TOXICOLOGY/CLINICAL POLICY
Clinical Policy: Critical Issues in the Management of Patients
Presenting to the Emergency Department With
Acetaminophen Overdose
From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Critical
Issues in the Management of Patients Presenting to the Emergency Department With Acetaminophen Overdose:
Stephen J. Wolf, MD (Chair)
Kennon Heard, MD
Edward P. Sloan, MD, MPH
Andy 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 20062007)
Wyatt W. Decker, MD (Co-Chair 2006-2007)
Deborah B. Diercks, MD
Jonathan A. Edlow, MD
Francis M. Fesmire, MD
Steven A. Godwin, MD
Sigrid A. Hahn, MD
John M. Howell, MD
J. Stephen Huff, MD
Thomas W. Lukens, MD, PhD
Donna L. Mason, RN, MS, CEN (ENA Representative
2004-2006)
Michael Moon, RN, CNS, MSN, CEN (ENA
Representative 2004)
Anthony M. Napoli, MD (EMRA Representative 20042006)
Devorah Nazarian, MD
Jim Richmann, RN, BS, MA(c), CEN (ENA Representative
2006-2007)
Scott M. Silvers, MD
Edward P. Sloan, MD, MPH
Molly E. W. Thiessen, MD (EMRA Representative 20062007)
Robert L. Wears, MD, MS (Methodologist)
Stephen J. Wolf, MD
Cherri 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
Policy statements and clinical policies are the official policies of the American College of Emergency
Physicians and, as such, are not subject to the same peer review process as articles appearing in the print
journal. Policy statements and clinical policies of ACEP do not necessarily reflect the policies and beliefs
of Annals of Emergency Medicine and its editors.
0196-0644/$-see front matter
Copyright © 2007 by the American College of Emergency Physicians.
doi:10.1016/j.annemergmed.2007.06.014
[Ann Emerg Med. 2007;50:292-313.]
ABSTRACT
This clinical policy focuses on critical issues concerning the
management of patients presenting to the emergency
department (ED) with acetaminophen overdose. The
292 Annals of Emergency Medicine
subcommittee reviewed the medical literature relevant to the
questions posed. The critical questions are:
1. What are the indications for N-acetylcysteine (NAC) in the
acetaminophen overdose patient with a known time of acute
ingestion who can be risk stratified by the RumackMatthew nomogram?
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Clinical Policy
2. What are the indications for NAC in the acetaminophen
overdose patient who cannot be risk stratified by the
Rumack-Matthew nomogram?
Recommendations are provided on the basis of the strength
of evidence of the literature. Level A recommendations represent
patient management principles that reflect a high degree of
clinical certainty; Level B recommendations represent patient
management principles that reflect moderate clinical certainty;
and Level C recommendations represent other patient
management strategies that are based on preliminary,
inconclusive, or conflicting evidence, or based on committee
consensus. This guideline is intended for physicians working in
EDs.
INTRODUCTION
Since the early 1970s, N-acetylcysteine (NAC) has been used
as an antidote to acetaminophen overdose.1 Acetaminophen is
not only metabolized through glucuronidation and sulfation to
nontoxic metabolites but also, in small part, to N-acetyl-pbenzoquinoneimine (NAPQI), a hepatotoxic metabolite at a
cellular level. This latter metabolic pathway is used to a greater
extent in the overdose setting when physiologic stores of
sulfhydryl donors are depleted, thereby limiting the nontoxic
means for acetaminophen metabolism. NAC has been shown to
limit hepatotoxicity in acetaminophen-toxic patients by several
mechanisms. First, NAC serves as a sulfhydryl group donor,
allowing continued nontoxic metabolism; second, NAC can
serve to conjugate NAPQI into a nontoxic metabolite; and
finally, NAC has been shown to blunt the hepatocellular
toxicity of NAPQI. In the setting of acetaminophen overdose,
hepatotoxicity is defined as any increase in aspartate
aminotransferase (AST) concentrations, severe hepatotoxicity as
an AST greater than 1,000 IU/L, and hepatic failure as
hepatotoxicity with hepatic encephalopathy. These definitions
will be used for this policy unless otherwise stated.
Multiple protocols for the administration of NAC in the
patient with known or suspected acetaminophen toxicity exist
for both the oral and intravenous routes.2-7 Both have been
shown to be equally efficacious.3,4,8 Orally, NAC has been
shown to have a minimal adverse effect profile, consisting
mostly of nausea and emesis, and increased tolerance can be
achieved with co-administration of an antiemetic.9-11 Studies
have shown that the dose of oral NAC does not need to change
when activated charcoal is given concomitantly.12 The
intravenous preparation was approved by the US Food and
Drug Administration (FDA) for use in the United States in
2004. Common adverse effects include pruritus, flushing, and a
rash (approximately 15% of patients), which is most often
treated by holding the infusion, administering an antihistamine,
and restarting the infusion at a lower rate.13 Bronchospasm and
hypotension are rare (⬍2%).14 Fatal reactions are rare but have
been reported.15
The Rumack-Matthew nomogram is a tool used to stratify
patients at risk for hepatotoxicity after a single acute
acetaminophen ingestion at a known point in time16,17 (Figure).
Volume , .  : September 
Figure. Rumack-Matthew nomogram. Plasma acetaminophen
concentration versus time post–acetaminophen ingestion.
Printed with permission.17 Copyright©1981 American Medical
Association.
A serum acetaminophen concentration in these patients, taken
after 4 hours and before 24 hours postingestion, can be plotted
on the nomogram to indicate whether or not a patient is at no
risk, possible risk, or probable risk of developing hepatotoxicity.
