This clinical policy focuses on critical issues concerning the management of patients presenting to the emergency department (ED) with acetaminophen overdose. The 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 Rumack-Matthew nomogram?

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-p-benzoquinoneimine (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, 3, 4, 5, 6, 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, 10, 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). 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.

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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 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 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 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 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 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, 28, 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 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, 25, 26, 27, 28, 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, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 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 μg/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), 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, 36, 37, 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.

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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.

Appendix

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 series	Case series
	Case report	Case report	Case report
	Other (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	III
1 level	II	III	X
2 levels	III	X	X
Fatally flawed	X	X	X

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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

PII: S0196-0644(07)00731-7

doi:10.1016/j.annemergmed.2007.06.014

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