Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Aug;32(2):143–149. doi: 10.1111/j.1365-2125.1991.tb03873.x

Paracetamol poisoning in children and hepatotoxicity.

A Penna 1, N Buchanan 1
PMCID: PMC1368435  PMID: 1931463

Abstract

1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re-evaluate the safety of paracetamol in the context of chronic therapy in infants and young children.

Full text

PDF
143

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson G. M., Harman A. W. A role for the glutathione peroxidase/reductase enzyme system in the protection from paracetamol toxicity in isolated mouse hepatocytes. Biochem Pharmacol. 1989 Oct 1;38(19):3323–3330. doi: 10.1016/0006-2952(89)90630-8. [DOI] [PubMed] [Google Scholar]
  2. Agran P. F., Zenk K. E., Romansky S. G. Acute liver failure and encephalopathy in a 15-month-old infant. Am J Dis Child. 1983 Nov;137(11):1107–1114. doi: 10.1001/archpedi.1983.02140370067022. [DOI] [PubMed] [Google Scholar]
  3. Aguilar M. I., Hart S. J., Calder I. C. Complete separation of urinary metabolites of paracetamol and substituted paracetamols by reversed-phase ion-pair high-performance liquid chromatography. J Chromatogr. 1988 Apr 29;426(2):315–333. doi: 10.1016/s0378-4347(00)81959-3. [DOI] [PubMed] [Google Scholar]
  4. Alam S. N., Roberts R. J., Fischer L. J. Age-related differences in salicylamide and acetaminophen conjugation in man. J Pediatr. 1977 Jan;90(1):130–135. doi: 10.1016/s0022-3476(77)80787-7. [DOI] [PubMed] [Google Scholar]
  5. Arena J. M., Rourk M. H., Jr, Sibrack C. D. Acetaminophen: report of an unusual poisoning. Pediatrics. 1978 Jan;61(1):68–72. [PubMed] [Google Scholar]
  6. Benson G. D. Hepatotoxicity following the therapeutic use of antipyretic analgesics. Am J Med. 1983 Nov 14;75(5A):85–93. doi: 10.1016/0002-9343(83)90237-1. [DOI] [PubMed] [Google Scholar]
  7. Blake K. V., Bailey D., Zientek G. M., Hendeles L. Death of a child associated with multiple overdoses of acetaminophen. Clin Pharm. 1988 May;7(5):391–397. [PubMed] [Google Scholar]
  8. Calvert L. J., Linder C. W. Acetaminophen poisoning. J Fam Pract. 1978 Nov;7(5):953–956. [PubMed] [Google Scholar]
  9. Clark J. H., Russell G. J., Fitzgerald J. F. Fatal acetaminophen toxicity in a 2-year-old. J Indiana State Med Assoc. 1983 Dec;76(12):832–835. [PubMed] [Google Scholar]
  10. Clements J. A., Critchley J. A., Prescott L. F. The role of sulphate conjugation in the metabolism and disposition of oral and intravenous paracetamol in man. Br J Clin Pharmacol. 1984 Oct;18(4):481–485. doi: 10.1111/j.1365-2125.1984.tb02495.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Critchley J. A., Nimmo G. R., Gregson C. A., Woolhouse N. M., Prescott L. F. Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol. 1986 Dec;22(6):649–657. doi: 10.1111/j.1365-2125.1986.tb02953.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cummings A. J., King M. L., Martin B. K. A kinetic study of drug elimination: the excretion of paracetamol and its metabolites in man. Br J Pharmacol Chemother. 1967 Feb;29(2):150–157. doi: 10.1111/j.1476-5381.1967.tb01948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Davidson D. G., Eastham W. N. Acute liver necrosis following overdose of paracetamol. Br Med J. 1966 Aug 27;2(5512):497–499. doi: 10.1136/bmj.2.5512.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Davis M. Protective agents for acetaminophen overdose. Semin Liver Dis. 1986 May;6(2):138–147. doi: 10.1055/s-2008-1040597. [DOI] [PubMed] [Google Scholar]
  15. Davis M., Simmons C. J., Harrison N. G., Williams R. Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage. Q J Med. 1976 Apr;45(178):181–191. [PubMed] [Google Scholar]
