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This article was downloaded by:[Alerta - Chile 2005/2006 Consortium] [Alerta - Chile 2005/2006 Consortium] Access Details: [subscription number 758063447] Publisher: Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Clinical Toxicology Publication details, including instructions for authors and subscription information: Acetaminophen Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management Richard C. Dart a; Andrew R. Erdman a; Kent R. Olson a; Gwenn Christianson a; Anthony S. Manoguerra a; Peter A. Chyka a; E. Martin Caravati a; Paul M. Wax a; Daniel C. Keyes a; Alan D. Woolf a; Elizabeth J. Scharman a; Lisa L. Booze a; William G. Troutman a a American Association of Poison Control Centers. Washington, District of Columbia.
To cite this Article: Richard C. Dart, Andrew R. Erdman, Kent R. Olson, Gwenn Christianson, Anthony S. Manoguerra, Peter A. Chyka, E. Martin Caravati, Paul M. Wax, Daniel C. Keyes, Alan D. Woolf, Elizabeth J. Scharman, Lisa L. Booze and William G. Troutman , 'Acetaminophen Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management', Clinical Toxicology, 44:1, 1 - 18 To link to this article: DOI: 10.1080/15563650500394571 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
Taylor and Francis 2007 Clinical Toxicology, 44:1–18, 2006Copyright Taylor & Francis LLCISSN: 0731-3810 print / 1097-9875 online DOI: 10.1080/15563650500394571 Acetaminophen Poisoning: an Evidence-Based Consensus
Guideline for Out-of-Hospital Management*
out-of-hospital management of Acetaminophen Poisoning Richard C. Dart, M.D., Ph.D., Andrew R. Erdman, M.D., Kent R. Olson, M.D.,
Gwenn Christianson, M.S.N., Anthony S. Manoguerra, Pharm.D., Peter A.
Chyka, Pharm.D., E. Martin Caravati, M.D., M.P.H., Paul M. Wax, M.D., Daniel
C. Keyes, M.D., M.P.H., Alan D. Woolf, M.D., M.P.H., Elizabeth J. Scharman,
Pharm.D., Lisa L. Booze, Pharm.D. and William G. Troutman, Pharm.D.
American Association of Poison Control Centers, Washington, District of Columbia, USA
tus changes) should be referred to an emergency department for
The objective of this guideline is to assist poison center personnel
evaluation (Grade D). 2) Patients less than 6 years of age should be
in the appropriate out-of-hospital triage and initial management of
referred to an emergency department if the estimated acute ingestion
patients with suspected ingestions of acetaminophen. An evidence-
amount is unknown or is 200 mg/kg or more. Patients can be
based expert consensus process was used to create this guideline. This
observed at home if the dose ingested is less than 200 mg/kg (Grade
guideline applies to ingestion of acetaminophen alone and is based on
B). 3) Patients 6 years of age or older should be referred to an emer-
an assessment of current scientific and clinical information. The
gency department if they have ingested at least 10 g or 200 mg/kg
Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 expert consensus panel recognizes that specific patient care decisions
(whichever is lower) or when the amount ingested is unknown
may be at variance with this guideline and are the prerogative of the
(Grade D). 4) Patients referred to an emergency department should
patient and the health professionals providing care. The panel's rec-
arrive in time to have a stat serum acetaminophen concentration
ommendations follow. These recommendations are provided in chro-
determined at 4 hours after ingestion or as soon as possible thereaf-
nological order of likely clinical use. The grade of recommendation is
ter. If the time of ingestion is unknown, the patient should be referred
provided in parentheses. 1) The initial history obtained by the spe-
to an emergency department immediately (Grade D). 5) If the initial
cialist in poison information should include the patient's age and
contact with the poison center occurs more than 36 hours after the
intent (Grade B), the specific formulation and dose of acetami-
ingestion and the patient is well, the patient does not require further
nophen, the ingestion pattern (single or multiple), duration of inges-
evaluation for acetaminophen toxicity (Grade D). Repeated suprath-
tion (Grade B), and concomitant medications that might have been
erapeutic ingestion of acetaminophen (RSTI): 1) Patients under 6
ingested (Grade D). 2) Any patient with stated or suspected self-harm
years of age should be referred to an emergency department immedi-
or who is the recipient of a potentially malicious administration of
ately if they have ingested: a) 200 mg/kg or more over a single 24-
acetaminophen should be referred to an emergency department
hour period, or b) 150 mg/kg or more per 24-hour period for the pre-
immediately regardless of the amount ingested. This referral should
ceding 48 hours, or c) 100 mg/kg or more per 24-hour period for the
be guided by local poison center procedures (Grade D). 3) Activated
preceding 72 hours or longer (Grade C). 2) Patients 6 years of age or
charcoal can be considered if local poison center policies support its
older should be referred to an emergency department if they have
prehospital use, a toxic dose of acetaminophen has been taken, and
ingested: a) at least 10 g or 200 mg/kg (whichever is less) over a single
fewer than 2 hours have elapsed since the ingestion (Grade A). Gas-
24-hour period, or b) at least 6 g or 150 mg/kg (whichever is less) per
trointestinal decontamination could be particularly important if ace-
24-hour period for the preceding 48 hours or longer. In patients with