This information is often used to determine whether or not
NAC is indicated. Some experts will use the nomogram to
stratify patients with multiple ingestions within an 8-hour
period, using the time that the series of ingestions started as the
time of ingestion. Patients with delayed presentation (⬎24
hours after ingestion), an unknown time or duration of
ingestion, ingestion of extended-release preparation, or a
repeated supratherapeutic ingestion cannot be risk stratified
with this nomogram.
Repeated supratherapeutic ingestions are a unique clinical
situation entailing a pattern of multiple ingestions of
acetaminophen during a period of greater than 8 hours that
result in a cumulative dosage of greater than 4 g per 24
hours.18,19 Two case series reported that approximately 30% of
patients admitted for acetaminophen overdose had repeated
supratherapeutic ingestions. These studies also suggested that
patients with repeated supratherapeutic ingestions have a worse
prognosis than patients admitted after acute overdose.20,21 Most
Annals of Emergency Medicine 293
Clinical Policy
often, repeated supratherapeutic ingestions are not suicide
attempts but rather therapeutic misadventures. A recent
systematic review with consensus recommendations states that
repeated supratherapeutic ingestions need to be referred to an
emergency 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 g
or 150 mg/kg (whichever is less) per 24-hour period for the
preceding 48 hours or longer, is ingested.19 These authors
suggest that these thresholds should be decreased to 4 g or 100
mg/kg (whichever is less) for patients potentially at increased
risk for acetaminophen toxicity (eg, isoniazid use, prolonged
fasting).
This clinical policy uses an evidence-based approach to
evaluate the literature and make recommendations about the
management of acetaminophen overdose. The subcommittee
generated the critical questions with input from the American
College of Emergency Physicians (ACEP) Toxicology Section,
and the questions are believed to be important for emergency
physicians initially providing care in the ED.
This policy evolved from the 1999 ACEP “Clinical Policy
for the Initial Approach to Patients Presenting with Acute Toxic
Ingestion or Dermal or Inhalation Exposure.”22
METHODOLOGY
This clinical policy was created after careful review and
critical analysis of the medical literature. MEDLINE searches
for articles published between January 1974 and January 2006
were performed using a combination of key words and their
variations, 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 to
English-language sources. Additional articles were reviewed
from the bibliography of articles cited and from published
textbooks and review articles. Subcommittee members also
supplied articles from their own files.
The reasons for developing clinical policies in emergency
medicine and the approaches used in their development have
been enumerated.23 This policy is a product of the ACEP
clinical policy development process, including expert review,
and is based on the existing literature; when literature was not
available, consensus of emergency physicians and toxicologists
was used. Expert review comments were received from
individual emergency physicians and toxicologists and
individual members from the American Academy of Pediatrics
Committee and Section on Pediatric Emergency Medicine,
American Association for the Study of Liver Diseases, American
Gastroenterological Association, and ACEP’s Toxicology
Section. Their responses were used to further refine and enhance
this policy. Clinical policies are scheduled for revision every 3
years; however, interim reviews are conducted when technology
or 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
294 Annals of Emergency Medicine
evidence and classified by the subcommittee members into 3
classes of evidence on the basis of the design of the study, with
design 1 representing the strongest evidence and design 3
representing the weakest evidence for therapeutic, diagnostic,
and prognostic clinical reports, respectively (Appendix A).
Articles were then graded on 6 dimensions thought to be most
relevant to the development of a clinical guideline: blinded
versus nonblinded outcome assessment, blinded or randomized
allocation, direct or indirect outcome measures (reliability and
validity), biases (eg, selection, detection, transfer), external
validity (ie, generalizability), and sufficient sample size. Articles
received a final grade (Class I, II, III) on the basis of a
predetermined formula, taking into account design and quality
of study (Appendix B). Articles with fatal flaws were given an
“X” grade and not used in formulating recommendations in this
policy. Evidence grading was done with respect to the specific
data being extracted and the specific critical question being
reviewed. Thus, the level of evidence for any one study may vary
according to the question, and it is possible for a single article to
receive different levels of grading as different critical questions
are answered. Question-specific level of evidence grading may be
found in the Evidentiary Table included at the end of this policy.
Clinical findings and strength of recommendations regarding
patient management were then made according to the following
criteria:
Level A recommendations. Generally accepted principles
for patient management that reflect a high degree of clinical
certainty (ie, based on strength of evidence Class I or
overwhelming evidence from strength of evidence Class II
studies that directly address all of the issues).
Level B recommendations. Recommendations for patient
management that may identify a particular strategy or range of
management strategies that reflect moderate clinical certainty
(ie, based on strength of evidence Class II studies that directly
address the issue, decision analysis that directly addresses the
issue, or strong consensus of strength of evidence Class III
studies).
Level C recommendations. Other strategies for patient
management that are based on preliminary, inconclusive, or
conflicting evidence, or in the absence of any published
literature, based on panel consensus.
There are certain circumstances in which the
recommendations stemming from a body of evidence should
not be rated as highly as the individual studies on which they
are based. Factors such as heterogeneity of results, uncertainty
about effect magnitude and consequences, strength of prior
beliefs, and publication bias, among others, might lead to such a
downgrading of recommendations.
It is the goal of the Clinical Policies Committee to provide
an evidence-based recommendation when the medical literature
provides enough quality information to answer a critical
question. When the medical literature does not contain enough
quality information to answer a critical question, the members
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Clinical Policy
of the Clinical Policies Committee believe that it is equally
important to alert emergency physicians to this fact.
