Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity

Rivera-Penera, Teresa; Gugig, Roberto; Davis, J.; McDiarmid, Sue V.; Vargas, Jorge; Rosenthal, Philip; Berquist, William; Heyman, Melvin B.; Ament, Marvin E.

doi:10.1016/s0022-3476(97)70359-7

Cited by 181 publications

(131 citation statements)

References 10 publications

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“…They can misunderstand the recommended dose, frequency or length of therapy, use an incorrect measuring device, or even give the wrong preparation. 30,31 In our second case report, well-intentioned parents were giving their child what they perceived to be only an antipyretic; however, because of package labeling-the Cold portion of the http://www.pediatrics.org/cgi/content/full/108/3/e52name Children's Tylenol: Cold was in much smaller print-they did not realize that what they had actually been giving was a cough and cold preparation.…”

Section: Discussionmentioning

confidence: 86%

Toxicity of Over-the-Counter Cough and Cold Medications

Gunn¹,

Taha²,

Liebelt³

et al. 2001

Pediatrics

134

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ABSTRACT. Over-the-counter (OTC) cough and cold medications are marketed widely for relief of common cold symptoms, and yet studies have failed to demonstrate a benefit of these medications for young children. In addition, OTC medications can be associated with significant morbidity and even mortality in both acute overdoses and when administered in correct doses for chronic periods of time. Physicians often do not inquire about OTC medication use, and parents (or other caregivers) often do not perceive OTCs as medications. We present 3 cases of adverse outcomes over a 13-month period-including 1 death-as a result of OTC cough and cold medication use. We explore the toxicities of OTC cough and cold medications, discuss mechanisms of dosing errors, and suggest why physicians should be more vigilant in specifically inquiring about OTCs when evaluating an ill child. Pediatrics 2001;108(3). URL: http://www.pediatrics.org/cgi/content/full/108/3/e52; over-the-counter medications, cough and cold preparations, morbidity, mortality, phenylpropanolamine.ABBREVIATIONS. OTC, over-the-counter; PPA, phenylpropanolamine; ED, emergency department; PICU, pediatric intensive care unit; CBC, complete blood (cell) count; WBC, white blood cell (count); bpm, beats per minute; AAP, American Academy of Pediatrics; CNS, central nervous system; FDA, Food and Drug Administration. C olds, coughs, and upper respiratory infections are common childhood illnesses. The average child suffers from 6 to 10 colds per year, and each cold can last from 10 to 14 days, providing several days and nights of discomfort for the child as well as for his/her caregiver. 1 Many times parents will turn to one of many hundreds of cough and cold preparations for relief. However, over-the-counter (OTC) cough and cold preparations-although generally safe-have no demonstrated benefit. No studies have proven the efficacy of cough and cold preparations in facilitating recovery from these illnesses, 2-6 and most children will eventually improve on their own. However, a small number of children may suffer significant adverse effects from the administration of the very cough and cold formulations they were given in an attempt to relieve their symptoms. For example, the Food and Drug Administration recently issued an advisory to remove phenylpropanolamine (PPA)-a common constituent of OTC decongestants-from those products because of concern for increased risk of hemorrhagic stroke. 7,8 We present 3 cases of children who suffered significant morbidity from OTC cough and cold preparations requiring admission and treatment in a tertiary care hospital during a 13-month period; they ranged from a self-limited reaction requiring an intensive care unit admission to death in 1 patient. Because no cases of death or heart failure attributable to OTC cough and cold preparations have been reported in recent literature, these cases are presented to serve as points for additional discussion on the risks of OTC cough and cold preparations in children. CASE REPORTS Case 1A 36-month-old b...

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Section: Discussionmentioning

confidence: 86%

Toxicity of Over-the-Counter Cough and Cold Medications

Gunn¹,

Taha²,

Liebelt³

et al. 2001

Pediatrics

134

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“…The development of this assay provides a tool for the systematic study of APAP toxicity in humans following toxic exposures or therapeutic misadventures with APAP. Recent literature has highlighted the occurrence of therapeutic misadventures with APAP (Seeff et al, 1986;Eriksson et al, 1992;Bonkovsky et al, 1994;Whitcomb and Block, 1994;Rivera-Penera et al, 1997;Heubi et al, 1998). These articles describe the development of hepatotoxicity in patients using APAP with therapeutic intent.…”

Section: Discussionmentioning

confidence: 99%

“…Acetaminophen-and glutathione-derived metabolites have previously been assayed by HPLC-ECD methods (Riggin et al, 1975;Munson et al, 1978;Miner and Kissinger, 1979;Hall et al, 1986;Whitcomb and Block, 1994;Alonso et al, 1995;Bonkovsky, 1995;Rivera-Penera et al, 1997). The advantage of the HPLC-ECD assay for acetaminophen-cysteine in proteins is its ability to quantify conjugates in serum protease digestion.…”

mentioning

confidence: 99%

Determination of Acetaminophen-Protein Adducts in Mouse Liver and Serum and Human Serum after Hepatotoxic Doses of Acetaminophen Using High-Performance Liquid Chromatography with Electrochemical Detection