tylcysteine cannot be administered within 8 hours of ingestion. Acute,
conditions purported to increase susceptibility to acetaminophen tox-
single, unintentional ingestion of acetaminophen: 1) Any patient with
icity (alcoholism, isoniazid use, prolonged fasting), the dose of ace-
signs consistent with acetaminophen poisoning (e.g., repeated vomit-
taminophen considered as RSTI should be greater than 4 g or 100
ing, abdominal tenderness in the right upper quadrant or mental sta-
mg/kg (whichever is less) per day (Grade D). 3) Gastrointestinal
decontamination is not needed (Grade D). Other recommendations:
1) The out-of-hospital management of extended-release acetami-
nophen or multi-drug combination products containing acetami-
*Guidelines for the Management of Poisoning. Supported in full nophen is the same as an ingestion of acetaminophen alone (Grade
by Cooperative Agreement 8 U4BHS00084 between the American D). However, the effects of other drugs might require referral to an
Association of Poison Control Centers and the Maternal and Child emergency department in accordance with the poison center's nor-
Health Bureau, Health Resources and Services Administration, mal triage criteria. 2) The use of cimetidine as an antidote is not rec-
Department of Human Services. Copyright 2005 American ommended (Grade A).
Association of Poison Control Centers.
Address correspondence to American Association of Poison Control Centers, 3201 New Mexico Avenue NW, Suite 330, Acetaminophen/poisoning; Poison control centers/stan- Washington, DC 20016, USA. E-mail: [email protected] dards; Practice guidelines R. C. DART ET AL.
system. When the production of NAPQI exceeds the capacity todetoxify it, as can occur in overdose, the excess NAPQI binds to Scope of the Problem and Importance of the Guideline
cellular components and can cause the death of hepatocytes.
Ingestion of acetaminophen is a common challenge for poi- While more than one cytochrome is capable of producing son centers. In 2003, poison centers in the US were contacted NAPQI, the primary source in humans is cytochrome P450 regarding ingestion of acetaminophen or an acetaminophen- isozyme 2E1 (CYP2E1) (9,10). CYP2E1 is an inducible containing product by 127,171 patients (1). Of these, 38,989 enzyme. Chemicals that bind to CYP2E1 may increase (induce) were children under the age of 6 years. A total of 65,030 or decrease (inhibit) the production of NAPQI.
patients (51%) were evaluated in healthcare facilities and 327 It is well established that the time between ingestion of ace- died. Of these, 34 (10.4%) were designated as chronic and 46 taminophen and administration of acetylcysteine affects the (14.1%) were designated as "acute on chronic" in which a outcome of acetaminophen poisoning. While the precise patient already on chronic acetaminophen therapy ingested an threshold is unknown, a delay of more than 8–10 hours results acute overdose (1). Published data suggest that the mortality in higher serum aminotransferase levels (11,12).
rate for patients with repeated ingestion is higher than that ofacute single ingestion of acetaminophen (2–4).
The evaluation of possible acetaminophen poisoning has Intended Users of This Guideline
medical, economic, and social costs. In 1995, Bond and Novak The intended users of this guideline are personnel in US (5) estimated that 30,000–40,000 adolescents and adults ingest poison centers. This guideline has been developed for the con- acetaminophen each year with the intent of self-harm. They ditions prevalent in the US. While the toxicity of acetami- calculated that about 15,000 adolescent and adult patients are nophen is not expected to vary in a clinically significant hospitalized for an average of 2.7 days because of acetami- manner in other nations, the out-of-hospital conditions could nophen overdose. Approximately 250 of these patients die and be much different. This guideline should not be extrapolated to another 50 receive liver transplants. At that time, they esti- other settings unless it has been determined that the conditions mated that the total annual cost of intentional acetaminophen assumed in this guideline are present.
ingestion in the US was $86.9 million. In addition, there arenumerous social and economic costs for families that arise Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 Objective of This Guideline
from disruption of their lives as well as the direct costs associ- The objective of this guideline is to assist poison center ated with emergent visits to healthcare facilities.
personnel in the appropriate out-of-hospital triage and initial The few data available indicate that the management of ace- management of patients with suspected ingestions of acetami- taminophen ingestion in the US is variable. The healthcare nophen by 1) describing the process by which an ingestion of facility referral threshold for acetaminophen ingestion among acetaminophen might be managed, 2) identifying the key deci- US poison centers ranges from 120 mg/kg to 201 mg/kg of ace- sion elements, 3) providing clear and practical recommenda- taminophen (6). A guideline that effectively determines the tions that reflect the current state of knowledge, and 4) need for referral could optimize patient outcome, reduce costs, identifying needs for research. This guideline applies to inges- and reduce disruption for patients and caregivers.
tion of acetaminophen alone. Co-ingestion of additional sub-stances could require different referral and management recommendations, depending on the combined toxicities of thesubstances.