Recommendations offered in this policy are not intended to
represent the only diagnostic and management options that the
emergency physician should consider. ACEP clearly recognizes
the importance of the individual physician’s judgment. Rather,
this guideline defines for the physician those strategies for which
medical literature exists to provide support for answers to the
crucial questions addressed in this policy.
Scope of Application. This guideline is intended for
physicians working in EDs.
Inclusion Criteria. This guideline is intended for patients
older than 12 years who present to the ED with acetaminophen
overdose.
Exclusion Criteria. This guideline is not intended for
application to patients 12 years and younger.
CRITICAL QUESTIONS
1. What are the indications for NAC in the acetaminophen
overdose patient with a known time of acute ingestion who
can be risk stratified by the Rumack-Matthew nomogram?
Level A recommendations. None specified.
Level B recommendations.
1. Administer NAC to acute acetaminophen overdose patients
with either possible or probable risk for hepatotoxicity as
determined by the Rumack-Matthew nomogram to reduce
the incidence of severe hepatotoxicity and mortality, ideally
within 8 to 10 hours postingestion.
2. Do not administer NAC to acute acetaminophen overdose
patients with no risk for hepatotoxicity as determined by the
Rumack-Matthew nomogram.
Level C recommendations. None specified.
In 1975, Rumack and Matthew16 published a review article
describing a nomogram that used previously published data on
30 patients older than 12 years to predict hepatic toxicity after
an acute acetaminophen ingestion. The proposed nomogram
applied only to patients with a single acute poisoning at a
known time who were no more than 24 hours postingestion.
Concentrations drawn between 4 and 24 hours were to be
plotted to determine whether the patient fell either above the
nomogram line, indicating a probable risk for hepatotoxicity, or
below the line, indicating no risk for hepatotoxicity.16
Four years later, Prescott et al24 (Class III) went on to show
that the incidence of severe hepatotoxicity in 100 patients at
probable risk by the nomogram was related to the time to first
treatment with NAC. Of 62 patients treated within 10 hours of
ingestion, those treated within 8 hours had no severe
hepatotoxicity and only 1 treated between 8 and 10 hours
developed severe nonlethal hepatotoxicity. Of the 38 patients
treated between 10 and 24 hours postingestion, 20 (53%)
developed severe hepatotoxicity, with 2 patients (5%) dying. In
the group treated between 10 and 24 hours, patients with the
longest time to initiation of NAC therapy had the greatest risk
of developing hepatotoxicity, and both patients who died had
Volume , .  : September 
substantial delays in treatment (17.8 and 24 hours
postingestion). These data were compared to a historical cohort
of acetaminophen-poisoned patients at probable risk who were
treated with supportive care and found to have an incidence of
severe hepatotoxicity of 58% and a mortality of 5%. The
supportive care group differed in baseline characteristics from
the group of patients treated greater than 10 hours postingestion
in that a greater portion of the treatment group was considered
high risk because of higher initial acetaminophen
concentrations. The authors propose that this difference
minimized the benefits of NAC treatment and resulted in equal
toxicity and mortality rates between the groups.24
In 1981, Rumack et al17 (Class II) published a retrospective
observational study of 662 acetaminophen overdose patients for
whom the nomogram applied. The data were presented with
respect to a modified version of the previously published
nomogram in which the authors incorporated a possible
hepatotoxic zone by moving the nomogram line 25% below the
original nomogram line (Figure). The FDA requested this be
done “to allow for possible errors in acetaminophen assay
measurements.” In this study, patients at possible or probable risk
for hepatotoxicity by the nomogram were treated with NAC.
Those categorized as having no risk by the nomogram were not
treated with NAC. The incidence of severe hepatotoxicity varied
by risk group. Only 1 of 297 patients with no risk on the
nomogram developed severe hepatotoxicity. In patients with
possible risk, 5% developed severe hepatotoxicity despite
treatment with NAC. In patients with probable risk,
development of severe hepatotoxicity was related to the time to
first treatment with NAC, with incidences of 7%, 29%, and
62% when time to NAC treatment was less than 10 hours, 10
to 16 hours, and 16 to 24 hours, respectively. No deaths
occurred among any patient treated within 24 hours.
In 1988, Smilkstein et al25 performed a prospective, Class II
study of 11,195 patients with suspected acetaminophen
poisonings. Patients with a nontoxic concentration on the
Rumack-Matthew nomogram were excluded from data analysis.
The remaining 2,540 patients either had APAP concentrations
that plotted in the possible or probable risk zones or had
unknown serum concentrations at the time of treatment, and
were treated with NAC. Of these patients, the incidence of
severe hepatotoxicity was 2.9% when the NAC treatment delay
was less than 8 hours and 6.1% when the treatment delay was
less than 10 hours. No acetaminophen-related mortality
occurred in these groups. However, this incidence of severe
hepatotoxicity rose to 26.4% when the treatment delay was
greater than 10 hours. Eleven patients (0.54%) died who were
considered at risk by the nomogram and treated with NAC
within 24 hours, 9 of whom were considered to be at high risk
according to presenting acetaminophen concentration and a
treatment delay of greater than 16 hours. A Class III study by
Parker et al26 showed that even patients at probable risk for
hepatotoxicity treated with NAC 12 to 24 hours after ingestion
Annals of Emergency Medicine 295
Clinical Policy
had a significant, time-dependent reduction of morbidity and
mortality.
Other studies included in the Evidentiary Table support the
use of NAC in treating acute acetaminophen overdose as early
as is feasible to maximize potential benefit.2,27-29
Some US poison centers are electing to treat acute APAP
overdoses only at probable risk for hepatotoxicity as determined
by the Rumack-Matthew nomogram. This evolving treatment
approach may be supported by expert consensus or future
publications of case series that describe the outcomes of
possible-risk patients who do not receive NAC therapy.