  16. Dawson A. H., Henry D. A., McEwen J. Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust. 1989 Mar 20;150(6):329–331. doi: 10.5694/j.1326-5377.1989.tb136496.x. [DOI] [PubMed] [Google Scholar]
  17. De Nardo V., Lapadula G., Soligno O. Danno epatico e morte di una bambina di tre anni per intossicazione da paracetamolo. Minerva Pediatr. 1988 Sep;40(9):571–571. [PubMed] [Google Scholar]
  18. Flanagan R. J. The role of acetylcysteine in clinical toxicology. Med Toxicol. 1987 Mar-Apr;2(2):93–104. doi: 10.1007/BF03260008. [DOI] [PubMed] [Google Scholar]
  19. Frank O. R., Coulthard K. P. Paracetamol for fever in children. Aust Fam Physician. 1988 Sep;17(9):771–771. [PubMed] [Google Scholar]
  20. Galinsky R. E., Levy G. Dose- and time-dependent elimination of acetaminophen in rats: pharmacokinetic implications of cosubstrate depletion. J Pharmacol Exp Ther. 1981 Oct;219(1):14–20. [PubMed] [Google Scholar]
  21. Greene J. W., Craft L., Ghishan F. Acetaminophen poisoning in infancy. Am J Dis Child. 1983 Apr;137(4):386–387. doi: 10.1001/archpedi.1983.02140300064018. [DOI] [PubMed] [Google Scholar]
  22. Hendrix-Treacy S., Wallace S. M., Hindmarsh K. W., Wyant G. M., Danilkewich A. The effect of acetaminophen administration on its disposition and body stores of sulphate. Eur J Clin Pharmacol. 1986;30(3):273–278. doi: 10.1007/BF00541527. [DOI] [PubMed] [Google Scholar]
  23. Henretig F. M., Selbst S. M., Forrest C., Kearney T. K., Orel H., Werner S., Williams T. A. Repeated acetaminophen overdosing. Causing hepatotoxicity in children. Clinical reports and literature review. Clin Pediatr (Phila) 1989 Nov;28(11):525–528. doi: 10.1177/000992288902801107. [DOI] [PubMed] [Google Scholar]
  24. Hickson G. B., Altemeier W. A., Martin E. D., Campbell P. W. Parental administration of chemical agents: a cause of apparent life-threatening events. Pediatrics. 1989 May;83(5):772–776. [PubMed] [Google Scholar]
  25. Hickson G. B., Greene J. W., Ghishan F. K., Craft L. T. Apparent intentional poisoning of an infant with acetaminophen. Am J Dis Child. 1983 Sep;137(9):917–917. doi: 10.1001/archpedi.1983.02140350089025. [DOI] [PubMed] [Google Scholar]
  26. Jollow D. J., Mitchell J. R., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther. 1973 Oct;187(1):195–202. [PubMed] [Google Scholar]
  27. Klutch A., Levin W., Chang R. L., Vane F., Conney A. H. Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man. Clin Pharmacol Ther. 1978 Sep;24(3):287–293. doi: 10.1002/cpt1978243287. [DOI] [PubMed] [Google Scholar]
  28. Lauterburg B. H., Mitchell J. R. Therapeutic doses of acetaminophen stimulate the turnover of cysteine and glutathione in man. J Hepatol. 1987 Apr;4(2):206–211. doi: 10.1016/s0168-8278(87)80081-8. [DOI] [PubMed] [Google Scholar]
  29. Lauterburg B. H., Vaishnav Y., Stillwell W. G., Mitchell J. R. The effects of age and glutathione depletion on hepatic glutathione turnover in vivo determined by acetaminophen probe analysis. J Pharmacol Exp Ther. 1980 Apr;213(1):54–58. [PubMed] [Google Scholar]
  30. Lederman S., Fysh W. J., Tredger M., Gamsu H. R. Neonatal paracetamol poisoning: treatment by exchange transfusion. Arch Dis Child. 1983 Aug;58(8):631–633. doi: 10.1136/adc.58.8.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Levy G., Khanna N. N., Soda D. M., Tsuzuki O., Stern L. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics. 1975 Jun;55(6):818–825. [PubMed] [Google Scholar]
  32. Lieh-Lai M. W., Sarnaik A. P., Newton J. F., Miceli J. N., Fleischmann L. E., Hook J. B., Kauffman R. E. Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. J Pediatr. 1984 Jul;105(1):125–128. doi: 10.1016/s0022-3476(84)80376-5. [DOI] [PubMed] [Google Scholar]
