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TOXICOLOGY/CLINICAL POLICY

Clinical Policy: Critical Issues in the Management of PatientsPresenting to the Emergency Department With

Acetaminophen Overdose

From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on CriticalIssues in the Management of Patients Presenting to the Emergency Department With Acetaminophen Overdose:

Stephen J. Wolf, MD (Chair)Kennon Heard, MDEdward P. Sloan, MD, MPHAndy S. Jagoda, MD

Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee):

Andy S. Jagoda, MD (Chair 2003-2006, Co-Chair 2006-2007)

Wyatt W. Decker, MD (Co-Chair 2006-2007)Deborah B. Diercks, MDJonathan A. Edlow, MDFrancis M. Fesmire, MDSteven A. Godwin, MDSigrid A. Hahn, MDJohn M. Howell, MDJ. Stephen Huff, MDThomas W. Lukens, MD, PhDDonna L. Mason, RN, MS, CEN (ENA Representative

2004-2006)Michael Moon, RN, CNS, MSN, CEN (ENA

Representative 2004)Anthony M. Napoli, MD (EMRA Representative 2004-

2006)
De
doi:10.1016/j.annemergmed.2007.06.014

department (ED) with acetaminophen overdose. The

292 Annals of Emergency Medicine

Jim Richmann, RN, BS, MA(c), CEN (ENA Representative2006-2007)

Scott M. Silvers, MDEdward P. Sloan, MD, MPHMolly E. W. Thiessen, MD (EMRA Representative 2006-

2007)Robert L. Wears, MD, MS (Methodologist)Stephen J. Wolf, MDCherri D. Hobgood, MD (Board Liaison 2004-2006)David C. Seaberg, MD, CPE (Board Liaison 2006-2007)Rhonda R. Whitson, RHIA, Staff Liaison, Clinical Policies

Committee and Subcommittees

Approved by the ACEP Board of Directors, June 13,2007

Supported by the Emergency Nurses Association, July
22, 2007
vorah Nazarian, MD

Policy statements and clinical policies are the official policies of the American College of EmergencyPhysicians and, as such, are not subject to the same peer review process as articles appearing in the printjournal. Policy statements and clinical policies of ACEP do not necessarily reflect the policies and beliefsof Annals of Emergency Medicine and its editors.

0196-0644/$-see front matterCopyright © 2007 by the American College of Emergency Physicians.

[Ann Emerg Med. 2007;50:292-313.]

ABSTRACTThis clinical policy focuses on critical issues concerning the

management of patients presenting to the emergency

subcommittee reviewed the medical literature relevant to thequestions posed. The critical questions are:1. What are the indications for N-acetylcysteine (NAC) in the

acetaminophen overdose patient with a known time of acuteingestion who can be risk stratified by the Rumack-
Matthew nomogram?
Volume , . : September

Clinical Policy

2. What are the indications for NAC in the acetaminophenoverdose patient who cannot be risk stratified by theRumack-Matthew nomogram?

Recommendations are provided on the basis of the strengthof evidence of the literature. Level A recommendations representpatient management principles that reflect a high degree ofclinical certainty; Level B recommendations represent patientmanagement principles that reflect moderate clinical certainty;and Level C recommendations represent other patientmanagement strategies that are based on preliminary,inconclusive, or conflicting evidence, or based on committeeconsensus. This guideline is intended for physicians working inEDs.

INTRODUCTIONSince the early 1970s, N-acetylcysteine (NAC) has been used

as an antidote to acetaminophen overdose.1 Acetaminophen isnot only metabolized through glucuronidation and sulfation tonontoxic metabolites but also, in small part, to N-acetyl-p-benzoquinoneimine (NAPQI), a hepatotoxic metabolite at acellular level. This latter metabolic pathway is used to a greaterextent in the overdose setting when physiologic stores ofsulfhydryl donors are depleted, thereby limiting the nontoxicmeans for acetaminophen metabolism. NAC has been shown tolimit hepatotoxicity in acetaminophen-toxic patients by severalmechanisms. First, NAC serves as a sulfhydryl group donor,allowing continued nontoxic metabolism; second, NAC canserve to conjugate NAPQI into a nontoxic metabolite; andfinally, NAC has been shown to blunt the hepatocellulartoxicity of NAPQI. In the setting of acetaminophen overdose,hepatotoxicity is defined as any increase in aspartateaminotransferase (AST) concentrations, severe hepatotoxicity asan AST greater than 1,000 IU/L, and hepatic failure ashepatotoxicity with hepatic encephalopathy. These definitionswill be used for this policy unless otherwise stated.

Multiple protocols for the administration of NAC in thepatient with known or suspected acetaminophen toxicity existfor both the oral and intravenous routes.2-7 Both have beenshown to be equally efficacious.3,4,8 Orally, NAC has beenshown to have a minimal adverse effect profile, consistingmostly of nausea and emesis, and increased tolerance can beachieved with co-administration of an antiemetic.9-11 Studieshave shown that the dose of oral NAC does not need to changewhen activated charcoal is given concomitantly.12 Theintravenous preparation was approved by the US Food andDrug Administration (FDA) for use in the United States in2004. Common adverse effects include pruritus, flushing, and arash (approximately 15% of patients), which is most oftentreated by holding the infusion, administering an antihistamine,and restarting the infusion at a lower rate.13 Bronchospasm andhypotension are rare (�2%).14 Fatal reactions are rare but havebeen reported.15

The Rumack-Matthew nomogram is a tool used to stratifypatients at risk for hepatotoxicity after a single acute
acetaminophen ingestion at a known point in time16,17 (Figure).

