 The half-life of 2 hours has been generally assumed in the absence of measured acetaminophen levels.4

Therapeutic dosing:

Therapeutic use of acetaminophen entails administration of sufficient quantities to attain a plasma level between 10 and 20 mcg/mL (10 to 20 mg/kg loading dose). Typical dosing regimens generally produce a level at or below this range. One study looked at children with a larger initial dosage of 30 mg/kg rather than the usual 10 - 15 mg/kg.5 Plasma levels were demonstrated in the 15-to 40-mcg/mL range at 30 minutes, which decreased to to 20 to 30 mcg/mL at one hour and then falling over the next few hours with half the patients below therapeutic levels. This study demonstrated a clear dose-response relationship between the acetaminophen dose and the anti-pyretic effect . Following 5 mg/kg the drop was less than 0.5 degrees centigrade, following 10 mg/kg the drop was 1.5 degrees centigrade and following 20 mg/kg the drop was 2.5 degrees centigrade.6 A dose of 12.4 mg/kg resulted in a drop in temperature but the plasma level barely reached 10 mcg/mL and had dropped to half this level by 3 hours.8

Metabolism and induction:

Metabolism of acetaminophen is primarily hepatic with sulfation and glucuronidation accounting for 94% of the metabolism. In children below the age of 12, sulfation is the predominant pathway whereas glucuronidation predominates in adults.10

Co-ingestion of other agents such as alcohol has not been shown to increase the toxicity in the pediatric age group.11 While there are data to suggest that simultaneous ingestion of ethanol in children is hepatoprotective, lethargy can result with large ethanol ingestions. 11

Hepatotoxicity:

In adults it is well established that hepatic damage corresponds to a 70% depletion of glutathione (12). Given an average 1.5-liter liver with 6 mmoles of glutathione, then 4.2 mmoles would have to be depleted to reach the threshold of toxicity. Since approximately 4% of a dose of acetaminophen is converted to NAPQI, we could calculate the dose of acetaminophen would be expected to produce toxicity. Since there is 151 mg/mmole of acetaminophen then (4.2)(151.2) / 0.04 equals 15.9 g, which would have to be absorbed in a 70 kg human to produce threshold toxicity (13). Further, 4% of 15.9 g results in 0.635 g of NAPQI produced assuming the same molecular weight.

It is believed that the young human would develop the same hepatotoxicity when 70% depletion occurs as well or may, in fact require higher doses (see below). Given that this child is 14Kg if the same hepatic ratio were maintained the child’s liver would be 0.3 liters containing 1.2 mmoles of glutathione. 70% of that would be 0.84mmoles. Multiplying (0.84) (151.2 /0.04 equals 3.18 grams required for threshold toxicity.

Adult and pediatric differences:

Children are believed to be resistant to acetaminophen compared to adults when compared on a mg/kg basis. While the direct benefit of having more sulfation than glucuronidation in children is not clear, the reduced concentration of CYP2E1 and the increased availability of glutathione may help explain the observed differences between children and adults. The maturation from the childhood to the adult pattern of hepatotoxicity following overdose of acetaminophen, occurs between, age 9 and 12.10 In the largest series of cases of acetaminophen overdose, the incidence of developing a toxic AST was 5.5% in children aged less than 6 years and 29% in adults.11 This difference was noted even though the plasma acetaminophen levels were considered toxic in both groups. Further data in that article showed no toxicity in 2,787 children under age 5. Typically, poison center protocols do not consider it necessary to evaluate a patient in the hospital unless the dose of acetaminophen exceeds 200 mg/Kg.14 This same report notes that there have been no deaths in 324,752 cases of childhood preparations reported to the American Association of Poison Control Centers.

