Therapeutic Acetaminophen Is Not Associated With Liver Injury in Children: A Systematic Review

Reynolds, Kate M.; Dart, Richard C.

doi:10.1542/peds.2009-3352

Cited by 40 publications

(30 citation statements)

References 79 publications

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“…Its safety in daily doses not exceeding 90 mg/kg (15 mg/kg every 4 hours) has been extensively supported (Lesko and Mitchell, 1999;Mohler et al, 2000;Muniz et al, 2004). This was validated by the systematic review from Lavonas et al (2010) that included 62 pediatric studies encompassing 32,414 patients receiving therapeutic doses of acetaminophen and found no cases of overt liver injury. In addition, the report of Pershad et al (1991) that described an 18-month-old child who received acetaminophen at a dose of 19.5 mg/kg at 4-hour intervals for 4 days and who subsequently developed hepatorenal failure has emphasized that a schedule exceeding the 90 mg/ kg threshold risks serious liver injury.…”

Section: Discussionmentioning

confidence: 93%

Acute Liver Failure following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity

Iorio

Cheerharan²,

Kaufman

et al. 2013

The Cleft Palate-Craniofacial Journal

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Background : Acetaminophen is a widely used analgesic and antipyretic agent in the pediatric population. While the hepatotoxic effects of the drug have been well recognized in cases of acute overdose and chronic supratherapeutic doses, the toxic effects of acetaminophen are rarely documented in cases where therapeutic guidelines are followed. Case : An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1. On day 3, the child was profoundly lethargic with multiple episodes of emesis and was taken to the emergency department. He suffered a 45-second tonic-clonic seizure in transport to the regional children's medical center, and initial laboratory results demonstrated acute hepatitis with AST 24,424 U/L, ALT 12,885 U/L, total bilirubin 3.1 mg/dL, and a serum acetaminophen level of 83 μg/mL. Aggressive supportive measures including blood products and periprocedural fresh frozen plasma, piperacillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. His metabolic acidosis and acute hepatitis began to correct by day 4, and he was discharged home without further surgical intervention on day 15. Conclusion : Although acetaminophen is an effective and commonly used analgesic in pediatric practice, hepatotoxicity is a potentially devastating complication. This report challenges the appropriateness of existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery.

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Section: Discussionmentioning

confidence: 93%

Acute Liver Failure following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity

Iorio

Cheerharan²,

Kaufman

et al. 2013

The Cleft Palate-Craniofacial Journal

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“…While the elevations observed in this study were minimal, it is possible that acetaminophen-induced ALT elevations could progress to clinical liver injury if potentiated by other factors such as CYP 2E1 induction, malnutrition or oxidative stress. However, analysis of prospective trials that treated adult or pediatric patients with the therapeutic doses for a variety of medical conditions found no cases of acute liver failure [1,21]. …”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

Heard

Green

Anderson

et al. 2014

BMC Pharmacol Toxicol

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BackgroundAcetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days.MethodsA randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction.Results157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction.ConclusionsA minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued.Trials registrationClintrials.gov NCT00743093 registered August 26, 2008

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“…All of the deaths and all but 6 cases of hepatic abnormalities involved doses of paracetamol greater than 75 mg/kg/day. Another recent systematic reviews reported no cases of hepatic injury among 32,414 children who received adequate therapeutic doses of paracetamol, and those studies showed that there are very few cases of children who develop hepatic abnormalities when given repeated doses of paracetamol 5,6 .…”

Section: Epidemiologymentioning

confidence: 98%

“…Accumulation of the toxic metabolite can then exert untoward effect of oxidative stress with mitochondrial dysfunction, cytokines and chemokines disbalance which leads to cell death alterations in hepatic blood flow, inflammation, and liver necrosis 7 . Children younger than six years of age appear to be less susceptible to hepatotoxicity due to greater capacity for conjugation with sulfate and increased supply and regeneration of glutathione 6 , with adult patterns of metabolism are reached between 10 and 12 years of age. Pathophysiology of liver damage is important for understanding significance and pivotal role of acetylcysteine (also known as N-acetylcysteine) as primary therapeutic option.…”

Section: Pathophysiologymentioning

confidence: 99%

Paracetamol poisoning in children

et al. 2016

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Abstract. Paracetamol is the most commonly used antipyretic and analgesic in children and the association between paracetamol and hepatotoxicity has been well established. With it's widespread use, it became one of the most common pharmaceuticals associated with both unintentional and intentional poisoning and toxicity. Although therapeutic and unintentional overdosage typically occurs in children, hepatic damage or death due to paracetamol poisoning appears to be rare compared to adults. Despite this fact, paracetamol is currently a major and the most common identifiable cause of acute liver failure in children. Therefore, we bring this review article on well established modes of pathophysiologycal mechanisms of liver damage, current diagnostic and treatment concepts of acute paracetamol poisoning, and special overview of acetylcystein as cornerstone of therapy with proven safety and eficacy in children.Key words: acetylcysteine; children; diagnosis; paracetamol; poisoning; treatment Sažetak. Paracetamol je najčešće korišteni antipiretik i analgetik u djece i dobro je znana njegova potencijalna hepatotoksičnost. Današnja široka upotreba dovela je do činjenice da je to lijek koji najčešće dovodi do namjernih i nenamjernih otrovanja, kao i jetrene toksičnosti. Iako se terapijsko i nenamjerno predoziranje događa tipično u djece, oštećenje jetre i smrt zbog trovanja paracetamolom ipak su rijetki u odnosu na adultnu populaciju. Unatoč tome, paracetamol je trenutno najznačajniji i najčešće identificirani uzrok akutnog jetrenog zatajenja u djece. U tom svjetlu donosimo ovaj pregledni članak o dobro utvrđenim patofiziološkim mehanizmima jetrenog oštećenja i aktualnim konceptima dijagnostike i liječenja akutnog otrovanja paracetamolom, s posebnim osvrtom na acetilcistein kao temeljnu, sigurnu i učin-kovitu terapijsku opciju u liječenju djece i adolescenata.

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Therapeutic Acetaminophen Is Not Associated With Liver Injury in Children: A Systematic Review

Abstract: Hepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies. Case reports suggest that this phenomenon may occur, but few reports contain sufficient data to support a probable causal relationship.

Cited by 40 publications

References 79 publications

Acute Liver Failure following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity

Acute Liver Failure following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

Paracetamol poisoning in children

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