A serum acetaminophen concentration in these patients, takenafter 4 hours and before 24 hours postingestion, can be plottedon the nomogram to indicate whether or not a patient is at norisk, possible risk, or probable risk of developing hepatotoxicity.This information is often used to determine whether or notNAC is indicated. Some experts will use the nomogram tostratify patients with multiple ingestions within an 8-hourperiod, using the time that the series of ingestions started as thetime of ingestion. Patients with delayed presentation (�24hours after ingestion), an unknown time or duration ofingestion, ingestion of extended-release preparation, or arepeated supratherapeutic ingestion cannot be risk stratifiedwith this nomogram.

Repeated supratherapeutic ingestions are a unique clinicalsituation entailing a pattern of multiple ingestions ofacetaminophen during a period of greater than 8 hours thatresult in a cumulative dosage of greater than 4 g per 24hours.18,19 Two case series reported that approximately 30% ofpatients admitted for acetaminophen overdose had repeatedsupratherapeutic ingestions. These studies also suggested thatpatients with repeated supratherapeutic ingestions have a worse

Figure. Rumack-Matthew nomogram. Plasma acetaminophenconcentration versus time post–acetaminophen ingestion.Printed with permission.17 Copyright©1981 American MedicalAssociation.

prognosis than patients admitted after acute overdose.20,21 Most

Annals of Emergency Medicine 293

Clinical Policy

often, repeated supratherapeutic ingestions are not suicideattempts but rather therapeutic misadventures. A recentsystematic review with consensus recommendations states thatrepeated supratherapeutic ingestions need to be referred to anemergency department (ED) only if at least 10 g or 200 mg/kg(whichever is less) during a single 24-hour period, or at least 6 gor 150 mg/kg (whichever is less) per 24-hour period for thepreceding 48 hours or longer, is ingested.19 These authorssuggest that these thresholds should be decreased to 4 g or 100mg/kg (whichever is less) for patients potentially at increasedrisk for acetaminophen toxicity (eg, isoniazid use, prolongedfasting).

This clinical policy uses an evidence-based approach toevaluate the literature and make recommendations about themanagement of acetaminophen overdose. The subcommitteegenerated the critical questions with input from the AmericanCollege of Emergency Physicians (ACEP) Toxicology Section,and the questions are believed to be important for emergencyphysicians initially providing care in the ED.

This policy evolved from the 1999 ACEP “Clinical Policyfor the Initial Approach to Patients Presenting with Acute ToxicIngestion or Dermal or Inhalation Exposure.”22

METHODOLOGYThis clinical policy was created after careful review and

critical analysis of the medical literature. MEDLINE searchesfor articles published between January 1974 and January 2006were performed using a combination of key words and theirvariations, including “acetaminophen,” “paracetamol,” “APAP,”“extended release,” “acetylcysteine,” “N-acetylcysteine,”“Mucomyst,” “NAC,” “liver disease,” “aminotransferase,”“aspartate transaminase,” “alanine transferase,” “SGOT,”“AST,” “ALT,” and “hepatitis, toxic.” Searches were limited toEnglish-language sources. Additional articles were reviewedfrom the bibliography of articles cited and from publishedtextbooks and review articles. Subcommittee members alsosupplied articles from their own files.

The reasons for developing clinical policies in emergencymedicine and the approaches used in their development havebeen enumerated.23 This policy is a product of the ACEPclinical policy development process, including expert review,and is based on the existing literature; when literature was notavailable, consensus of emergency physicians and toxicologistswas used. Expert review comments were received fromindividual emergency physicians and toxicologists andindividual members from the American Academy of PediatricsCommittee and Section on Pediatric Emergency Medicine,American Association for the Study of Liver Diseases, AmericanGastroenterological Association, and ACEP’s ToxicologySection. Their responses were used to further refine and enhancethis policy. Clinical policies are scheduled for revision every 3years; however, interim reviews are conducted when technologyor the practice environment changes significantly.

All articles used in the formulation of this clinical policy were
graded by at least 2 subcommittee members for strength of

evidence and classified by the subcommittee members into 3classes of evidence on the basis of the design of the study, withdesign 1 representing the strongest evidence and design 3representing the weakest evidence for therapeutic, diagnostic,and prognostic clinical reports, respectively (Appendix A).Articles were then graded on 6 dimensions thought to be mostrelevant to the development of a clinical guideline: blindedversus nonblinded outcome assessment, blinded or randomizedallocation, direct or indirect outcome measures (reliability andvalidity), biases (eg, selection, detection, transfer), externalvalidity (ie, generalizability), and sufficient sample size. Articlesreceived a final grade (Class I, II, III) on the basis of apredetermined formula, taking into account design and qualityof study (Appendix B). Articles with fatal flaws were given an“X” grade and not used in formulating recommendations in thispolicy. Evidence grading was done with respect to the specificdata being extracted and the specific critical question beingreviewed. Thus, the level of evidence for any one study may varyaccording to the question, and it is possible for a single article toreceive different levels of grading as different critical questionsare answered. Question-specific level of evidence grading may befound in the Evidentiary Table included at the end of this policy.

Clinical findings and strength of recommendations regardingpatient management were then made according to the followingcriteria:

Level A recommendations. Generally accepted principlesfor patient management that reflect a high degree of clinicalcertainty (ie, based on strength of evidence Class I oroverwhelming evidence from strength of evidence Class IIstudies that directly address all of the issues).

Level B recommendations. Recommendations for patientmanagement that may identify a particular strategy or range ofmanagement strategies that reflect moderate clinical certainty(ie, based on strength of evidence Class II studies that directlyaddress the issue, decision analysis that directly addresses theissue, or strong consensus of strength of evidence Class IIIstudies).

Level C recommendations. Other strategies for patientmanagement that are based on preliminary, inconclusive, orconflicting evidence, or in the absence of any publishedliterature, based on panel consensus.