This guideline is based on an assessment of current scien- The term out-of-hospital is defined as the period before a tific and clinical information. The expert consensus panel rec- patient reaches a healthcare facility. An acute ingestion is ognizes that specific patient care decisions may be at variance defined as any number of ingestions that occur within a period with this guideline and are the prerogative of the patient and of up to 8 hours. In recent years, the phenomenon of "chronic" health professionals providing care, considering all of the cir- acetaminophen toxicity has been described (7,8). Repeated cumstances involved. This guideline does not substitute for supratherapeutic ingestion (RSTI) involves any pattern of mul- clinical judgment.
tiple ingestions over a period of greater than 24 hours thatresults in a total dosage of more than 4 g per day.
Pathophysiology of Acetaminophen Toxicity The methodology used for the preparation of this guideline Acetaminophen is rapidly and completely absorbed after oral was developed after reviewing the list of key elements of administration. It exhibits a large first-pass effect with uptake guidelines described by Shaneyfelt et al. (13). An expert con- and metabolism in the liver. The toxicity of acetaminophen is sensus panel was established to oversee the guideline develop- related to the production of the reactive intermediate N-acetyl-p- ment process (Appendix 1). The American Association of benzoquinonimine (NAPQI) by the hepatic cytochrome P450 Poison Control Centers (AAPCC), the American Academy of OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING Clinical Toxicology (AACT), and the American College of Medical Toxicology (ACMT) appointed members of their All articles that were retrieved from the search were organizations to serve as panel members. To serve on the reviewed by a single abstractor. Each article was assigned a expert consensus panel, an individual had to have an excep- level of evidence score from 1 to 6 using the rating scheme tional record of accomplishment in clinical care and scientific developed by the Centre for Evidence-Based Medicine at research in toxicology, board certification as a clinical or med- Oxford University (Appendix 2); the complete paper was then ical toxicologist, significant US poison center experience, and reviewed for original human data regarding the toxic effects of be an opinion leader with broad esteem. Two Specialists in acetaminophen or original human data directly relevant to the Poison Information were included as full panel members to out-of-hospital management of patients with acetaminophen provide the viewpoint of the end-users of the guideline.
overdose. Articles without original human data were not evalu-ated. Doses of acetaminophen, resultant effects, times of onset of effects, therapeutic interventions or decontamination mea-sures given, efficacy or results of any interventions, and overall The National Library of Medicine's MEDLINE database patient outcomes were compiled into a table and a brief sum- was searched (1966 to January 2003) using acetaminophen as a mary description of each article was written. The completed MeSH term with the subheadings poisoning (po) or toxicity table of all abstracted articles was then forwarded to the guide- (to), limited to humans. MEDLINE and PreMEDLINE (1966– line primary author and panel members for review and consid- January 2003) were searched using acetaminophen or paraceta- eration in developing the guideline. This full evidence table is mol as textwords (title, abstract, MeSH term, CAS registry) plus either poison* or overdos*, limited to humans. This same 20tables/apap%20evidence%20table.pdf. Every attempt was process was repeated in International Pharmaceutical Abstracts made to locate significant foreign language articles and have (1970–January 2003, excluding abstracts of meeting presenta- their crucial information extracted, translated, and tabulated. In tions), Science Citation Index (1977–January 2003), Database addition to the evidence table, several brief sub-tables were of Abstracts of Reviews of Effects (accessed January 2003), generated that included all of the articles and data relating to a Cochrane Database of Systematic Reviews (accessed January particular topic (e.g., dose of acetaminophen in acute pediatric 2003), and Cochrane Central Register of Controlled Trials Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 ingestions reported to cause toxicity). These were also for- (accessed January 2003). A similar search was conducted in warded to the primary author and guideline panel members.
EMBASE using both acetaminophen and paracetamol as pri- Finally, a written summary of the data was created and distrib- mary search terms. Index Medicus was hand-searched (1960– uted by the abstractor. Copies of all of the articles were made 1965) using the term "analgesics and antipyretics" through available for reading by the panel members on a secure 1964 and "acetaminophen" for 1965. Reactions (1980–January AAPCC website.