  33. Mant T. G., Tempowski J. H., Volans G. N., Talbot J. C. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984 Jul 28;289(6439):217–219. doi: 10.1136/bmj.289.6439.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meredith T. J., Goulding R. Paracetamol. Postgrad Med J. 1980 Jul;56(657):459–473. doi: 10.1136/pgmj.56.657.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Meredith T. J., Newman B., Goulding R. Paracetamol poisoning in children. Br Med J. 1978 Aug 12;2(6135):478–479. doi: 10.1136/bmj.2.6135.478-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meredith T. J., Prescott L. F., Vale J. A. Why do patients still die from paracetamol poisoning? Br Med J (Clin Res Ed) 1986 Aug 9;293(6543):345–346. doi: 10.1136/bmj.293.6543.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miller R. P., Roberts R. J., Fischer L. J. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther. 1976 Mar;19(3):284–294. doi: 10.1002/cpt1976193284. [DOI] [PubMed] [Google Scholar]
  38. Mitchell J. R., Jollow D. J., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973 Oct;187(1):185–194. [PubMed] [Google Scholar]
  39. Mitchell J. R., Jollow D. J., Potter W. Z., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973 Oct;187(1):211–217. [PubMed] [Google Scholar]
  40. Mitchell J. R., Thorgeirsson S. S., Potter W. Z., Jollow D. J., Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974 Oct;16(4):676–684. doi: 10.1002/cpt1974164676. [DOI] [PubMed] [Google Scholar]
  41. Nahata M. C., Powell D. A., Durrell D. E., Miller M. A. Acetaminophen accumulation in pediatric patients after repeated therapeutic doses. Eur J Clin Pharmacol. 1984;27(1):57–59. [PubMed] [Google Scholar]
  42. Nogen A. G., Bremner J. E. Fatal acetaminophen overdosage in a young child. J Pediatr. 1978 May;92(5):832–833. doi: 10.1016/s0022-3476(78)80169-3. [DOI] [PubMed] [Google Scholar]
  43. Notarianni L. J., Oldham H. G., Bennett P. N. Passage of paracetamol into breast milk and its subsequent metabolism by the neonate. Br J Clin Pharmacol. 1987 Jul;24(1):63–67. doi: 10.1111/j.1365-2125.1987.tb03137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Peterson R. G. Antipyretics and analgesics in children. Dev Pharmacol Ther. 1985;8(1):68–84. doi: 10.1159/000457023. [DOI] [PubMed] [Google Scholar]
  45. Potter W. Z., Davis D. C., Mitchell J. R., Jollow D. J., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther. 1973 Oct;187(1):203–210. [PubMed] [Google Scholar]
  46. Prescott L. F. Effects of non-narcotic analgesics on the liver. Drugs. 1986;32 (Suppl 4):129–147. doi: 10.2165/00003495-198600324-00010. [DOI] [PubMed] [Google Scholar]
  47. Prescott L. F. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs. 1983 Mar;25(3):290–314. doi: 10.2165/00003495-198325030-00002. [DOI] [PubMed] [Google Scholar]
  48. Prescott L. F., Roscoe P., Wright N., Brown S. S. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet. 1971 Mar 13;1(7698):519–522. doi: 10.1016/s0140-6736(71)91125-1. [DOI] [PubMed] [Google Scholar]
  49. Prescott L. F., Sutherland G. R., Park J., Smith I. J., Proudfoot A. T. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Lancet. 1976 Jul 17;2(7977):109–113. doi: 10.1016/s0140-6736(76)92842-7. [DOI] [PubMed] [Google Scholar]
  50. Prescott L. F. Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Arch Intern Med. 1981 Feb 23;141(3 Spec No):386–389. doi: 10.1001/archinte.141.3.386. [DOI] [PubMed] [Google Scholar]