There are certain circumstances in which therecommendations stemming from a body of evidence shouldnot be rated as highly as the individual studies on which theyare based. Factors such as heterogeneity of results, uncertaintyabout effect magnitude and consequences, strength of priorbeliefs, and publication bias, among others, might lead to such adowngrading of recommendations.

It is the goal of the Clinical Policies Committee to providean evidence-based recommendation when the medical literatureprovides enough quality information to answer a criticalquestion. When the medical literature does not contain enough
quality information to answer a critical question, the members

Clinical Policy

of the Clinical Policies Committee believe that it is equallyimportant to alert emergency physicians to this fact.

Recommendations offered in this policy are not intended torepresent the only diagnostic and management options that theemergency physician should consider. ACEP clearly recognizesthe importance of the individual physician’s judgment. Rather,this guideline defines for the physician those strategies for whichmedical literature exists to provide support for answers to thecrucial questions addressed in this policy.

Scope of Application. This guideline is intended forphysicians working in EDs.

Inclusion Criteria. This guideline is intended for patientsolder than 12 years who present to the ED with acetaminophenoverdose.

Exclusion Criteria. This guideline is not intended forapplication to patients 12 years and younger.

CRITICAL QUESTIONS1. What are the indications for NAC in the acetaminophenoverdose patient with a known time of acute ingestion whocan be risk stratified by the Rumack-Matthew nomogram?

Level A recommendations. None specified.Level B recommendations.

1. Administer NAC to acute acetaminophen overdose patientswith either possible or probable risk for hepatotoxicity asdetermined by the Rumack-Matthew nomogram to reducethe incidence of severe hepatotoxicity and mortality, ideallywithin 8 to 10 hours postingestion.

2. Do not administer NAC to acute acetaminophen overdosepatients with no risk for hepatotoxicity as determined by theRumack-Matthew nomogram.

Level C recommendations. None specified.

In 1975, Rumack and Matthew16 published a review articledescribing a nomogram that used previously published data on30 patients older than 12 years to predict hepatic toxicity afteran acute acetaminophen ingestion. The proposed nomogramapplied only to patients with a single acute poisoning at aknown time who were no more than 24 hours postingestion.Concentrations drawn between 4 and 24 hours were to beplotted to determine whether the patient fell either above thenomogram line, indicating a probable risk for hepatotoxicity, orbelow the line, indicating no risk for hepatotoxicity.16

Four years later, Prescott et al24 (Class III) went on to showthat the incidence of severe hepatotoxicity in 100 patients atprobable risk by the nomogram was related to the time to firsttreatment with NAC. Of 62 patients treated within 10 hours ofingestion, those treated within 8 hours had no severehepatotoxicity and only 1 treated between 8 and 10 hoursdeveloped severe nonlethal hepatotoxicity. Of the 38 patientstreated between 10 and 24 hours postingestion, 20 (53%)developed severe hepatotoxicity, with 2 patients (5%) dying. Inthe group treated between 10 and 24 hours, patients with thelongest time to initiation of NAC therapy had the greatest risk
of developing hepatotoxicity, and both patients who died had

substantial delays in treatment (17.8 and 24 hourspostingestion). These data were compared to a historical cohortof acetaminophen-poisoned patients at probable risk who weretreated with supportive care and found to have an incidence ofsevere hepatotoxicity of 58% and a mortality of 5%. Thesupportive care group differed in baseline characteristics fromthe group of patients treated greater than 10 hours postingestionin that a greater portion of the treatment group was consideredhigh risk because of higher initial acetaminophenconcentrations. The authors propose that this differenceminimized the benefits of NAC treatment and resulted in equaltoxicity and mortality rates between the groups.24

In 1981, Rumack et al17 (Class II) published a retrospectiveobservational study of 662 acetaminophen overdose patients forwhom the nomogram applied. The data were presented withrespect to a modified version of the previously publishednomogram in which the authors incorporated a possiblehepatotoxic zone by moving the nomogram line 25% below theoriginal nomogram line (Figure). The FDA requested this bedone “to allow for possible errors in acetaminophen assaymeasurements.” In this study, patients at possible or probable riskfor hepatotoxicity by the nomogram were treated with NAC.Those categorized as having no risk by the nomogram were nottreated with NAC. The incidence of severe hepatotoxicity variedby risk group. Only 1 of 297 patients with no risk on thenomogram developed severe hepatotoxicity. In patients withpossible risk, 5% developed severe hepatotoxicity despitetreatment with NAC. In patients with probable risk,development of severe hepatotoxicity was related to the time tofirst treatment with NAC, with incidences of 7%, 29%, and62% when time to NAC treatment was less than 10 hours, 10to 16 hours, and 16 to 24 hours, respectively. No deathsoccurred among any patient treated within 24 hours.

In 1988, Smilkstein et al25 performed a prospective, Class IIstudy of 11,195 patients with suspected acetaminophenpoisonings. Patients with a nontoxic concentration on theRumack-Matthew nomogram were excluded from data analysis.The remaining 2,540 patients either had APAP concentrationsthat plotted in the possible or probable risk zones or hadunknown serum concentrations at the time of treatment, andwere treated with NAC. Of these patients, the incidence ofsevere hepatotoxicity was 2.9% when the NAC treatment delaywas less than 8 hours and 6.1% when the treatment delay wasless than 10 hours. No acetaminophen-related mortalityoccurred in these groups. However, this incidence of severehepatotoxicity rose to 26.4% when the treatment delay wasgreater than 10 hours. Eleven patients (0.54%) died who wereconsidered at risk by the nomogram and treated with NACwithin 24 hours, 9 of whom were considered to be at high riskaccording to presenting acetaminophen concentration and atreatment delay of greater than 16 hours. A Class III study byParker et al26 showed that even patients at probable risk for
hepatotoxicity treated with NAC 12 to 24 hours after ingestion

Clinical Policy

had a significant, time-dependent reduction of morbidity andmortality.

Other studies included in the Evidentiary Table support theuse of NAC in treating acute acetaminophen overdose as earlyas is feasible to maximize potential benefit.2,27-29

Some US poison centers are electing to treat acute APAPoverdoses only at probable risk for hepatotoxicity as determinedby the Rumack-Matthew nomogram. This evolving treatmentapproach may be supported by expert consensus or futurepublications of case series that describe the outcomes ofpossible-risk patients who do not receive NAC therapy.

On rare occasions patients will be risk stratified by theRumack-Matthew nomogram as having no risk forhepatotoxicity after acetaminophen ingestions despite beingfound to have increases in their hepatic transaminase levels.These cases may be due to inaccurate medical histories orincreased susceptibility in some patients. However, the treatingphysician should also consider alternative causes of hepaticinjury.

2. What are the indications for NAC in the acetaminophenoverdose patient who cannot be risk stratified by theRumack-Matthew nomogram?

Level A recommendations. None specified.Level B recommendations. Administer NAC to patients

with hepatic failure thought to be due to acetaminophen.Level C recommendations. Administer NAC to patients

who have hepatotoxicity thought to be due to acetaminophenand have a suspected or known acetaminophen overdose,including repeated supratherapeutic ingestions.

The Rumack-Matthew nomogram allows for riskstratification for hepatotoxicity of patients who present with asingle known time of an acetaminophen overdose within 24hours of ingestion. However, in the literature there are no clearstrategies for risk stratifying patients presenting greater than 24hours postingestion, with an unknown time or unreliablehistory of ingestion, or with extended-release or repeatedsupratherapeutic ingestions. Recommendations for treatmentwith NAC in these situations can be inferred, however, bylooking at its efficacy in various patient cohorts with isolateddetectable acetaminophen concentrations, elevated hepatictransaminase levels, or fulminant hepatic failure, with specialconsideration given to patients with extended-release orrepeated supratherapeutic ingestions of acetaminophen.

Emergency physicians often obtain an acetaminophenconcentration when patients present after an unknown oruncertain overdose. In this situation, physicians can be facedwith a detectable acetaminophen concentration and anunavailable or unreliable ingestion history. There are nosystematic studies that evaluate treatment protocols for thesepatients. Some experts suggest that screening for hepatotoxicityby performing aminotransferase concentrations in these patientsmay help guide management to reduce the risk of hepatic failure
even though the finding of normal serum transaminase levels in

the ED does not always exclude the risk of acetaminophentoxicity developing during the next several hours.

Currently, there are no controlled studies evaluating theeffectiveness of NAC for patients already with hepatotoxicitydue to acetaminophen but without hepatic failure. However,there are data that demonstrate that NAC reduces theincidence of hepatotoxicity, hepatic failure, and mortality whenpatients present with normal liver function and knowningestions,2,16,17,24-29 and data that demonstrates that NACreduces disease progression in patients with fulminant hepaticfailure.30,31 Even though there are no controlled studies to showthat NAC is effective for patients with hepatic injury who donot have hepatic failure, the potential for benefit suggests thatNAC be considered for these patients.

Two studies have demonstrated that intravenous NACdecreases disease progression in the setting of hepatic failurebelieved to be due to acetaminophen toxicity, irrespective of thetime of ingestion.30,31 In a prospective Class II study, Keays etal30 found a 28% absolute reduction in mortality (80% versus52%), decreased rates of cerebral edema, and decreased need forinotropic support with NAC use in patients with hepatic failure.In a Class III study, Harrison et al31 compared 41 patients withhepatic failure who received NAC to 57 similar patients whodid not receive NAC. They showed a 21% reduction inmortality, a 24% decrease in progression to coma, and 16%decrease in the need for dialysis.

Only 2 Class III case reports32,33 exist in the peer-reviewedliterature pertaining to overdoses with extended-releasepreparations of acetaminophen, both reporting on patients witha single known time of ingestion. The larger study, by Cetaruket al,32 reviewed 13 patients and showed that the eliminationhalf-life was similar to that of immediate-release acetaminophenoverdoses but the absorption was prolonged. Given the limitedsystematic data about risk stratification of these patients forhepatotoxicity, no therapeutic recommendations can be madeand the decision to treat must be individualized.

Repeated supratherapeutic ingestions of acetaminophen alsoprovide a challenging clinical situation for emergencyphysicians. One Class II study18 and multiple Class IIIreports20,34-48 have demonstrated that repeated supratherapeuticingestions of acetaminophen may result in hepatotoxicity,hepatic failure, and even death. Doses in these reports haveranged from just over 4 g per day to greater than 15 g per day.

In 2004, Daly et al18 (Class II) completed the onlyprospective descriptive analysis examining a managementalgorithm for repeated supratherapeutic ingestions. Within thealgorithm, treatment with NAC was recommended for serumacetaminophen concentrations of greater than or equal to 10�g/mL or greater than normal aminotransferase concentrations(AST or alanine transaminase (ALT) �50 IU/L). No patientwith normal AST at presentation went on to develophepatotoxicity despite having a mean acetaminophen dosing of10.6 g per day over a median duration of 34 hours. Of patients
who presented with hepatotoxicity (AST 50 to 1,000 IU/L),

Clinical Policy

15% went on to develop severe hepatotoxicity, with 1 patient(2%) dying from liver failure. The mean acetaminophen dosingin this group was 12 g per day over a median duration of 72hours. Finally, of patients who presented with severehepatotoxicity (AST �1,000 IU/L), 5 (14%) died and 1underwent liver transplant. This group had a meanacetaminophen dosing of 12.6 g per day over a median durationof 72 hours. Although no patient with a normal AST developedhepatotoxicity in this study, this finding is confounded by thefact that 50% of these patients received at least some NACtherapy. Given this, definitive recommendations cannot bemade about patients with repeated supratherapeutic ingestionsand no hepatotoxicity but with a detectable acetaminophenconcentration.

Finally, although unrelated to these specificrecommendations, the literature provides information thatattempts to relate presumed therapeutic acetaminopheningestions to the likelihood for hepatotoxicity. A recent Class IIarticle49 and several Class III34,50,51 reports found thattherapeutic ingestions of APAP may result in mild elevations ofserum transaminases of unknown significance. However, reportshave additionally shown that dosing regimens provided bypatients may not be reliable and may be clinicallymisleading.35-38 Furthermore, despite 3 Class III case series thathave postulated that chronic alcohol abuse predisposes patientsto acetaminophen-induced hepatotoxicity at therapeuticdoses,20,39,52 a Class I study53 and 2 Class III studies54,55 foundno evidence to support this.

Relevant industry relationships for the following AcetaminophenOverdose Subcommittee members are as follows: Dr. Heard is theMedical Toxicology Fellowship Director at the Rocky Mountain Poisonand Drug Center, which has research and business contracts withMcNeil Consumer Products and Cumberland Pharmaceuticals. Dr.Heard has received honoraria from Cumberland Pharmaceuticals andfrom McNeil Consumer Products to provide educational lectures andmaterials for projects other than this clinical policy.

Relevant industry relationships are those relationships withcompanies associated with products or services that significantly impactthe specific aspect of disease addressed in the critical question.

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21. Bond GR, Hite LK. Population-based incidence and outcome ofacetaminophen poisoning by type of ingestion. Acad Emerg Med.1999;6:1115-1120.

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acetylcysteine in the treatment of acetaminophen overdose.

Clinical Policy

Analysis of the national multicenter study (1976 to 1985). N EnglJ Med. 1988;319:1557-1562.

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28. Prescott LF, Ballantyne A, Proudfoot AT, et al. Treatment ofparacetamol (acetaminophen) poisoning with N-acetylcysteine.Lancet. 1977;310:432-434.

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31. Harrison PM, Keays R, Bray GP, et al. Improved outcome ofparacetamol-induced fulminant hepatic failure by lateadministration of acetylcysteine. Lancet. 1990;335:1572-1573.

32. Cetaruk EW, Dart RC, Hurlbut KM, et al. Tylenol Extended Reliefoverdose. Ann Emerg Med. 1997;30:104-108.

33. Bizovi KE, Aks SE, Paloucek F, et al. Late increase inacetaminophen concentration after overdose of Tylenol ExtendedRelief. Ann Emerg Med. 1996;28:549-551.

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36. Davis AM, Helms CM, Mitros FA, et al. Severe hepatic damageafter acetaminophen use in psittacosis. Am J Med. 1983;74:349-352.

37. Lane JE, Belson MG, Brown DK, et al. Chronic acetaminophentoxicity: a case report and review of the literature. J Emerg Med.2002;23:253-256.

38. Kaysen GA, Pond SM, Roper MH, et al. Combined hepatic andrenal injury in alcoholics during therapeutic use ofacetaminophen. Arch Intern Med. 1985;145:2019-2023.

39. Wootton FT, Lee WM. Acetaminophen hepatotoxicity in thealcoholic. South Med J. 1990;83:1047-1049.

40. McClain CJ, Holtzman J, Allen J, et al. Clinical features ofacetaminophen toxicity. J Clin Gastroenterol. 1988;10:76-80.

41. Black M, Cornell JF, Rabin L, et al. Late presentation of
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42. Bravo-Fernandez EF, Reddy KR, Jeffers L, et al. Hepatotoxicityafter prolonged use of acetaminophen: a case report. Bol AsocMed P R. 1988;80:417-419.

43. Goldfinger R, Ahmed KS, Pitchumoni CS, et al. Concomitantalcohol and drug abuse enhancing acetaminophen toxicity. Reportof a case. Am J Gastroenterol. 1978;70:385-388.

44. O’Dell JR, Zetterman RK, Burnett DA. Centrilobular hepaticfibrosis following acetaminophen-induced hepatic necrosis in analcoholic. JAMA. 1986;255:2636-2637.

45. Johnson MW, Friedman PA, Mitch WE. Alcoholism,nonprescription drug and hepatotoxicity. The risk from unknownacetaminophen ingestion. Am J Gastroenterol. 1981;76:530-533.

46. Barker JD Jr, de Carle DJ, Anuras S. Chronic excessiveacetaminophen use and liver damage. Ann Intern Med. 1977;87:299-301.

47. Gerber MA, Kaufmann H, Klion F, et al. Acetaminophenassociated hepatic injury, report of two cases showing unusualportal tract reactions. Hum Pathol. 1980;11:37-42.

48. Leist MH, Gluskin LE, Payne JA. Enhanced toxicity ofacetaminophen in alcoholics: report of three cases. J ClinGastroenterol. 1985;7:55-59.

49. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferaseelevations in healthy adults receiving 4 grams of acetaminophendaily: a randomized controlled trial. JAMA. 2006;296:87-93.

50. Floren CH, Thesleff P, Nilsson A. Severe liver damage caused bytherapeutic doses of acetaminophen. Acta Med Scand. 1987;222:285-288.

51. Bolesta S, Haber SL. Hepatotoxicity associated with chronicacetaminophen administration in patients without risk factors.Ann Pharmacother. 2002;36:331-333.

52. Kumar S, Rex DK. Failure of physicians to recognizeacetaminophen hepatotoxicity in chronic alcoholics. Arch InternMed. 1991;151:1189-1191.

53. Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal dailydoses of acetaminophen on the liver of alcoholic patients: arandomized, double-blind, placebo-controlled trial. Arch InternMed. 2001;161:2247-2252.

54. Benson GD. Acetaminophen in chronic liver disease. ClinPharmacol Ther. 1983;33:95-101.

55. Dart RC, Kuffner EK, Rumack BH. Treatment of pain or fever withparacetamol (acetaminophen) in the alcoholic patient: a
systematic review. Am J Ther. 2000;7:123-134.

n(s)/Test(s)/ Outcome Measure/ Criterion Standard

Results Limitations/Comments Class

report of APAP patients at

obable, and high risk xicity treated with

Dose ingested; APAP and transaminase levels; severe hepatotoxicity; mortality rates

n=179 included (44 excluded); of all possible-risk patients, 2 (4.5%) developed severe hepatotoxicity; of probable-risk patients, 10% developed severe hepatotoxicity when treatment <10 h, and 27% when treatment 10-24 h; of high-risk patients, 4.2% developed severe hepatotoxicity when treatment <10 h and 32% when treatment 10-24 h; 2 deaths: 1 possible-risk patient with a treatment delay of 13.5 h; 1 high-risk patient with a treatment delay of 17.5 h

Limitations: small sample size for each risk group when considering treatment delays; no randomization of treatment; unclear whether consecutive vs convenience enrollment; unclear whether entrance was triggered by poison center referral, which would result in selection bias

III

PAP poisoning and posed nomogram t data already in

;weiver rof sdohtem oN detneserp margomoN no data presented for derivation of nomogram

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Evidentiary Table. Study Year Design Interventio

ModalitySmilkstein et al2

1991 Prospective multicenter, observationalstudy

Descriptivepoisoning inpossible, prfor hepatotoIV NAC

Rumack and Matthew16

1975 Review Review of Atoxicity; prousing patienliterature

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Evidentiary Table (continued). Study Year Design Intervention(s)/Test(s)/

ModalityOutcome Measure/ Criterion Standard


Rumack et al17 1981 Retrospective observationalstudy

Multicenter open-label;modified nomogram used with 3 zones: no, possible, and probable risk for hepatotoxicity; patients with a possible or probable risk for hepatotoxicity were treated with NAC; serial laboratory tests performed; inclusions: possible or probable hepatotoxic APAP level, history of ingestion of >7.5 g in previous 24 h, and age >12 y

Dose ingested; APAP and transaminase levels; mortality

n=662; in no-risk patients, 0.3% hepatotoxicity with no mortality; in possible- risk patients, 5% hepatotoxicity with no mortality; in probable- risk patients treated <10 h, 7% hepatotoxicity with no mortality; in probable- risk patients treated 10-16 h, 29% hepatotoxicity with no mortality; in probable- risk patients treated 16-24 h, 62% hepatotoxicity, with no mortality

Limitations: open-label study; unreported blinding for assessment but should not effect outcome

II

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Daly et al18 2004 Prospective observational

Descriptive analysis of clinical algorithm for RSTIs

Group 1: AST <50 IU/L; group 2: AST 50-1,000 IU/L; group 3: AST >1,000 IU/L

n=277 enrolled, age >12 y; group 1: 126 patients (51%); mean dose 10.6 g/d; mean level 27 mg/L; 50% treated with NAC; no progression to hepatotoxicity or mortality; group 2: 47 patients (19%); mean dose 11.7 g/d; mean level 19 mg/L; all patients treated with NAC; 15% hepatotoxicity and 2% mortality; dose in the patient withmortality=12 g/d x 3 days; group 3: 37 patients (15%); mean dose 12.6 g/d; mean level 34 mg/L; all patients treated with NAC; 14% mortality; 39 patients had no laboratory results

Limitations: reporting bias for enrollment; reporting/recall bias for data collection

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Schiodt et al20 1997 Retrospective cohort study withstructuredenrollment

Descriptive analysis of APAP liver injury (intentional overdose vs RSTI)

Accidental versussuicidal cohorts; descriptive data on APAP levels, liver function tests, and mortality

n=71; 70% suicidal with mean APAP dose of 24 g/d (range of 3-125 g), 4% toxicity reported with therapeutic doses, 25% chronic alcohol use, 20% severe hepatotoxicity, and 2% mortality; 30% accidental with APAP mean dose of 11 g (range of 2-30 g/d), 14% toxicity with therapeutic doses; 33% toxicity with doses >10 g/d; 63% chronic alcohol use; 19% mortality

Limitations: dosing information by history; missing data on some variables

III

Prescott et al24 1979 Retrospective cohort study

Descriptive report of APAP poisoning in patients at probable risk for hepatotoxicity treated with NAC

Dose ingested; APAP andtransaminase levels; severe hepatotoxicity, mortality rates

n=100 (compared to a supportive care cohort of n=57); for treatment delays of <10 h, 2% severe hepatotoxicity with no mortality; for treatment delays 10-24 h, 53% severe hepatotoxicity with 5% mortality; for supportive care, 58% severe hepatotoxicity with 5% mortality, all <24 h

Comments: treatment group had significantly more patients considered to be at high risk by initial APAP level

Limitations: retrospective cohort with no description of continuous vs convenience enrollment

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Smilkstein et al25

1988 Population prospectivecohort study

Multicenter open-label;modified nomogram used with 3 zones: no, possible, and probable hepatotoxicity; all patients received NAC; series laboratory tests performed; inclusions: possible or probable hepatotoxic APAP level, history of ingestion of >7.5 g in previous 24 h, and age >12 y

Dose ingested; data analysis only on patients with possible or probable risk for hepatotoxicity; APAP andtransaminase levels; mortality

n=2,540 patients; 2.9% patients with severe hepatotoxicity when treated <8 h; 6.1% patients with severe hepatotoxicity when treated <10 h; increased incidences with treatment delays; 11 deaths; all in the probable risk zone treated >10 h, 9 of which were high risk and treated 16-24 h

Limitations: possible referral bias

II

Parker et al26 1990 Population prospectivecohort study

Descriptive report of APAP toxicity; patients with probable risk for hepatotoxicity treated with NAC 12-15 h and 15-24 h postingestion

Dose ingested; APAP andtransaminase levels; mortality

n=20; consecutive enrollment; median ingested dose=25 g; median delay to treatment=15.5 h; 30% severe hepatotoxicity when treatment 12-15 h; 40% severe hepatotoxicity when treatment 15-24 h; no hepatic failure or mortality; results compared to a historical supportive care cohort with 56% severe hepatotoxicity (12-15 h) and 82% severe hepatotoxicity (15-24 h)

Limitations: no reported blinded assessment; small sample size; enrolled patients compared to a historical cohort of supportive care patients

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Peterson and Rumack27

1977 Case report Descriptive report of APAP poisoning in a high-risk patient treated with NAC

Dose ingested; APAP andtransaminase levels

n=1; dose: 15.6 g ingestion; treatment delay=8 h; minor elevations in transaminases reported

Limitations: dosing information by history; not biopsy proven

III

Prescott et al28 1977 Case series Descriptive report of APAP poisoning in patients at probable risk for hepatotoxicity; patients treated with NAC

Dose ingested; APAP andtransaminase levels

n=15; only 1 treated <10 h developed severe hepatotoxicity

Limitations: convenience sample; small sample size

III

Oh and Shenfield29

1980 Case series Descriptive report of APAP poisoning in patients treated with NAC

APAP andtransaminase levels; incidence of morbidity and mortality

n=11 (3 high risk, 3 probable risk and 5 less than probable risk); treatment delay=7.7 h (maximum=20 h); no morbidity or mortality

Limitations: retrospective cohort with no description of continuous vs convenience enrollment; 5 patients of unknown risk (less than probable risk)

III

Keays et al30 1991 Prospective randomized controlledstudy

Comparison of NAC versus placebo control in fulminant hepatic failure due to APAP ingestion

Study group characteristics; outcomes: mortality, cerebral edema, and inotropic rates

n=50 (25 NAC arm, 25 control arm); NAC treatment arm: 40% cerebral edema, 48% inotropic support, 52% mortality; placebo treatment arm: 68% cerebral edema, 80% inotropic support, 80% mortality

Limitations: comorbidities of each group not reported; no description of blinded outcomes assessment

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Harrison et al31 1990 Retrospective cohort study

Retrospective cohort of fulminant hepatic failure due to APAP ingestion

Cohort characteristics; outcomes: mortality, progression of disease, need for dialysis

n=100 (2 patients treated <10 h; 41 patients treated >10 h, 57 patients treated with supportive care); early treatment group: both survived without progression or dialysis; late treatment group: 51% progression, 51% dialysis, 37% mortality; supportive treatment group: 75% progression, 67% dialysis, 58% mortality

Limitations: no description of blinded outcomes assessment

III

Cetaruk et al32 1997 Case series Descriptive report of extended release APAP toxicokinetics

Dose ingested, APAP and transaminase concentrations

n=13 with single ingestions and normal transaminases at presentation; dose: 10.4-65 g; elimination phase=8 h postingestion (suggesting delayed absorption);elimination half-life=3.1 (similar to immediate release); absorption; no second peak in APAP concentrationsoccurred

Limitations: dosing information by history; small cohort

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Bizovi et al33 1996 Case report Descriptive report of an extended release APAP ingestion

Dose ingested; APAP and transaminase concentrations;mortality

n=1; late increase in serum APAP concentration at 14 h

Limitations: coingested with agents known to slow gastrointestinal motility

III

Seeff at al34 1986 Case series Descriptive report of APAP toxicity with therapeutic ingestions and RSTI


n=6 new patients plus19 patients reported in the literature; dose range: 2.6-16.5 g/d, median=6.4 g/d; all chronic alcoholics; mortality 20%

Limitations: dosing information by history; correlation to alcohol speculative due to biased enrollment

III

Ambre and Alexander35

1977 Case series Descriptive report of lack of APAP toxicity in overdose patients


n=5; all gave history of significant overdose;none developed toxic level; none developed significant toxicity

Limitations: dosing information by history

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Davis et al36 1983 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 10 g over 48 h; died 28 days postingestion, ?APAP related; pathology- proven diagnosis

Limitations: dosing information by history; correlation to psittacosis speculative

III

Lane et al37 2002 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 5-6.5 g/d; no alcohol use; survived

Limitations: dosing information by history; no biopsy performed

III

Kaysen et al38 1985 Case series Descriptive report of APAP toxicity with therapeutic use and RSTI of APAP


n=5; dose: 2.5-10 g/d; all with chronic alcohol use; pathology proven in 3; all developed severe hepatotoxicity; 2 survived

Limitations: dosing information by history; correlation to alcohol speculative

III

Wootton and Lee39

1990 Case series Descriptive report of APAP toxicity with RSTI


n=7; dose: 4-11 g/d; all with chronic alcohol use; none biopsied; all developed severe hepatotoxicity; 3 died


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McClain et al40 1988 Case series Descriptive report of APAP toxicity with RSTI compared to intentional overdose


n=13 (6 RSTI, 7 overdose); all developed severe hepatotoxicity; RSTI patients: mean APAP=9 g/d; 2 developed hepatic encephalopathy; 1 died; overdose patients: mean APAP=23 g/d; 1 developed hepatic encephalopathy; 1 died


III

Black et al41 1982 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 10 g/d; chronic alcohol use; died; pathology-proven diagnosis


III

Bravo-Fernandez et al42

1988 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 4-5 g/d for months; chronic alcohol use; survived; biopsy-provendiagnosis


III

Goldfinger et al43

1978 Case report Descriptive report of APAP toxicity with supratherapeutic dose


n=1; dose: 9.75 g over unknown time; chronic alcohol use; required dialysis, pressors, and blood products; survived

Limitations: dosing information by history; correlation to alcohol speculative;no biopsy performed

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O’Dell et al44 1986 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 6 g/d; chronic alcohol use; hepatotoxicity resolved with discontinuation of APAP; recurrent hepatotoxicity developed with 6 g/d APAP 8 months later; survived; biopsy- proven diagnosis


III

Johnson et al45 1981 Case report Descriptive report of APAP toxicity with RSTI


n=1; dose: 6 g/d; chronic alcohol use; survived

Limitations: dosing information by history; correlation to alcohol speculative; no biopsy performed

III

Barker et al46 1977 Case series Descriptive report of APAP toxicity with RSTI


n=3; dose: 5-8 g/d; 1 with chronic alcohol use; biopsy proven in 2 patients; severe hepatotoxicity in 2 and hepatotoxicity in 1; all survived


III

Gerber et al47 1980 Case series Descriptive report of APAP toxicity with RSTI


n=2; dose: 4-6.4 g/d; both with chronic alcohol use; biopsy proven; both developed severe hepatotoxicity; both survived


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Leist et al48 1985 Case series Descriptive report of APAP toxicity with RSTI


n=3; dose: 5-8.75 g/d; all with chronic alcohol use; pathology proven in 2; all developed severe hepatotoxicity; 1 died


III

Watkins et al49 2006 Randomized, single-blinded,placebo-controlled

Comparison trial of 5 treatment groups at therapeutic dosings (placebo, APAP, morphine/APAP, hydromorphone/APAP, and oxycodone/APAP); diet-controlled

Treatment given every 6 h for 14 days; APAP dose=4 g/d; routine LFTs and serum alpha glutathione S-transferase

n=147 normal adults 18-45 y without concomitant medication use or medical history; of 39 patients receiving placebo max ALT rise ≤3 x normal; of 108 patients receiving APAP, 31%–41% max ALT rise >3 x normal; following APAP discontinuation, ALT concentrations often returned to normal; all APAP treatment groups showed similar findings

Limitations: single-blinded II

Floren et al50 1987 Case series Descriptive report of APAP toxicity with therapeutic ingestions


n=2; doses: 1-1.5 g/d and 3.5 g/d; biopsy- proven diagnosis


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Bolesta and Haber51

2002 Case series Descriptive report of APAP toxicity with therapeutic ingestions


n=4; doses: 1-4 g/d; all with hepatotoxicity, no severe hepatotoxicity, and no mortality; not pathology proven; no chronic alcohol use

Limitations: dosing information by history; alternative etiologies possible

III

Kumar and Rex52

1991 Case series Descriptive report of APAP toxicity with RSTI


n=6; alcoholics with RSTI; doses: 5-20 gm/day; all with severe hepatotoxicity; mortality: 33%; only 1 of 6 identified on admit

Limitations: dosing information by history; correlation to alcohol speculative due to biased enrollment

III

Kuffner et al53 2001 Randomized, double-blinded,placebo-controlledtrial

Effect of APAP 4 d/g x 2 days vs placebo on liver function in alcoholic patients

Baseline LFTs, coagulations;daily LFTs, coagulations and APAP level drawn; incidence of hepatotoxicity reported

n=201 (102 APAP treated vs 99 placebo); baseline characteristics equal; no statistically significant difference in enzymatic activity

I

Benson54 1983 Double-blinded,placebo-controlled,cross-overtrial

Effect of therapeutic APAP doses (4 g/d) vs placebo on liver function and metabolism in chronic liver disease patients

Baseline LFTs, coagulations; routine LFTs, coagulations and APAP level drawn through crossover; APAP half-lifecalculated as a marker of drug metabolism and accumulation; incidence of hepatotoxicity reported for treatment and placebo periods

N=6 pilot patients; N=20 double-blinded crossover patients; no statistically significant difference in enzymatic activity or metabolism with 13 days of therapeutic APAP

Limitations: blinded assessment not described; small sample size

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Dart et al55 2000 Literature review

Systematic literature review assessing safety of therapeutic APAP doses in the alcoholic patient

Systematic review with grading of the literature

7 Class I/II studies, 20 Class III reports; Class I/II results: therapeutic ingestion dose did not cause hepatotoxicity; Class III results: conflicting data

Limitations: methodology of review incompletely described

III

ALT, alanine transaminase; APAP, acetaminophen; AST, aspartate aminotransferase; h, hour; IV, intravenous; LFT, liver function test; NAC, N-acetylcysteine; RSTI, repeated supratherapeutic ingestion; y, year.

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Appendix A. Literature classification schema.*

Design/Class Therapy† Diagnosis‡ Prognosis§

1 Randomized, controlled trial ormeta-analyses ofrandomized trials

Prospective cohort using acriterion standard

Population prospective cohort

2 Nonrandomized trial Retrospective observational Retrospective cohortCase control

3 Case series Case series Case seriesCase report Case report Case reportOther (eg, consensus, review) Other (eg, consensus, review) Other (eg, consensus, review)

*Some designs (eg, surveys) will not fit this schema and should be assessed individually.†Objective is to measure therapeutic efficacy comparing �2 interventions.‡Objective is to determine the sensitivity and specificity of diagnostic tests.§
Objective is to predict outcome including mortality and morbidity.
Appendix B. Approach to downgrading strength of evidence.

Downgrading Design/Class

1 2 3

None I II III1 level II III X2 levels III X XFatally flawed X X X


clinical policy: critical issues in the management of ... · acetaminophen overdose from the...

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