On rare occasions patients will be risk stratified by the
Rumack-Matthew nomogram as having no risk for
hepatotoxicity after acetaminophen ingestions despite being
found to have increases in their hepatic transaminase levels.
These cases may be due to inaccurate medical histories or
increased susceptibility in some patients. However, the treating
physician should also consider alternative causes of hepatic
injury.
2. What are the indications for NAC in the acetaminophen
overdose patient who cannot be risk stratified by the
Rumack-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 acetaminophen
and have a suspected or known acetaminophen overdose,
including repeated supratherapeutic ingestions.
The Rumack-Matthew nomogram allows for risk
stratification for hepatotoxicity of patients who present with a
single known time of an acetaminophen overdose within 24
hours of ingestion. However, in the literature there are no clear
strategies for risk stratifying patients presenting greater than 24
hours postingestion, with an unknown time or unreliable
history of ingestion, or with extended-release or repeated
supratherapeutic ingestions. Recommendations for treatment
with NAC in these situations can be inferred, however, by
looking at its efficacy in various patient cohorts with isolated
detectable acetaminophen concentrations, elevated hepatic
transaminase levels, or fulminant hepatic failure, with special
consideration given to patients with extended-release or
repeated supratherapeutic ingestions of acetaminophen.
Emergency physicians often obtain an acetaminophen
concentration when patients present after an unknown or
uncertain overdose. In this situation, physicians can be faced
with a detectable acetaminophen concentration and an
unavailable or unreliable ingestion history. There are no
systematic studies that evaluate treatment protocols for these
patients. Some experts suggest that screening for hepatotoxicity
by performing aminotransferase concentrations in these patients
may help guide management to reduce the risk of hepatic failure
even though the finding of normal serum transaminase levels in
296 Annals of Emergency Medicine
the ED does not always exclude the risk of acetaminophen
toxicity developing during the next several hours.
Currently, there are no controlled studies evaluating the
effectiveness of NAC for patients already with hepatotoxicity
due to acetaminophen but without hepatic failure. However,
there are data that demonstrate that NAC reduces the
incidence of hepatotoxicity, hepatic failure, and mortality when
patients present with normal liver function and known
ingestions,2,16,17,24-29 and data that demonstrates that NAC
reduces disease progression in patients with fulminant hepatic
failure.30,31 Even though there are no controlled studies to show
that NAC is effective for patients with hepatic injury who do
not have hepatic failure, the potential for benefit suggests that
NAC be considered for these patients.
Two studies have demonstrated that intravenous NAC
decreases disease progression in the setting of hepatic failure
believed to be due to acetaminophen toxicity, irrespective of the
time of ingestion.30,31 In a prospective Class II study, Keays et
al30 found a 28% absolute reduction in mortality (80% versus
52%), decreased rates of cerebral edema, and decreased need for
inotropic support with NAC use in patients with hepatic failure.
In a Class III study, Harrison et al31 compared 41 patients with
hepatic failure who received NAC to 57 similar patients who
did not receive NAC. They showed a 21% reduction in
mortality, 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-reviewed
literature pertaining to overdoses with extended-release
preparations of acetaminophen, both reporting on patients with
a single known time of ingestion. The larger study, by Cetaruk
et al,32 reviewed 13 patients and showed that the elimination
half-life was similar to that of immediate-release acetaminophen
overdoses but the absorption was prolonged. Given the limited
systematic data about risk stratification of these patients for
hepatotoxicity, no therapeutic recommendations can be made
and the decision to treat must be individualized.
Repeated supratherapeutic ingestions of acetaminophen also
provide a challenging clinical situation for emergency
physicians. One Class II study18 and multiple Class III
reports20,34-48 have demonstrated that repeated supratherapeutic
ingestions of acetaminophen may result in hepatotoxicity,
hepatic failure, and even death. Doses in these reports have
ranged from just over 4 g per day to greater than 15 g per day.
In 2004, Daly et al18 (Class II) completed the only
prospective descriptive analysis examining a management
algorithm for repeated supratherapeutic ingestions. Within the
algorithm, treatment with NAC was recommended for serum
acetaminophen 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 patient
with normal AST at presentation went on to develop
hepatotoxicity despite having a mean acetaminophen dosing of
10.6 g per day over a median duration of 34 hours. Of patients
who presented with hepatotoxicity (AST 50 to 1,000 IU/L),
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Clinical Policy
15% went on to develop severe hepatotoxicity, with 1 patient
(2%) dying from liver failure. The mean acetaminophen dosing
in this group was 12 g per day over a median duration of 72
hours. Finally, of patients who presented with severe
hepatotoxicity (AST ⬎1,000 IU/L), 5 (14%) died and 1
underwent liver transplant. This group had a mean
acetaminophen dosing of 12.6 g per day over a median duration
of 72 hours. Although no patient with a normal AST developed
hepatotoxicity in this study, this finding is confounded by the
fact that 50% of these patients received at least some NAC
therapy. Given this, definitive recommendations cannot be
made about patients with repeated supratherapeutic ingestions
and no hepatotoxicity but with a detectable acetaminophen
concentration.