  51. Proudfoot A. T., Wright N. Acute paracetamol poisoning. Br Med J. 1970 Sep 5;3(5722):557–558. doi: 10.1136/bmj.3.5722.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Reicks M., Hathcock J. N. Prolonged acetaminophen ingestion in mice: effects on the availability of methionine for metabolic functions. J Nutr. 1989 Jul;119(7):1042–1049. doi: 10.1093/jn/119.7.1042. [DOI] [PubMed] [Google Scholar]
  53. Roberts I., Robinson M. J., Mughal M. Z., Ratcliffe J. G., Prescott L. F. Paracetamol metabolites in the neonate following maternal overdose. Br J Clin Pharmacol. 1984 Aug;18(2):201–206. doi: 10.1111/j.1365-2125.1984.tb02453.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Rollins D. E., von Bahr C., Glaumann H., Moldéus P., Rane A. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science. 1979 Sep 28;205(4413):1414–1416. doi: 10.1126/science.38505. [DOI] [PubMed] [Google Scholar]
  55. Rose P. G. Paracetamol overdose and liver damage. Br Med J. 1969 Feb 8;1(5640):381–382. doi: 10.1136/bmj.1.5640.381-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Rumack B. H. Acetaminophen overdose in young children. Treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child. 1984 May;138(5):428–433. doi: 10.1001/archpedi.1984.02140430006003. [DOI] [PubMed] [Google Scholar]
  57. Rumack B. H. Acetaminophen overdose. Am J Med. 1983 Nov 14;75(5A):104–112. doi: 10.1016/0002-9343(83)90240-1. [DOI] [PubMed] [Google Scholar]
  58. Rumack B. H., Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975 Jun;55(6):871–876. [PubMed] [Google Scholar]
  59. Rumack B. H., Peterson R. C., Koch G. G., Amara I. A. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981 Feb 23;141(3 Spec No):380–385. doi: 10.1001/archinte.141.3.380. [DOI] [PubMed] [Google Scholar]
  60. Slattery J. T., Levy G. Acetaminophen kinetics in acutely poisoned patients. Clin Pharmacol Ther. 1979 Feb;25(2):184–195. doi: 10.1002/cpt1979252184. [DOI] [PubMed] [Google Scholar]
  61. Slattery J. T., Wilson J. M., Kalhorn T. F., Nelson S. D. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther. 1987 Apr;41(4):413–418. doi: 10.1038/clpt.1987.50. [DOI] [PubMed] [Google Scholar]
  62. Smilkstein M. J., Knapp G. L., Kulig K. W., Rumack B. H. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) N Engl J Med. 1988 Dec 15;319(24):1557–1562. doi: 10.1056/NEJM198812153192401. [DOI] [PubMed] [Google Scholar]
  63. Smith D. W., Isakson G., Frankel L. R., Kerner J. A., Jr Hepatic failure following ingestion of multiple doses of acetaminophen in a young child. J Pediatr Gastroenterol Nutr. 1986 Sep-Oct;5(5):822–825. doi: 10.1097/00005176-198609000-00028. [DOI] [PubMed] [Google Scholar]
  64. Swetnam S. M., Florman A. L. Probable acetaminophen toxicity in an 18-month-old infant due to repeated overdosing. Clin Pediatr (Phila) 1984 Feb;23(2):104–105. doi: 10.1177/000992288402300208. [DOI] [PubMed] [Google Scholar]
  65. Temple A. R. Pediatric dosing of acetaminophen. Pediatr Pharmacol (New York) 1983;3(3-4):321–327. [PubMed] [Google Scholar]
  66. Thomson J. S., Prescott L. F. Liver damage and impaired glucose tolerance after paracetamol overdosage. Br Med J. 1966 Aug 27;2(5512):506–507. doi: 10.1136/bmj.2.5512.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Weber J. L., Cutz E. Liver failure in an infant. Can Med Assoc J. 1980 Jul 19;123(2):112–117. [PMC free article] [PubMed] [Google Scholar]
  68. Where to draw the line. Lancet. 1986 Oct 11;2(8511):849–849. [PubMed] [Google Scholar]
  69. Wilson J. T., Brown R. D., Bocchini J. A., Jr, Kearns G. L. Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children. Ther Drug Monit. 1982;4(2):147–180. doi: 10.1097/00007691-198206000-00003. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES