Acetaminophen overdose with therapeutic intent
1998; Elsevier BV; Volume: 132; Issue: 1 Linguagem: Inglês
10.1016/s0022-3476(98)70476-7
ISSN1097-6833
AutoresGregory L. Kearns, J. Steven Leeder, Gary S. Wasserman,
Tópico(s)Pharmacogenetics and Drug Metabolism
ResumoSee related articles. Acetaminophen is the pharmaceutical most frequently ingested by small children worldwide. In the United States, formulations of acetaminophen and other over-the-counter medications that contain acetaminophen are ubiquitous and frequently advertised in the lay press and media. Without question, the safety and efficacy profile for acetaminophen generated in over 2 decades of pediatric use has cemented the drug in the minds of parents, patients, and care givers as a pharmacologic “friend.” However, it would appear that this commonly held notion is not, in every instance, correct. In this issue of The Journal, Heubi et al.1Heubi JE Barbacci MB Zimmerman HJ Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children.J Pediatr. 1998; 132: 22-27Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar report several cases of acetaminophen hepatotoxicity in children who apparently received overdoses of the drug as part of therapeutic administration (i.e., with therapeutic intent), and Perry and Shannon2Perry HE Shannon MW Efficacy of oral versus intravenous N-acetylcysteine (NAC) in acetaminophen overdose: results of an open-label clinical trial.J Pediatr. 1998; 132: 149-152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar focus on relevant issues of treatment of acetaminophen overdose with intravenous N-acetylcysteine. Collectively, these reports have rekindled interest in the adverse effects of acetaminophen, highlighting in particular, the potential for sustained acetaminophen treatment at doses generally exceeding the age-appropriate dose recommended in the product labeling (i.e., supratherapeutic doses) to produce liver injury in sick infants and children. The true incidence of hepatotoxicity after sustained, supratherapeutic acetaminophen administration in children is not known. Nonetheless, Heubi et al.1 provide a “profile” for this particular adverse drug effect, reporting summary data on a total of 47 known cases gleaned from the published medical literature (n = 28), previous reports filed with the United States Food and Drug Administration (n = 16), and their own clinical experience (n = 3). Of these cases, 47% involved children 2 years of age or younger, 88% had received acetaminophen for 1 to 5 days, and six (15%) had received daily doses ranging from 50 to 75 mg/kg/day; 52% had been given “adult-strength” acetaminophen products. Of those cases in which serum acetaminophen concentrations were available and the time of the last acetaminophen dose could be discerned with accuracy, 73% had serum concentrations, which when examined by using the nomogram for predicting toxicity from single, acute acetaminophen ingestions,1Heubi JE Barbacci MB Zimmerman HJ Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children.J Pediatr. 1998; 132: 22-27Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar were in the potentially “toxic” range. In marked contrast to previous reports of acute acetaminophen intoxication in children, in which more than 99% of patients recovered without clinically significant sequelae,3Rumack BH Acetaminophen overdose in children and adolescents.Pediatr Clin North Am. 1986; 33: 691-701PubMed Google Scholar 54% of the patients died,1Heubi JE Barbacci MB Zimmerman HJ Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children.J Pediatr. 1998; 132: 22-27Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar presumably of acetaminophen-associated hepatic failure and extrahepatic organ dysfunction as previously reported.4Nogen AG Bremner JE Fatal acetaminophen overdosage in a young child.J Pediatr. 1978; 92: 832-833Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 5Wilson JT Kasantikul V Harbison R Martin D Death in an adolescent following overdose of acetaminophen and phenobarbital.Am J Dis Child. 1978; 132: 466-473PubMed Google Scholar, 6Blake KV Bailey D Zientek GM Hendeles L Death of a child associated with multiple overdoses of acetaminophen.Clin Pharmacy. 1988; 105: 125-128Google Scholar, 7Webster PA Roberts DW Benson RW Kearns GL Acetaminophen toxicity in children: diagnostic confirmation using a specific antigenic biomarker.J Clin Pharmacol. 1996; 36: 397-402Crossref PubMed Scopus (50) Google Scholar Although the report of the cases from this series is somewhat incomplete with regard to other factors that could have significantly contributed to the clinical course of the patients reported (e.g., presence of preexisting, previously undiagnosed disease states capable of producing hepatic injury; prior or concomitant exposure to other drugs, chemicals, or natural products capable of producing or exacerbating hepatotoxicity; underestimation of the total acetaminophen dose ingested from all potential sources of the drug), it provides a convincing demonstration that acetaminophen overdose with therapeutic intent constitutes a toxicologic entity distinct from acute intoxication in both its presentation and epidemiology. The reported cases of acetaminophen intoxication after sustained administration of supratherapeutic doses probably represents the “tip of the iceberg.”8Heubi JE Bien JP Acetaminophen use in children: more is not better.J Pediatr. 1997; 130: 175-177PubMed Google Scholar However, available data do not permit an accurate projection of the incidence of recurrent, excessive acetaminophen dosing in the context of therapeutic use in infants and children. Other than historical information concerning acetaminophen dosing, which may be limited in accuracy9Wilson JT Brown RD Bocchini Jr, JA Kearns GL Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children.Ther Drug Monitor. 1982; 4: 147-180Crossref PubMed Scopus (89) Google Scholar consequent to recall bias and/or unsupervised drug administration (factors that may in part limit the accuracy of any retrospective study of acetaminophen toxicity), the physician examining a sick child has no routine, objective measurements with which to implicate acetaminophen intoxication as a potential factor contributing to illness. Complicating the accurate assessment of acetaminophen dosing history is the fact that many nonprescription combination products marketed in the United States contain potentially therapeutic doses of acetaminophen. This assertion is supported by a recent survey of the 1997 Physician's Desk Reference for Non-Prescription Drugs,101997 Physician’s Desk Reference for Nonprescription Drugs. 18th ed. Medical Economics Co., Inc, Montvale (NJ)1997Google Scholar which revealed a total of 96 acetaminophen-containing products, 22 (i.e., 23%) of which were liquid cough/cold preparations, which conceivably could be co-administered with acetaminophen formulations to an ill child. Such a scenario has been recently reported in a fatal case of sustained, supratherapeutic acetaminophen administration.7Webster PA Roberts DW Benson RW Kearns GL Acetaminophen toxicity in children: diagnostic confirmation using a specific antigenic biomarker.J Clin Pharmacol. 1996; 36: 397-402Crossref PubMed Scopus (50) Google Scholar There are three other potential therapeutic variables that could contribute to iatrogenic therapeutic acetaminophen poisoning in infants and young children.1Heubi JE Barbacci MB Zimmerman HJ Therapeutic misadventures with acetaminophen: hepatotoxicity after multiple doses in children.J Pediatr. 1998; 132: 22-27Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar The first resides with the potential for confusion on the part of the parent or care giver in interpretation of dosing information contained in the product label, and in some cases, failure to properly read such dosing guidelines. Clearly, significant dosing errors can result when formulation-specific differences in acetaminophen dose size are not considered.11Rivera-Penera T Gugig R Davis J McDiarmid S Vargas J Rosenthal P et al.Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity.J Pediatr. 1997; 130: 300-304Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Second, parents may elect to administer adult-strength acetaminophen formulations to febrile children consequent to the unavailability of appropriate pediatric formulations or a perceived improvement in compliance (e.g., less frequent dosing) associated with adult-strength products. Third, iatrogenic overdose may occur intentionally when parents or care givers perceive that effective therapy has not been achieved with pediatric acetaminophen formulations and assume that stronger products marketed for use in adults may produce or improve the desired pharmacologic effect. A common and contributory theme in the majority of cases of therapeutic misadventure resides with incomplete knowledge and inadequate perception of the toxicity risk for acetaminophen when doses in excess of those recommended on the product label are given to a sick child. Several factors in addition to acetaminophen dose and duration of therapy may occur in a given child who experiences hepatotoxicity after administration of supratherapeutic doses of the drug. It is our contention that interaction among development, disease, and drug metabolism as related to the production and detoxification of the toxic metabolic intermediate from acetaminophen (i.e., N-acetyl-p-benzoquinoneimine or NAPQI) may, in part, explain an enhanced susceptibility to cellular injury in certain individuals. Any consideration of the mechanisms involved in acetaminophen-associated hepatotoxicity after either the acute or sustained ingestion of supratherapeutic doses of the drug must embrace a host of factors, which modulate the balance between bioactivation and detoxification.12Dahlin DC Miwa GT Lu AYH Nelson SD N-Acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen.Proc Natl Acad Sci USA. 1984; 81: 1327-1331Crossref PubMed Google Scholar, 13Mitchell 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: 185-194PubMed Google Scholar Clearly, the induction of enzymes capable of bioactivating acetaminophen to NAPQI (e.g., the cytochromes P 450 CYP2E1, CYP3A4, and CYP1A2) by the co-ingestion of therapeutic drugs,5Wilson JT Kasantikul V Harbison R Martin D Death in an adolescent following overdose of acetaminophen and phenobarbital.Am J Dis Child. 