Finally, although unrelated to these specific
recommendations, the literature provides information that
attempts to relate presumed therapeutic acetaminophen
ingestions to the likelihood for hepatotoxicity. A recent Class II
article49 and several Class III34,50,51 reports found that
therapeutic ingestions of APAP may result in mild elevations of
serum transaminases of unknown significance. However, reports
have additionally shown that dosing regimens provided by
patients may not be reliable and may be clinically
misleading.35-38 Furthermore, despite 3 Class III case series that
have postulated that chronic alcohol abuse predisposes patients
to acetaminophen-induced hepatotoxicity at therapeutic
doses,20,39,52 a Class I study53 and 2 Class III studies54,55 found
no evidence to support this.
Relevant industry relationships for the following Acetaminophen
Overdose Subcommittee members are as follows: Dr. Heard is the
Medical Toxicology Fellowship Director at the Rocky Mountain Poison
and Drug Center, which has research and business contracts with
McNeil Consumer Products and Cumberland Pharmaceuticals. Dr.
Heard has received honoraria from Cumberland Pharmaceuticals and
from McNeil Consumer Products to provide educational lectures and
materials for projects other than this clinical policy.
Relevant industry relationships are those relationships with
companies associated with products or services that significantly impact
the specific aspect of disease addressed in the critical question.
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41.
Analysis of the national multicenter study (1976 to 1985). N Engl
J Med. 1988;319:1557-1562.
Parker D, White JP, Paton D, et al. Safety of late acetylcysteine
treatment in paracetamol poisoning. Hum Exp Toxicol. 1990;9:
25-27.
Peterson RG, Rumack BH. Treating acute acetaminophen
poisoning with acetylcysteine. JAMA. 1977;237:2406-2407.
Prescott LF, Ballantyne A, Proudfoot AT, et al. Treatment of
paracetamol (acetaminophen) poisoning with N-acetylcysteine.
Lancet. 1977;310:432-434.
Oh TE, Shenfield GM. Intravenous N-acetylcysteine for
paracetamol poisoning. Med J Aust. 1980;1:664-665.
Keays R, Harrison PM, Wendon JA, et al. Intravenous
acetylcysteine in paracetamol-induced fulminant hepatic failure: a
prospective controlled trial. BMJ. 1991;303:1026-1029.
Harrison PM, Keays R, Bray GP, et al. Improved outcome of
paracetamol-induced fulminant hepatic failure by late
administration of acetylcysteine. Lancet. 1990;335:1572-1573.
Cetaruk EW, Dart RC, Hurlbut KM, et al. Tylenol Extended Relief
overdose. Ann Emerg Med. 1997;30:104-108.
Bizovi KE, Aks SE, Paloucek F, et al. Late increase in
acetaminophen concentration after overdose of Tylenol Extended
Relief. Ann Emerg Med. 1996;28:549-551.
Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen
hepatotoxicity in alcoholics. A therapeutic misadventure. Ann
Intern Med. 1986;104:399-404.
Ambre J, Alexander M. Liver toxicity after acetaminophen
ingestion. Inadequacy of the dose estimate as an index of risk.
JAMA. 1977;238:500-501.
Davis AM, Helms CM, Mitros FA, et al. Severe hepatic damage
after acetaminophen use in psittacosis. Am J Med. 1983;74:349352.
Lane JE, Belson MG, Brown DK, et al. Chronic acetaminophen
toxicity: a case report and review of the literature. J Emerg Med.
2002;23:253-256.
Kaysen GA, Pond SM, Roper MH, et al. Combined hepatic and
renal injury in alcoholics during therapeutic use of
acetaminophen. Arch Intern Med. 1985;145:2019-2023.
Wootton FT, Lee WM. Acetaminophen hepatotoxicity in the
alcoholic. South Med J. 1990;83:1047-1049.
McClain CJ, Holtzman J, Allen J, et al. Clinical features of
acetaminophen toxicity. J Clin Gastroenterol. 1988;10:76-80.
Black M, Cornell JF, Rabin L, et al. Late presentation of
acetaminophen hepatotoxicity. Dig Dis Sci. 1982;27:370-374.
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42. Bravo-Fernandez EF, Reddy KR, Jeffers L, et al. Hepatotoxicity
after prolonged use of acetaminophen: a case report. Bol Asoc
Med P R. 1988;80:417-419.
43. Goldfinger R, Ahmed KS, Pitchumoni CS, et al. Concomitant
alcohol and drug abuse enhancing acetaminophen toxicity. Report
of a case. Am J Gastroenterol. 1978;70:385-388.
44. O’Dell JR, Zetterman RK, Burnett DA. Centrilobular hepatic
fibrosis following acetaminophen-induced hepatic necrosis in an
alcoholic. JAMA. 1986;255:2636-2637.
45. Johnson MW, Friedman PA, Mitch WE. Alcoholism,
nonprescription drug and hepatotoxicity. The risk from unknown
acetaminophen ingestion. Am J Gastroenterol. 1981;76:530-533.
46. Barker JD Jr, de Carle DJ, Anuras S. Chronic excessive
acetaminophen use and liver damage. Ann Intern Med. 1977;87:
299-301.
47. Gerber MA, Kaufmann H, Klion F, et al. Acetaminophen
associated hepatic injury, report of two cases showing unusual
portal tract reactions. Hum Pathol. 1980;11:37-42.
48. Leist MH, Gluskin LE, Payne JA. Enhanced toxicity of
acetaminophen in alcoholics: report of three cases. J Clin
Gastroenterol. 1985;7:55-59.
49. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase
elevations in healthy adults receiving 4 grams of acetaminophen
daily: a randomized controlled trial. JAMA. 2006;296:87-93.
50. Floren CH, Thesleff P, Nilsson A. Severe liver damage caused by
therapeutic doses of acetaminophen. Acta Med Scand. 1987;
222:285-288.