2003), the acetaminophen poisoning management in POISIN-DEX (14), the Cochrane systematic review of interventions foracetaminophen overdoses (15), and the chapter bibliographies Guideline Writing and Review
in four major toxicology textbooks (17–19) were reviewed for A guideline draft was prepared by the primary author. The citations of additional articles with original human data. The draft was submitted to the expert consensus panel for com- bibliographies of recovered articles were reviewed to identify ment. Using a modified Delphi process, comments from the previously undiscovered articles.
expert consensus panel members were collected, copied intoa table of comments, and submitted to the primary author forresponse. The primary author responded to each comment in the table and, when appropriate, the guideline draft was mod- The recovered citations were entered into an EndNote ified to incorporate changes suggested by the panel. The library and duplicate entries were eliminated. The abstracts of revised guideline draft was again reviewed by the panel and, these articles were reviewed, looking specifically for those that if there was no strong objection by any panelist to any of the dealt with 1) estimations of mg/kg or ingested doses with or changes made by the primary author, the draft was prepared without subsequent signs or symptoms, and 2) management for the external review process. External review of the second techniques that might be suitable for out-of-hospital use (e.g., draft was conducted by distributing it electronically to gastrointestinal decontamination). The panel agreed that ace- AAPCC, AACT, and ACMT members and the secondary tylcysteine therapy could be considered for initiation in the review panel. The secondary review panel consisted of repre- prehospital setting. Articles excluded were those that did not sentatives from the federal government, public health, emer- meet either of the preceding criteria, did not add new data (e.g., gency services, pediatrics, pharmacy practice, and consumer some reviews and editorials), described inpatient-only proce- organizations (Appendix 3). Comments were submitted via a dures (e.g., dialysis), or described treatments that were unlikely discussion thread on the AAPCC website or privately through to be used (e.g., methionine).
e-mail communication to AAPCC staff. All submitted R. C. DART ET AL.
comments were stripped of any information that would iden- acetaminophen metabolite may be disproportionately greater in tify their sources, copied into a table of comments, and small children; therefore, the capacity of a young child to reviewed by the expert consensus panel and the primary metabolize acetaminophen in a nontoxic manner may be author. The primary author responded to each comment in the greater than that of an adult.
table and his responses and subsequent changes in the guide-line were reviewed and accepted by the panel. Following ameeting of the expert consensus panel, the final revision of Dose and Pattern of Acetaminophen Ingestion
the guideline was prepared.
The evidence regarding the relationship between acetami- nophen dose and toxicity is limited primarily to case reportsand case series (level 4) and to cohort or case-control studies KEY DECISION ELEMENTS
(levels 2 and 3, respectively). Studies reviewed for this guide- The panel identified patient age and intent as well as the line were categorized by age (less than 6 years of age or 6 years estimated dose and timing of ingestion as critical elements of age and older) and by pattern (acute ingestion, repeated needed to evaluate an ingestion of acetaminophen. This pro- ingestion). In most cases, toxicity actually meant the potential cess has not been experimentally evaluated in published stud- for toxicity as predicted by the Rumack-Matthew nomogram.
ies. However, there are well-known practice patterns ascribed In some articles, information on pediatric overdoses was com- to by essentially all US poison centers. For example, all poison mingled with information on adult overdoses, making informa- centers obtain a defined information data set from each caller.
tion on the two groups impossible to separate. Furthermore, The standard poison center process includes ascertainment of some articles defined pediatric patients as less than 17 years of the history, assessment of this historical information in the age while others defined them as less than 7 or 12 years of age.
context of the patient's exposure, estimation of the dose A survey of US poison center managers found that the dose ingested, and recommendation for referral and initial out-of- threshold triggering referral to a healthcare facility varied greatly. Triage threshold values ranged from 120 to 201 mg/kgfor acute, unintentional ingestions of acetaminophen. Centersusing relatively low thresholds (e.g., 150 mg/kg) referredpatients to hospitals more frequently than centers using higher Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 REVIEW OF THE MEDICAL LITERATURE
thresholds (e.g., 200 mg/kg) (6).
Patient Age and Intent
A potentially toxic ingestion of acetaminophen may occur Acute Single Ingestions by Patients 6 Years of Age and Older in an adult or a child. There are fundamental differences No randomized clinical trials involving the out-of-hospital between patients below the age of 6 years and patients who are treatment of intentional acetaminophen overdose have been 6 years of age or older. Young patients are often discovered reported. Several randomized controlled trials (level 1b) have during or soon after ingestion. Older patients are more likely to reported the administration of an acute single supratherapeutic attempt self-harm and to conceal the attempt. Most deaths from dose of acetaminophen. Doses in these studies have ranged acetaminophen poisoning occur in adults with acute overdoses.
from 4 to 7.8 g (up to 75–80 mg/kg). Serum aminotransferase In contrast, nearly all deaths attributed to acetaminophen levels were not reported in these studies, but all of the patients reported in the medical literature regarding children under the survived and none was noted to develop clinical signs of age of 6 years have involved RSTI overdosage. There were no hepatotoxicity (25–30). The applicability of these studies to articles identified that directly addressed the relationship acetaminophen overdose is limited by the small number of between patient age and intent (i.e., unintentional vs. inten- subjects, the use of healthy subjects, and the lack of laboratory tional ingestion). The Toxic Exposure Surveillance System of investigations to assess subclinical hepatic toxicity.