Nutritional aspects:

Since glutathione plays such a central role in toxicity from acetaminophen it is worth exploring the production and metabolism of this tri-peptide. Immature animals have a higher turnover of glutathione reaching as much as 4 times that reported in older animals. It is postulated that this increase in rate of glutathione synthesis, as well as a capacity to increase glutathione levels after depletion, may explain relative hepato-protection in the young child.15 Analysis of LD 50 data in animals shows substantially higher levels of glutathione in young animals than in older animals.16 This provides a larger continuously available amount of glutathione available for detoxification. Additionally glutathione reductase and peroxidase levels are higher in hepatocytes of young mice.17

The importance of understanding these nutritional aspects is related to the concerns, which have been expressed regarding ill children with reduced food intake. While short term fasting may demonstrate certain metabolic changes such as development of ketones and acidosis this does not appear to affect metabolism of acetaminophen in children. In order to achieve the changes discussed above sustained reduction in food intake for more than 5 to 7 days is required. Much of the literature has been related to lack of food intake in chronic alcoholics, which is a case much different than a febrile acutely ill child. Studies in acute reduction of food in adults demonstrate no change in metabolism or toxicity of acetaminophen.18 There are no data to demonstrate any change in metabolism or toxicity related to an elevated temperature in a child.

Multiple ingestions:

There are published case reports of multiple overdose of acetaminophen in children producing hepatotoxicity. Those cases meeting reasonable quality criteria demonstrate an overdose well in excess of 100 mg/kg/day. Examining other cases of hepatotoxicity in children it is not possible to find a single documented case where a therapeutic dose produced hepatotoxicity. All cases, which have acceptable information regarding dose and plasma levels, have been at doses well in excess of therapeutic.

Conclusion:

This patient was either exposed to an additional hepatotoxin or, most likely, received substantially more acetaminophen than indicated in the history. The likely minimum toxic dose was in excess of 3 grams to achieve the observed toxicity, which is 4 to 5 times the dosage indicated in the history.

Reference List

  1. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55(6):871-876.
  2. Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose [see comments]. J Pediatr 1999; 135(3):290-295.
  3. Anderson BJ, Holford NH, Woollard GA, Kanagasundaram S, Mahadevan M. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90(2):411-421.
  4. Goodman LS, Gilman A, Hardman JG, Gilman AG, Limbird LE. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed ed. New York: McGraw-Hill, Health Professions Division, 1996.
  5. Peterson RG, Rumack BH. Age as a variable in acetaminophen overdose. Arch Intern Med 1981; 141(3 Spec No):390-393.
  6. Windorfer A, Vogel C. [Investigations concerning serum concentration and temperature following oral application of a new paracetamol preparation (author's transl)]. Klin Padiatr 1976; 188(5):430-434.
  7. Brown RD, Wilson JT, Kearns GL, Eichler VF, Johnson VA, Bertrand KM. Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. J Clin Pharmacol 1992; 32(3):231-241.
  8. Wilson JT, Brown RD, Bocchini JA, Jr., Kearns GL. Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children. Ther Drug Monit 1982; 4(2):147-180.
  9. al Obaidy SS, McKiernan PJ, Li Wan PA, Glasgow JF, Collier PS. Metabolism of paracetamol in children with chronic liver disease. Eur J Clin Pharmacol 1996; 50(1-2):69-76.
  10. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19(3):284-294.
  11. Rumack BH. Acetaminophen overdose in young children. Treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child 1984; 138(5):428-433.
  12. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 1973; 187(1):185-194.
  13. Rumack BH, Peterson RG. Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics 1978; 62(5 Pt 2 Suppl):898-903.
  14. Bond GR, Krenzelok EP, Normann SA, Tendler JD, Morris-Kukoski CL, McCoy DJ et al. Acetaminophen ingestion in childhood--cost and relative risk of alternative referral strategies. J Toxicol Clin Toxicol 1994; 32(5):513-525.
  15. Lauterburg BH, Vaishnav Y, Stillwell WG, Mitchell JR. The effects of age and glutathione depletion on hepatic glutathione turnover in vivo determined by acetaminophen probe analysis. J Pharmacol Exp Ther 1980; 213(1):54-58.
  16. Mancini RE, Sonawane BR, Yaffe SJ. Developmental susceptibility to acetaminophen toxicity. Res Commun Chem Pathol Pharmacol 1980; 27(3):603-606.
  17. Adamson GM, Harman AW. A role for the glutathione peroxidase/reductase enzyme system in the protection from paracetamol toxicity in isolated mouse hepatocytes. Biochem Pharmacol 1989; 38(19):3323-3330.
  18. Schenker S, Speeg KV, Jr., Perez A, Finch J. The effects of food restriction in man on hepatic metabolism of acetaminophen. Clin Nutr 2001; 20(2):145-150.

 



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