51. Bolesta S, Haber SL. Hepatotoxicity associated with chronic
acetaminophen administration in patients without risk factors.
Ann Pharmacother. 2002;36:331-333.
52. Kumar S, Rex DK. Failure of physicians to recognize
acetaminophen hepatotoxicity in chronic alcoholics. Arch Intern
Med. 1991;151:1189-1191.
53. Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal daily
doses of acetaminophen on the liver of alcoholic patients: a
randomized, double-blind, placebo-controlled trial. Arch Intern
Med. 2001;161:2247-2252.
54. Benson GD. Acetaminophen in chronic liver disease. Clin
Pharmacol Ther. 1983;33:95-101.
55. Dart RC, Kuffner EK, Rumack BH. Treatment of pain or fever with
paracetamol (acetaminophen) in the alcoholic patient: a
systematic review. Am J Ther. 2000;7:123-134.
Volume , .  : September 
Volume , .  : September 
Evidentiary Table.
Study
Year
Design
1991
Prospective
multicenter,
observational
study
Rumack and
Matthew16
1975
Review
Review of APAP poisoning and
toxicity; proposed nomogram
using patient data already in
literature
Outcome Measure/
Criterion Standard
Dose ingested; APAP
and transaminase
levels; severe
hepatotoxicity;
mortality rates
Results
Limitations/Comments
Class
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
Nomogram presented
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
N o m et h o d s f o r r ev i e w;
no data presented for
derivation of nomogram
III
Clinical Policy
Annals of Emergency Medicine 299
Smilkstein et
al2
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
poisoning in patients at
possible, probable, and high risk
for hepatotoxicity treated with
IV NAC
Clinical Policy
300 Annals of Emergency Medicine
Evidentiary Table (continued).
Year Design
Study
Rumack et al17
1981
Retrospective
observational
study
Intervention(s)/Test(s)/
Modality
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
Outcome Measure/
Criterion Standard
Dose ingested; APAP
and transaminase
levels; mortality
Results
Limitations/Comments
n=662; in no-risk
patients, 0.3%
hepatotoxicity with no
mortality; in possiblerisk patients, 5%
hepatotoxicity with no
mortality; in probablerisk patients treated
<10 h, 7%
hepatotoxicity with no
mortality; in probablerisk patients treated 1016 h, 29%
hepatotoxicity with no
mortality; in probablerisk patients treated 1624 h, 62%
hepatotoxicity, with no
mortality
Limitations: open-label
study; unreported blinding
for assessment but should
not effect outcome
Class
II
Volume , .  : September 
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Daly et al18
2004
Prospective
observational
Intervention(s)/Test(s)/
Modality
Descriptive analysis of clinical
algorithm for RSTIs
Outcome Measure/
Criterion Standard
Group 1: AST <50
IU/L; group 2: AST
50-1,000 IU/L;
group 3: AST >1,000
IU/L
Limitations/Comments
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 with
mortality=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
Class
II
Clinical Policy
Annals of Emergency Medicine 301
Results
Schiodt et al20
1997
Retrospective
cohort study
with
structured
enrollment
Prescott et al24
1979
Retrospective
cohort study
Clinical Policy
302 Annals of Emergency Medicine
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive analysis of APAP
liver injury (intentional
overdose vs RSTI)
Outcome Measure/
Criterion Standard
Accidental versus
suicidal cohorts;
descriptive data on
APAP levels, liver
function tests, and
mortality
Descriptive report of APAP
poisoning in patients at
probable risk for hepatotoxicity
treated with NAC
Dose ingested;
APAP and
transaminase levels;
severe hepatotoxicity,
mortality rates
Volume , .  : September 
Results
Limitations/Comments
Class
n=71; 70% suicidal
with mean APAP dose
of 24 g/d (range of 3125 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
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
Limitations: dosing
information by history;
missing data on some
variables
III
Comments: treatment group
had significantly more
patients considered to be at
high risk by initial APAP
level
III
Limitations: retrospective
cohort with no description of
continuous vs convenience
enrollment
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Smilkstein et
al25
1988
Population
prospective
cohort study
Parker et al26
1990
Population
prospective
cohort study
Intervention(s)/Test(s)/
Modality
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
Outcome Measure/
Criterion Standard
Dose ingested; data
analysis only on
patients with possible
or probable risk for
hepatotoxicity;
APAP and
transaminase levels;
mortality
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 and
transaminase levels;
mortality
Limitations/Comments
Class
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
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: possible referral
bias
II
Limitations: no reported
blinded assessment;
small sample size;
enrolled patients compared
to a historical cohort of
supportive care patients
III
Clinical Policy
Annals of Emergency Medicine 303
Results
Clinical Policy
304 Annals of Emergency Medicine
Evidentiary Table (continued).
Study
Year Design
Peterson and
Rumack27
1977
Case report
Prescott et al28
1977
Case series
Oh and
Shenfield29
1980
Case series
Keays et al30
1991
Prospective
randomized
controlled
study
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
poisoning in a high-risk patient
treated with NAC
Outcome Measure/
Criterion Standard
Dose ingested;
APAP and
transaminase levels
Descriptive report of APAP
poisoning in patients at
probable risk for hepatotoxicity;
patients treated with NAC
Descriptive report of APAP
poisoning in patients treated
with NAC
Dose ingested;
APAP and
transaminase levels
Comparison of NAC versus
placebo control in fulminant
hepatic failure due to APAP
ingestion
Study group
characteristics;
outcomes: mortality,
cerebral edema, and
inotropic rates
APAP and
transaminase levels;
incidence of morbidity
and mortality
Volume , .  : September 
Results
Limitations/Comments
Class
n=1; dose: 15.6 g
ingestion; treatment
delay=8 h;
minor elevations in
transaminases reported
n=15; only 1 treated
<10 h developed severe
hepatotoxicity
Limitations: dosing
information by history; not
biopsy proven
III
Limitations: convenience
sample; small sample size
III
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
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: retrospective
cohort with no description of
continuous vs convenience
enrollment; 5 patients of
unknown risk (less than
probable risk)
Limitations: comorbidities of
each group not reported; no
description of blinded
outcomes assessment
III
II
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Harrison et al31
1990
Retrospective
cohort study
Cetaruk et al32
1997
Case series
Intervention(s)/Test(s)/
Modality
Retrospective cohort of
fulminant hepatic failure due to
APAP ingestion
Outcome Measure/
Criterion Standard
Cohort characteristics;
outcomes: mortality,
progression of disease,
need for dialysis
Descriptive report of extended
release APAP toxicokinetics
Dose ingested, APAP
and transaminase
concentrations
Limitations/Comments
Class
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
n=13 with single
ingestions and normal
transaminases at
presentation; dose:
10.4-65 g; elimination
phase=8 h
postingestion
(suggesting delayed
absorption);
elimination halflife=3.1 (similar to
immediate release);
absorption; no second
peak in APAP
concentrations
occurred
Limitations: no description
of blinded outcomes
assessment
III
Limitations: dosing
information by history; small
cohort
III
Clinical Policy
Annals of Emergency Medicine 305
Results
Clinical Policy
306 Annals of Emergency Medicine
Evidentiary Table (continued).
Year Design
Study
Intervention(s)/Test(s)/
Modality
Descriptive report of an
extended release APAP
ingestion
Bizovi et al33
1996
Case report
Seeff at al34
1986
Case series
Descriptive report of APAP
toxicity with therapeutic
ingestions and RSTI
Ambre and
Alexander35
1977
Case series
Descriptive report of lack of
APAP toxicity in overdose
patients
Outcome Measure/
Criterion Standard
Dose ingested; APAP
and transaminase
concentrations;
mortality
Dose ingested;
APAP and
transaminase levels;
mortality
Dose ingested; APAP
and transaminase
levels; mortality
Results
Limitations/Comments
Class
n=1; late increase in
serum APAP
concentration at 14 h
Limitations: coingested with
agents known to slow
gastrointestinal motility
III
n=6 new patients plus
19 patients reported in
the literature; dose
range: 2.6-16.5 g/d,
median=6.4 g/d;
all chronic alcoholics;
mortality 20%
n=5; all gave history of
significant overdose;
none developed toxic
level; none developed
significant toxicity
Limitations: dosing
information by history;
correlation to alcohol
speculative due to biased
enrollment
III
Limitations: dosing
information by history
III
Volume , .  : September 
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
toxicity with RSTI
Outcome Measure/
Criterion Standard
Dose ingested;
APAP and
transaminase levels;
mortality
Dose ingested;
APAP and
transaminase levels;
mortality
Dose ingested;
APAP and
transaminase levels;
mortality
Davis et al36
1983
Case report
Lane et al37
2002
Case report
Descriptive report of APAP
toxicity with RSTI
Kaysen et al38
1985
Case series
Descriptive report of APAP
toxicity with therapeutic use
and RSTI of APAP
Wootton and
Lee39
1990
Case series
Descriptive report of APAP
toxicity with RSTI
Dose ingested; APAP
and transaminase
levels; mortality
Results
Limitations/Comments
Class
n=1; dose: 10 g over 48
h; died 28 days
postingestion, ?APAP
related; pathologyproven diagnosis
n=1; dose: 5-6.5 g/d;
no alcohol use;
survived
Limitations: dosing
information by history;
correlation to psittacosis
speculative
III
Limitations: dosing
information by history; no
biopsy performed
III
n=5; dose: 2.5-10 g/d;
all with chronic alcohol
use; pathology proven
in 3; all developed
severe hepatotoxicity; 2
survived
n=7; dose: 4-11 g/d;
all with chronic alcohol
use; none biopsied;
all developed severe
hepatotoxicity; 3 died
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Clinical Policy
Annals of Emergency Medicine 307
Clinical Policy
308 Annals of Emergency Medicine
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
toxicity with RSTI compared to
intentional overdose
Outcome Measure/
Criterion Standard
Dose ingested;
APAP and
transaminase levels;
mortality
Volume , .  : September 
McClain et al40
1988
Case series
Black et al41
1982
Case report
Descriptive report of APAP
toxicity with RSTI
Dose ingested;
APAP and
transaminase levels;
mortality
BravoFernandez et
al42
1988
Case report
Descriptive report of APAP
toxicity with RSTI
Dose ingested;
APAP and
transaminase levels;
mortality
Goldfinger et
al43
1978
Case report
Descriptive report of APAP
toxicity with supratherapeutic
dose
Dose ingested;
APAP and
transaminase levels;
mortality
Results
Limitations/Comments
Class
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
n=1; dose: 10 g/d;
chronic alcohol use;
died; pathology-proven
diagnosis
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