the American Association of Poison Control Centers lists 14 Only observational studies were found relating the esti- deaths in children under the age of 6 years in the period 1990– mated dose of acetaminophen to liver injury or potential toxic- 2003. One of these deaths involved an acute exposure to ace- ity as represented by the Rumack-Matthew nomogram. A taminophen but the child had also ingested diphenhydramine number of case reports and case series (level 4), and various and iron (20).
cohort or case-control studies (levels 2b and 3b) containing Published evidence suggests that preschool children are less specific information on ingested doses and patient outcome susceptible to the same weight-adjusted doses and serum con- have reported acetaminophen levels above the possible toxicity centrations of acetaminophen that are associated with severe line (31–33). The smallest reported doses associated with toxicity in older patients (21,22). This may be due to an evidence of hepatic injury have ranged from 3.25 to 10 g increased capacity to metabolize acetaminophen through non- (2,34–46). A cohort analysis (level 2b) described several toxic mechanisms (23). Furthermore, the liver size of a small patients in whom acute doses of less than 12 g were associated child is larger in proportion to body weight than that of an adult with hepatotoxicity, but the exact doses were not specified (24). The amount of glutathione available to detoxify the (47). This same study reported deaths in patients with reported OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING doses as low as 15 g. In contrast, some reports have described aminotransferase levels (40,64–66). Case reports (level 4), case large single ingestions with documented serum concentrations series (level 4), and cohort (level 2b) or case-control (level 3b) of acetaminophen above the possible or probable toxicity studies have reported either greater severity of injury or a nomogram lines that did not result in toxicity (48).
lower threshold dose for the development of hepatotoxicity The conflicting reports of hepatic injury following doses at after acetaminophen ingestion by patients chronically ingesting or just above the therapeutic dose are likely explained by the alcohol or other compounds thought to increase susceptibility nature of the evidence. Studies (levels 2b and 4) have docu- to acetaminophen toxicity (e.g., isoniazid use, prolonged fast- mented that there is poor correlation between the reported ing) (2,34,36–38,40,41,46,50,65,67–72). Evidence (level 4) dose and either subsequent acetaminophen serum concentra- indicating that a patient's alcoholic state does not contribute to tion or clinical outcome (31,42,43,49–53). The correlation outcome has also been reported (12,42).
between reported dose and subsequent serum concentration Each of these reports uses the theoretical framework of or toxicity for children with unintentional ingestion is also enhanced production of NAPQI and the reduction of defenses poor (53–55).
as represented by glutathione. Chronic ethanol abuse is a use- The history of ingestion might be inaccurate because it is ful condition to study because of its prevalence and because it often obtained during a period of extreme emotional stress for involves both increased production of NAPQI and reduction of both the patient and their family. Furthermore, there are often glutathione (73). The primary inducers of CYP2E1 with medi- confounding factors such as co-ingestion of ethanol or other cal relevance are ethanol, acetone, and isoniazid. It is important drugs that affect the central nervous system. In most reports to understand that drugs that induce CYP2E1 must bind to the available, the accuracy of the history was not addressed and the enzyme and thereby are competitive inhibitors of the enzyme.
history was not confirmed by outside sources (e.g., family Thus, when both ethanol and acetaminophen are ingested con- members) or objective evidence (e.g., empty product contain- currently, the metabolism by CYP2E1 and hepatotoxicity of ers). Fortunately, accurate dose information is usually not acetaminophen are decreased (10). When ethanol is subse- needed for patients 6 years of age or older because treatment is quently eliminated, however, the induced enzyme remains and guided by the serum acetaminophen concentration.
metabolism of acetaminophen is increased for several hours(10). Therefore, concurrent ingestion of acetaminophen and Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 Repeated Supratherapeutic Ingestion (RSTI) by Patients 6 ethanol is not expected to enhance injury from acetaminophen.
Years of Age and Older However, acetaminophen ingestion (especially in overdose) The maximum daily dosage of acetaminophen recom- soon after elimination of ethanol can theoretically potentiate mended by a major manufacturer is 1 g every 4 hours, not to the effect of acetaminophen overdosage.
exceed 4 g a day for patients 12 years of age or older (56). Four While animal and human data support the concept that randomized clinical trials (level 1b) were found that involved induction of CYP2E1 occurs during the use of ethanol, the multiple ingestions of acetaminophen over a period of more clinical meaning of this effect remains unclear. For example, than 1 day. Gelotte et al. (57) administered 4, 6, or 8 g/day in level 1b data indicate that the effect of ethanol is not clinically divided doses to adults for 3 days. These doses were not apparent at a therapeutic acetaminophen dosage. The adminis- associated with accumulation of acetaminophen, changes in tration of acetaminophen 4 g/day for 2 days to confirmed alco- serum aminotransferase levels, or effects on other monitoring holic patients under controlled conditions did not produce parameters. The application of this study in clinical practice is increases in serum aminotransferase levels or alterations of limited by its use of normal subjects and the controlled envi- international normalized ratios (74). Similarly, the administra- ronment of a clinical research center. Other prospective studies tion of the maximum dosage to patients with liver disease administered 4–6 g/day to patients without adverse clinical (hepatitis, cirrhosis) was also found to not affect serum ami- effect, including patients with acute stroke and head and neck notransferase levels (75).
cancer (58–61). Level 4 reports describe ingestion of over A systematic review (level 1a) of publications involving 20 g/day for years (62) and ingestion of 25 g over 25 hours alcohol and acetaminophen has documented a contrast between (63) without adverse effects.
prospective studies and case reports. All prospective articles The interpretation of the medical literature of repeated ace- failed to find liver injury at therapeutic doses. In contrast, taminophen doses is complicated by the effects of conditions many case reports and small case series found an association of that are thought to lower the threshold for toxicity. These are liver injury in alcoholic patients with dosages of 4 g/day or less generally categorized as either conditions that increase the (76). There are no data that address the issue of CYP2E1 on production of the reactive metabolite NAPQI or that decrease RSTI acetaminophen. If alcohol or other disease states enhance the ability to detoxify NAPQI (e.g., decreased concentration the toxicity of acetaminophen, the dosage at which the phe- of glutathione). Authors report that low daily doses of acetami- nomenon develops is unknown.
nophen, ranging from minimal daily doses of 2.4–6 g in Patients with acute co-ingestion of acetaminophen with alco- alcoholics, patients with starvation, or those on chronic antitu- hol or gastrointestinal antimotility agents and patients taking berculous medications have been associated with elevated cimetidine chronically have been reported to be at decreased R. C. DART ET AL.
risk of liver injury (levels 2b and 4) (31,47,50,53,77,78). Other 2.5 g of acetaminophen (84). A 14-year-old girl developed an authors have found no correlation between acute alcohol INR of 1.6 after an acute ingestion of 4 g acetaminophen; how- consumption and severity of toxicity (level 2b) (46). Schmidt ever, she had also received an excessive dose of acetylcysteine et al. (47) reported that acute ingestion of benzodiazepines (40 g) intravenously prior to the measurement (85). As for exacerbated hepatic encephalopathy after acute acetaminophen adults, the few cases of toxicity associated with low doses overdose but that acute use of opiates was protective against stand in contrast to the numerous cases in which toxicity was hepatotoxicity (level 2b). Schmidt et al. also reported that not observed until acute doses exceed 150 mg/kg/day (48). The chronic use of opioids, benzodiazepines, and acetaminophen most likely explanation is historical inaccuracy as described increased the risks of various negative outcomes after acute above under adult overdose.
acetaminophen overdoses. The meaning of the conflictingresults of these studies is unclear. It is likely that most differ-ences reported are the result of an unrecognized confounder or Repeated Supratherapeutic Ingestion (RSTI) by Patients Less systematic error. For example, the history of RSTI is typically than 6 Years of Age taken after days of ingestion. Often the period of ingestion No randomized clinical trials could be found that evaluated has included events known to impair memory such alcohol the minimum cumulative daily dose for the development of intoxication or co-ingestion of psychoactive drugs as well as laboratory evidence of liver injury after pediatric RSTI (69, difficulties imposed by an underlying illness (fever, sleep depri- 86–90). The dosages of acetaminophen associated with eleva- vation, etc.). While these results may stimulate future studies, tion of aminotransferase levels in case reports (level 4), case they are too uncertain to apply to a clinical guideline.
series (level 4), and cohort analyses (level 2b) have rangedfrom the normal therapeutic dosage (20 mg/kg/day) to 600 mg/ Acute Single Ingestions by Patients Less than 6 Years of Age kg/day or more (90). Most reports indicate that dosages of 120 No randomized clinical trials were found evaluating the to 174 mg/kg/day for multiple days are needed to produce tox- acute threshold dose for the development of clinical acetami- icity (69,82,87).
nophen toxicity (i.e., laboratory evidence of liver injury) or Two case series (level 4) reported toxicity associated with even potential toxicity as determined by the Rumack-Matthew histories of smaller ingestions. One report identified 47 children Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 nomogram in children of any age. Several observational studies below the age of 12 years with hepatotoxicity after acetami- investigated the potential safety and efficacy of various poison nophen RSTI. Toxicity developed after reported daily doses of center protocols in the management of acute, accidental pediat- 60–420 mg/kg/day for 1–21 days (89). A retrospective review of ric (less than 6 or 7 years of age) ingestions of acetaminophen a liver transplant service identified four children who developed (6,55,68,79,80). Most articles (levels 2b, 3b, and 4) suggest that severe hepatic injury after doses of 20–71 mg/kg/day for 7 days patients with ingestions of less than 200 mg/kg could be man- (90). Another case series recorded doses ranging from 23 to 100 aged at home, provided that the acetaminophen dose is known.