Muldrew¹,

James²,

Coop³

et al. 2002

Drug Metab Dispos

178

174

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Acetaminophen-induced hepatotoxicity has been attributed to covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cysteine groups on proteins as an acetaminophen-cysteine conjugate. We report a high-performance liquid chromatography with electrochemical detection (HPLC-ECD) assay for the conjugate with increased sensitivity compared with previous methods. Previous methods to quantitate the protein-bound conjugate have used a competitive immunoassay or radiolabeled acetaminophen. With HPLC-ECD, the protein samples are dialyzed and then digested with protease. The acetaminophen-cysteine conjugate is then quantified by HPLC-ECD using tyrosine as an internal reference. The lower limit of detection of the assay is approximately 3 pmol/mg of protein. Acetaminophen protein adducts were detected in liver and serum as early as 15 min after hepatotoxic dosing of acetaminophen to mice. Adducts were also detected in the serum of acetaminophen overdose patients. Analysis of human serum samples for the acetaminophen-cysteine conjugate revealed a positive correlation between acetaminophen-cysteine conjugate concentration and serum aspartate aminotransferase (AST) activity or time. Adducts were detected in the serum of patients even with relatively mild liver injury, as measured by AST and alanine aminotransferase. This assay may be useful in the diagnostic evaluation of patients with hepatotoxicity of an indeterminate etiology for which acetaminophen toxicity is suspect.Acetaminophen (N-acetyl-p-aminophenol; APAP 1 ; Paracetamol) is the most commonly used drug for the treatment of pain and fever. Although safe at therapeutic doses, in overdose, acetaminophen produces severe hepatotoxicity. The mechanism of toxicity is by initial metabolism to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 . At therapeutic doses, the reactive metabolite is detoxified by glutathione, but following overdoses, glutathione is depleted and the metabolite covalently binds to proteins as 3-(cystein-S-yl)-acetaminophen (APAP-CYS) (Streeter et al., 1984). Covalent binding to protein is thought to be a critical step in the development of hepatotoxicity.A number of methods have been used to quantify the amount of acetaminophen covalently bound to proteins. In initial studies showing the correlation between acetaminophen toxicity and covalent binding, Jollow and coworkers (1973) used radiolabeled acetaminophen. Subsequently, polyclonal antisera were raised that recognized the acetaminophen-cysteine adducts (Bartolone et al., 1987;Roberts et al., 1987), and the relationship between covalent binding and toxicity was studied extensively. coworkers (1989, 1990) developed a competitive enzyme-linked immunosorbent assay to quantify acetaminophen covalent binding in the liver and serum of treated mice. In addition, Western blot assays were performed. Although these latter assays were not quantitative, they were useful in comparing t...

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“…5 Parents of febrile children usually suffer from "fever phobia." This could lead to antipyretic overdose, [6][7][8] although temperatures lower than 39 °C do not need to be treated. [9][10][11][12] Acetaminophen is the most widely used drug for reducing fever in children.…”

Section: Introductionmentioning

confidence: 99%

Comparação da eficácia de doses iguais de acetaminofeno retal e oral em crianças

Karbasi¹,

Modares-Mosadegh²,

Golestan³

2010

J. Pediatr. (Rio J.)

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Objective: To compare a dose of oral and rectal acetaminophen and to evaluate acceptability of rectal acetaminophen, since oral and rectal acetaminophen is widely used as an antipyretic agent in febrile children and the comparative effectiveness of these two preparations is not well established. Methods:In this prospective parallel group designed study, 60 children who presented to the emergency department or outpatient pediatric clinic at a tertiary hospital and aged from 6 months to 6 years with rectal temperature over 39 °C were enrolled. Patients were randomly assigned to two equal-sized groups. Group 1 received 15 mg/kg acetaminophen rectally and group 2 received the same dose orally. Temperature was recorded at baseline and 1 and 3 hours after drug administration. Results:In the first group, mean decrease in temperature, 1 and 3 hours after administration of acetaminophen was 1.07±0.16 (p < 0.001) and 1.74±0.25 °C (p < 0.001), respectively, and in the second group it was 1.98±0.19 (p < 0.001) and 1.70±0.14 °C (p < 0.001), respectively (p > 0.05). Conclusion:Rectal and oral acetaminophen preparations have equal antipyretic effectiveness in children. The rectal route proved to be as acceptable as the oral one among parents. J Pediatr (Rio J). 2010;86(3):228-232:Oral acetaminophen, rectal acetaminophen, fever.

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Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity

Cited by 181 publications

References 10 publications

Toxicity of Over-the-Counter Cough and Cold Medications

Toxicity of Over-the-Counter Cough and Cold Medications

Determination of Acetaminophen-Protein Adducts in Mouse Liver and Serum and Human Serum after Hepatotoxic Doses of Acetaminophen Using High-Performance Liquid Chromatography with Electrochemical Detection

Comparação da eficácia de doses iguais de acetaminofeno retal e oral em crianças

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