n=1; dose: 4-5 g/d for
months; chronic
alcohol use; survived;
biopsy-proven
diagnosis
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
III
Limitations: dosing
information by history;
correlation to alcohol
speculative;
no biopsy performed
III
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
toxicity with RSTI
Outcome Measure/
Criterion Standard
Dose ingested;
APAP and
transaminase levels;
mortality
1986
Case report
Johnson et al45
1981
Case report
Descriptive report of APAP
toxicity with RSTI
Dose ingested;
APAP and
transaminase levels;
mortality
Barker et al46
1977
Case series
Descriptive report of APAP
toxicity with RSTI
Dose ingested; APAP
and transaminase
levels; mortality
Gerber et al47
1980
Case series
Descriptive report of APAP
toxicity with RSTI
Dose ingested; APAP
and transaminase
levels; mortality
Limitations/Comments
Class
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; biopsyproven diagnosis
n=1; dose: 6 g/d;
chronic alcohol use;
survived
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Limitations: dosing
information by history;
correlation to alcohol
speculative; no biopsy
performed
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
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
n=2; dose: 4-6.4 g/d;
both with chronic
alcohol use; biopsy
proven; both developed
severe hepatotoxicity;
both survived
III
Clinical Policy
Annals of Emergency Medicine 309
O’Dell et al44
Results
Clinical Policy
310 Annals of Emergency Medicine
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
toxicity with RSTI
Outcome Measure/
Criterion Standard
Dose ingested; APAP
and transaminase
levels; mortality
Volume , .  : September 
Leist et al48
1985
Case series
Watkins et al49
2006
Randomized,
singleblinded,
placebocontrolled
Comparison trial of 5 treatment
groups at therapeutic dosings
(placebo, APAP,
morphine/APAP,
hydromorphone/APAP, and
oxycodone/APAP); dietcontrolled
Treatment given every
6 h for 14 days; APAP
dose=4 g/d;
routine LFTs and
serum alpha
glutathione
S-transferase
Floren et al50
1987
Case series
Descriptive report of APAP
toxicity with therapeutic
ingestions
Dose ingested; APAP
and transaminase
levels; mortality
Results
Limitations/Comments
Class
n=3; dose: 5-8.75 g/d;
all with chronic alcohol
use; pathology proven
in 2; all developed
severe hepatotoxicity; 1
died
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
n=2; doses: 1-1.5 g/d
and 3.5 g/d; biopsyproven diagnosis
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Limitations: single-blinded
II
Limitations: dosing
information by history;
correlation to alcohol
speculative
III
Volume , .  : September 
Evidentiary Table (continued).
Study
Year Design
Intervention(s)/Test(s)/
Modality
Descriptive report of APAP
toxicity with therapeutic
ingestions
Outcome Measure/
Criterion Standard
Dose ingested; APAP
and transaminase
levels; mortality
2002
Case series
Kumar and
Rex52
1991
Case series
Descriptive report of APAP
toxicity with RSTI
Dose ingested; APAP
and transaminase
levels; mortality
Kuffner et al53
2001
Randomized,
doubleblinded,
placebocontrolled
trial
Effect of APAP 4 d/g x 2 days
vs placebo on liver function in
alcoholic patients
Benson54
1983
Doubleblinded,
placebocontrolled,
cross-over
trial
Effect of therapeutic APAP
doses (4 g/d) vs placebo on liver
function and metabolism in
chronic liver disease patients
Baseline LFTs,
coagulations;
daily LFTs,
coagulations and
APAP level drawn;
incidence of
hepatotoxicity reported
Baseline LFTs,
coagulations; routine
LFTs, coagulations
and APAP level drawn
through crossover;
APAP half-life
calculated as a marker
of drug metabolism
and accumulation;
incidence of
hepatotoxicity reported
for treatment and
placebo periods
Limitations/Comments
Class
n=4; doses: 1-4 g/d;
all with hepatotoxicity,
no severe
hepatotoxicity, and no
mortality; not
pathology proven; no
chronic alcohol use
n=6; alcoholics with
RSTI; doses: 5-20
gm/day; all with severe
hepatotoxicity;
mortality: 33%; only 1
of 6 identified on admit
n=201 (102 APAP
treated vs 99 placebo);
baseline characteristics
equal; no statistically
significant difference in
enzymatic activity
Limitations: dosing
information by history;
alternative etiologies
possible
III
Limitations: dosing
information by history;
correlation to alcohol
speculative due to biased
enrollment
III
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
I
III
Clinical Policy
Annals of Emergency Medicine 311
Bolesta and
Haber51
Results
Clinical Policy
312 Annals of Emergency Medicine
Evidentiary Table (continued).
Study
Year Design
Dart et al55
Intervention(s)/Test(s)/
Modality
Systematic literature review
assessing safety of therapeutic
APAP doses in the alcoholic
patient
Outcome Measure/
Criterion Standard
Systematic review
with grading of the
literature
Results
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
ALT, alanine transaminase; APAP, acetaminophen; AST, aspartate aminotransferase; h, hour; IV, intravenous; LFT, liver
acetylcysteine; RSTI, repeated supratherapeutic ingestion; y, year.
2000
Literature
review
Limitations/Comments
Limitations: methodology of
review incompletely
described
function test; NAC, N-
Class
III
Volume , .  : September 
Clinical Policy
Appendix A. Literature classification schema.*
Design/
Class
Therapy†
Diagnosis‡
Prognosis§
1
Randomized, controlled trial or
meta-analyses of
randomized trials
Prospective cohort using a
criterion standard
Population prospective cohort
2
Nonrandomized trial
Retrospective observational
Retrospective cohort
Case control
3
Case series
Case report
Other (eg, consensus, review)
Case series
Case report
Other (eg, consensus, review)
Case series
Case report
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 ⱖ2 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
None
1 level
2 levels
Fatally flawed
Design/Class
1
2
3
I
II
III
X
II
III
X
X
III
X
X
X
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Annals of Emergency Medicine 313