mg/kg day associated with liver injury in children (91). Perhaps One level 4 study created a model to predict serum concentra- due to inaccurate histories provided by patients, the data pre- tions after ingestion of acetaminophen (81). The authors con- sented contain many inconsistencies. For example, the highest cluded that a referral dose of 250 mg/kg was appropriate for serum acetaminophen concentration reported among children children. This study did not include any children with serum with presumed acetaminophen toxicity was 14 mg/L after dos- acetaminophen concentrations above the "probable toxicity" ages ranging from 20 to 200 mg/kg/day.
line of the Rumack-Matthew nomogram. However, it is likely In contrast, prospective and retrospective studies in children that all of these studies had insufficient power to detect the rare have used acetaminophen dosages up to and exceeding 90 mg/ event of toxicity after a single dose of acetaminophen in a child kg/day without liver injury. Lesko and Mitchell (92) found no under the age of 6 years. Very few cases of toxicity after acute clinical evidence of toxicity in a prospective study of 28,130 single ingestion by a child under the age of 6 years were found children administered up to 60 mg/kg/day (level 1b). Further, in the medical literature and in the AAPCC TESS database (20).
both level 1b and level 4 studies have documented the use of If this type of toxicity occurs, it is rare.
dosage above 90 mg/kg/day without adverse effect (93–96).
In contrast, case reports and case series (level 4) and various Thus, the data for pediatric RSTI are conflicting and with a pat- cohort (level 2b) or case-control studies (level 3b) containing tern similar to reports involving acute overdose—prospectively information on specific ingested doses and patient outcome collected data are sparse and do not indicate potential for hepatic have reported potential toxicity or actual toxicity in children injury, while retrospectively collected data provide evidence of less than 6 years old with single doses thought to be in the an association of relatively low dosages, even therapeutic dos- range of 146 to 190 mg/kg (82,83).
ages, with liver injury. Again, the cause is likely to be historical Acute single ingestion resulting in toxicity has been inaccuracies. Overdoses in children are subject to the same con- reported more commonly in adolescents. The lowest dose cerns as in adults but also present their own unique set of con- resulting in liver injury involved a 13-year-old of unknown cerns as parents may over- or underestimate the actual ingested weight who died of hepatic failure after reportedly ingesting dose depending on the circumstances.
OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING Potential Out-of-Hospital Management Techniques to
charcoal, lavage, or untreated control). However, the primary out- Prevent or Ameliorate Acetaminophen Toxicity After
come measure was percent reduction of the serial serum acetami- nophen concentration (first concentration compared with last), The consensus panel identified these potential strategies which might not be an adequate outcome indicator (97). The for reducing acetaminophen absorption in the out-of-hospital study found that the three decontamination methods reduced setting: 1) reducing absorption, 2) inhibiting metabolism, or 3) acetaminophen serum concentrations by 39–51%.
detoxifying the reactive intermediate metabolite, NAPQI.
Two randomized controlled trials (level 1b) were identified Absorption can be decreased by gastrointestinal decontamina- that examined the efficacy of ipecac-induced emesis in simu- tion, metabolism can be inhibited by drugs such as cimetidine, lated overdose. In one study, ipecac syrup given within 5 min- and detoxification can be accomplished by the administration of utes of ingestion was effective at reducing overall acetylcysteine. The risk-benefit analysis of these techniques is acetaminophen absorption by 66%, as measured by the area difficult. The primary difficulty is that the treatment of acetami- under the curve (AUC) but was not effective when adminis- nophen toxicity with acetylcysteine is usually successful when tered at 30 or 60 minutes after ingestion (98). In the second acetylcysteine is initiated within 8–10 hours of acute ingestion study, ipecac syrup given 1 hour after simulated overdose was (11,12). Thus, it is difficult to show an improvement in patient effective at reducing the acetaminophen AUC compared with outcome for any out-of-hospital intervention because the admin- control by about 25% and its efficacy was comparable to acti- istration of acetylcysteine reduces the potential benefit of the vated charcoal (99).
intervention to near zero. However, potential benefit could be Several cohort analyses (level 2b) based on retrospective realized in situations where acetylcysteine is not available.
reviews evaluated the efficacy of ipecac syrup after acetami- There were data available in the literature for each type of nophen overdose. One found a decrease in the likelihood of intervention; however, there were no studies found that specif- developing severe hepatotoxicity or death in the cohort of ically addressed the out-of-hospital administration of various patients who had emesis or gastric lavage within 6 hours of antidotes or treatments.
ingestion (100). The two other studies focused on children.
One found that ipecac-induced emesis within 60 minutesreduced the mean 4-hour serum acetaminophen concentration Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 by 77% based on a comparison with 4-hour concentrations pre- The potential strategies for reducing absorption after ace- dicted by a pharmacokinetic model. After 60 minutes, the taminophen ingestion that could be reasonably be performed in mean reduction of the 4-hour concentration was about 40% an out-of-hospital setting include emesis with ipecac syrup or (101). The second pediatric cohort investigation found that administration of activated charcoal. Only those articles that 4-hour acetaminophen concentrations were reduced by about contained specific information about these measures as well as 50%, compared with untreated controls when emesis occurred some description of their outcomes have been included.
within 90 minutes of the ingestion (79).