1978; 132: 466-473PubMed Google Scholar, 14Kearns GL CYP3A4 modulates acetaminophen toxicity in man [abstract].Pediatr Res. 1994; 35: 85AGoogle Scholar foodstuffs, or other environmentally acquired xenobiotics (e.g., heterocyclic hydrocarbons from tobacco smoke)15Bock KW Schrenk D Forster A Griese E-U Morike K Brockmeier D et al.The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.Pharmacogenetics. 1994; 4: 209-218Crossref PubMed Scopus (203) Google Scholar could serve to predispose an individual to acetaminophen-associated hepatotoxicity after the administration of supratherapeutic doses, and in the case of long-term ethanol use,16Seeff LB Cuccherini BA Zimmerman HJ Adler E Benjamin SB Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure.Ann Intern Med. 1986; 104: 399-404Crossref PubMed Scopus (388) Google Scholar possibly therapeutic doses of acetaminophen. Other considerations include the potential for developmentally associated increases in the activity of certain bioactivating enzymes (e.g., CYP1A2 and CYP3A4)17Leeder JS Kearns GL Pharmacogenetics in pediatrics: implications for practice.Pediatr Clin North Am. 1997; 44: 55-77Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 18Kearns GL Pharmacogenetics and development: Are infants and children at increased risk for adverse outcomes?.Curr Opin Pediatr. 1995; 7: 220-233Crossref PubMed Scopus (66) Google Scholar and for concomitant infection to selectively inhibit enzymes (e.g., CYP1A2),19Renton KW Armstrong SG Immune-mediated downregulation of cytochrome P450 and related drug biotransformation.in: 2nd ed. Immunotoxicology and immunopharmacology. Raven Press, Ltd, New York1994: 501-512Google Scholar which represent minor pathways for NAPQI formation, thus leaving predominant bioactivation enzymes (e.g., CYP2E1)20Thummel KE Lee CA Kunze KL Nelson SD Slattery JT Oxidation of acetaminophen to N-actyl-p-aminobenzoquinone imine by human CYP3A4.Biochem Pharmacol. 1993; 45: 1563-1569Crossref PubMed Scopus (273) Google Scholar unopposed. Finally, the potential role of acute malnutrition (e.g., reduced availability of sulfate and glucuronide precursors, as well as glutathione depletion) to downregulate the conjugation of acetaminophen and/or NAPQI must also be taken into account,13Mitchell 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: 185-194PubMed Google Scholar, 21Mitchell JR Jollow DJ Potter WZ Gillette JR Brodie BB Acetaminophen-induced hepatic necrosis. IV. Role of glutathione.J Pharmacol Exp Ther. 1973; 187: 211-217PubMed Google Scholar especially in the sick child unable to maintain a normal, balanced pattern of dietary intake. Fortunately, the clinician can often use a careful history of acetaminophen ingestion, co-medication, chemical exposure, comorbid conditions, and diet to arrive at some perspective of “risk” for acetaminophen-associated hepatotoxicity. However, routine patient assessment does not afford insights into the phenotypic expression of enzyme activities that govern the bioactivation of acetaminophen and its detoxification. In our opinion, the assessment of acetaminophen-associated hepatotoxicity must collectively consider all of these factors. This is especially true for sick children who receive multiple, supratherapeutic doses of the drug when, as suggested by Rivera-Penera et al.,11Rivera-Penera T Gugig R Davis J McDiarmid S Vargas J Rosenthal P et al.Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity.J Pediatr. 1997; 130: 300-304Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar the therapeutic index for acetaminophen may be much lower than that associated with intermittent, therapeutic administration of the drug. Monitoring of circulating complexes, which represent adducts of host protein and the reactive metabolite of acetaminophen [i.e., 3-(cystein-S-yl) acetaminophen adducts] in serum, has been proposed as a surrogate biomarker to diagnose acetaminophen toxicity after supratherapeutic administration of the drug.7Webster PA Roberts DW Benson RW Kearns GL Acetaminophen toxicity in children: diagnostic confirmation using a specific antigenic biomarker.J Clin Pharmacol. 1996; 36: 397-402Crossref PubMed Scopus (50) Google Scholar To determine the potential clinical utility of serum markers such as 3-cys-A adducts, several issues need to be addressed; for example, the relationship between covalent binding and cell damage or death needs to be established. In the mid 1980s, the relative importance of covalent binding, oxidative stress, or other mechanisms in mediating cytotoxicity was the subject of considerable interest. Indeed, both acetaminophen-induced arylation22Tsokos-Kuhn JO Hughes H Smith CV Mitchell JR Alkylation of the liver plasma membrane and inhibition of the Ca2+ ATPase by acetaminophen.Biochem Pharmacol. 1988; 37: 2125-2131Crossref PubMed Scopus (75) Google Scholar and thiol oxidation23Moore M Thor H Moore G Nelson S Moldéus P Orrenius S The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+.J Biol Chem. 1985; 260: 13035-13040Abstract Full Text PDF PubMed Google Scholar were associated with increases in cytosolic [Ca2+], an event thought to be key to the development of cellular toxicity. Although studies with dimethylated acetaminophen analogs indicate that covalent binding can be dissociated from cytotoxicity and acetaminophen-induced alterations in cellular redox status,24Birge RB Bartolone JB Nishanian EV Bruno MK Mangold JB Cohen SD et al.Dissociation of covalent binding from the oxidative effects of acetaminophen.Biochem Pharmacol. 1988; 37: 3383-3393Crossref PubMed Scopus (37) Google Scholar it is likely that both covalent adduct formation and oxidative stress contribute to hepatotoxicity. It is important to recognize, however, that demonstration of covalent adducts (i.e., irreversibly bound drug) in a given tissue is not sufficient proof that the reactive metabolite mediated the toxicity to that tissue.25Gillette JR A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity.Biochem Pharmacol. 1974; 23: 2785-2794Crossref PubMed Scopus (190) Google Scholar Nevertheless, it is reasonable to expect that the incidence and severity of organ toxicity mediated by a reactive metabolite would be proportional to the number of metabolite–target protein conjugates present in that tissue.26Jollow DJ Mitchell JR Potter WZ Davis DC Gillette JR Brodie BB Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo.J Pharmacol Exp Ther. 1973; 187: 195-202PubMed Google Scholar Two points can be made concerning the presence of 3-cys-A adducts in serum: (1) at the very least, they are indicative of acetaminophen bioactivation; (2) if the human serum adducts can be determined to be of hepatic origin, as appears to be the case in mice,27Pumford NR Hinson JA Potter DW Rowland KL Benson RW Roberts DW Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice.J Pharmacol Exp Ther. 1989; 248: 190-196PubMed Google Scholar they may be useful in assessing the degree of hepatic damage attributed to acetaminophen. However, sufficient clinical data are not yet available to draw this conclusion. Prospective data obtained during both intermittent and sustained therapeutic dosing of acetaminophen, as well as in acute and long-term overdose situations, will be required to determine the sensitivity and reliability of serum 3-cys-A adducts as determinants of risk or markers of overt hepatocellular damage caused by acetaminophen toxicity. Collectively, the available data suggest that the benefit associated with providing NAC treatment to children who are at increased risk for the development of hepatic injury as a result of sustained administration of acetaminophen at supratherapeutic doses may outweigh the risks of such therapy. If this is the case, what is the best way to provide NAC therapy? Perry and Shannon2Perry HE Shannon MW Efficacy of oral versus intravenous N-acetylcysteine (NAC) in acetaminophen overdose: results of an open-label clinical trial.J Pediatr. 1998; 132: 149-152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar report the results of a 10-year investigation, which compared the efficacy and clinical outcome of two different NAC dosing regimens: a 52-hour intravenous versus the “conventional” 72-hour oral regimen. Both regimens were of apparently equal efficacy and safety. This confirms a previous report evaluating the efficacy and safety of a 48-hour intravenous NAC regimen for treatment of acute acetaminophen intoxication.28Smilkstein MJ Bronstein AC Linden C Augenstein WL Kulig KW Rumack BH Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.Ann Emerg Med. 1991; 20: 1058-1063Abstract Full Text PDF PubMed Scopus (240) Google Scholar Repeated emesis associated with the rather unpleasant taste and odor of extemporaneous oral formulations of NAC is a generally accepted side effect, which may delay the administration of an effective dose by requiring the concomitant administration of antiemetic agents (e.g., ondansetron)29Tobias JD Gregory DF Deshpande JK Ondansetron to prevent emesis following N-acetylcysteine for acetaminophen intoxication.Pediatr Emerg Care. 1992; 8: 345-346Crossref PubMed Scopus (13) Google Scholar or prokinetic agents (e.g., metoclopramide) and/or the placement of a gastric tube. Although intravenous NAC can indeed produce vomiting,2Perry HE Shannon MW Efficacy of oral versus intravenous N-acetylcysteine (NAC) in acetaminophen overdose: results of an open-label clinical trial.J Pediatr. 1998; 132: 149-152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar the only delays in providing NAC treatment by this route are those associated with the preparation of the dosage form. However, as noted by Flanagan and Meredith,30Flanagan RJ Meredith TJ Use of N-acetylcysteine in clinical toxicology.Am J Med. 1991; 91: 131S-139SAbstract Full Text PDF PubMed Scopus (173) Google Scholar intravenous NAC can produce serious adverse effects (e.g., anaphylactoid reactions, angioedema, bronchospasm, hypotension, and respiratory distress) in up to 10% of patients receiving a 20-hour dosing regimen.31Prescott LF Illingworth RN Critchley JAJH Stewart MJ Adam RD Proudfoot AT Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning.Br Med J. 1979; 2: 1097-1100Crossref PubMed Scopus (663) Google Scholar These particular adverse effects appear to be minimized when longer intravenous NAC treatment regimens (of 48 hours or more) are used.2Perry HE Shannon MW Efficacy of oral versus intravenous N-acetylcysteine (NAC) in acetaminophen overdose: results of an open-label clinical trial.J Pediatr. 1998; 132: 149-152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 28Smilkstein MJ Bronstein AC Linden C Augenstein WL Kulig KW Rumack BH Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.Ann Emerg Med. 1991; 20: 1058-1063Abstract Full Text PDF PubMed Scopus (240) Google Scholar Accordingly, the abbreviated intravenous NAC treatment regimen described by Perry and Shannon2Perry HE Shannon MW Efficacy of oral versus intravenous N-acetylcysteine (NAC) in acetaminophen overdose: results of an open-label clinical trial.J Pediatr. 1998; 132: 149-152Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar merits consideration for use in treating acetaminophen overdose when historical and clinical evidence suggest that acetaminophen and/or NAPQI may be present after any intoxication episode. Available epidemiologic and historical data have enabled us to propose a “risk profile” regarding the potential for therapeutic acetaminophen use to produce hepatotoxicity—sustained administration of high doses of acetaminophen (i.e., ≥ 90 mg/kg/day) to a sick child (e.g., one with repeated vomiting/diarrhea and poor oral food intake) who is 2 years of age or younger for a duration of more than 1 day. This “risk” is further increased in children during administration of drugs capable of inducing hepatic microsomal enzymes (e.g., phenytoin, phenobarbital, rifampin), co-administration of other products that also contain acetaminophen (e.g., over-the-counter cough-cold remedies), use of acetaminophen-containing products that are not age-appropriate (e.g., adult-strength formulations for children, concentrated drop formulations of acetaminophen for an older child), and administration of acetaminophen for conditions outside the label indications. Clearly, the acetaminophen dose contained in this “profile” and the use of adult-strength acetaminophen formulations for infants and small children are well outside of the recommended instructions for the use of this drug contained in the currently approved product labeling.101997 Physician’s Desk Reference for Nonprescription Drugs. 18th ed. Medical Economics Co., Inc, Montvale (NJ)1997Google Scholar However, the continued occurrence of these practices warrants restatement of the obvious. Finally, it is imperative that clinicians recognize the full toxic potential of acetaminophen in both the settings of acute (i.e., intentional) overdose and therapeutic administration of the drug. Alonso et al.32Alonso EM Sokol RJ Hart J Tyson RW Narkewicz MR Whitington PF Fulminant hepatitis associated with centrilobular hepatic necrosis in young children.J Pediatr. 1995; 127: 888-894Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar reported a series of young children with fulminant hepatitis associated with centrilobular hepatic necrosis; some cases were suspected to have been the result of acetaminophen toxicity, despite the unavailability of tests to confirm this diagnosis (Dr. R. J. Sokol, personal communication, 1997). Clearly, the key to the continued safe use of acetaminophen as an antipyretic and analgesic agent in Pediatrics is to prevent its misuse by recognizing and appreciating all of the qualities that make the drug unique. The Departments of Pediatrics and Pharmacology , University of Missouri–Kansas City , The Sections of Pediatric Clinical Pharmacology, Experimental Therapeutics, and Clinical Toxicology , The Children's Mercy Hospital , Kansas City, MO 64108
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