All reports in the medical literature combined out-of-hospi- One case-control study (level 3b) of patients with acute ace- tal and in-hospital interventions in the setting of acute inges- taminophen overdose found that the group that developed tion. There were no articles specifically investigating the out- hepatic injury was less likely to have undergone gastric empty- of-hospital use of induced emesis or activated charcoal. There ing by lavage or induced emesis than the group that did not were also no articles addressing the effectiveness of decontam- develop hepatic injury; however, the difference was not statis- ination measures for an RSTI pattern of ingestion. Since stud- tically significant (33).
ies of RSTI demonstrate that liver injury develops after more Six randomized controlled trials (level 1b) have investi- than 1 day of ingestion, these patients probably present for care gated the efficacy of activated charcoal in reducing acetami- too late for decontamination to be effective.
nophen absorption in healthy volunteers receiving Two level-1 articles examined decontamination measures supratherapeutic, but nontoxic, doses of acetaminophen. In after acute overdose. The remaining decontamination data are these studies, activated charcoal (50–60 g) reduced the serum limited to randomized controlled trials (level 1b) of simulated acetaminophen AUC by 25–67% if given at 1 hour after inges- overdose in healthy volunteers given a single subtoxic, but tion (102–105). Another study found that activated charcoal supratherapeutic, dose of acetaminophen, and observational (1 g/kg) mixed with soda and given 15 minutes after simulated studies such as cohort (level 2b) or case-control (level 3b) anal- overdose reduced acetaminophen absorption by 74% (30). The yses of patients who had ingested single overdoses.
efficacy of activated charcoal decreased when it was adminis- A systematic review (level 1a) concluded that activated char- tered more than 1 hour after ingestion in most studies and one coal, gastric lavage, and ipecac-induced emesis are able to reduce study found no benefit in AUC or 4-hour serum concentration the absorption of acetaminophen, but also concluded that their when activated charcoal was given 2–4 hours after simulated clinical benefit is unclear (15). One randomized controlled trial overdose (29,103). One study reported a reduction in AUC of (level 1b) of overdose patients examined the efficacy of different 23% compared with control when activated charcoal was given decontamination procedures (ipecac-induced emesis, activated 2 hours after ingestion (104).
R. C. DART ET AL.
Two nonrandomized but controlled studies (level 2b) using less with left lateral decubitus and supine positions compared simulated overdose were identified. One found a decrease in to prone, sitting, or right lateral decubitus (26).
AUC (about 60%) with immediate administration of activatedcharcoal, but the difference was smaller and not statistically Limitations of Published Decontamination Data significant when activated charcoal was given at 1 hour after Simulated overdose studies in volunteers might be a poor ingestion (106). The other study found an AUC reduction of representation of what occurs in real acetaminophen overdoses, about 50% with both immediate and 30-minute activated char- in which larger doses are ingested, patients are not fasting, and coal administration (107).
co-ingestants that affect gastrointestinal motility might be One prospective cohort (level 2b) study of activated char- involved. Volunteer studies might underestimate the efficacy coal in adult acetaminophen overdoses found that patients who of decontamination if gastric emptying is delayed in overdoses received activated charcoal plus acetylcysteine within 8 hours or they might overestimate efficacy if the decontamination of their overdoses were significantly less likely to develop liver measures become less effective with massive acetaminophen injury or hepatotoxicity when compared with those receiving doses (by stoichiometry), tablet bezoar formation, or because acetylcysteine alone within 8 hours (108). Another cohort of activated charcoal binding to food or other co-ingestants study (level 2b) in overdose patients found that the group that rather than acetaminophen.
received activated charcoal within 2 hours had fewer patients There are also challenges in the interpretation of cohort and who subsequently developed 4-hour serum acetaminophen case-control studies. There could be other differences between concentrations in the possible or probable toxicity range com- the cases and controls other than the variable being tested (e.g., pared with the group that did not receive activated charcoal.
ingested doses, times to treatment might differ, and use of ace- The benefit decreased after 2 hours (109).
tylcysteine might differ). They also tend to rely on retrospec- Two studies directly compared ipecac-induced emesis to tive data-gathering, a process that produces its own unique activated charcoal. One randomized controlled (level 1b) study disadvantages (e.g., decisions on treatment could have been in simulated overdose patients found no difference between the based on some piece of history that was not recorded or two in efficacy as measured by reduction in AUC (99). A ran- recorded inaccurately in the medical record).
domized trial (level 1b) in simulated overdose patients found a Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 slightly more rapid decline in acetaminophen serum concentra- Inhibition of Acetaminophen Metabolism tions with activated charcoal compared to ipecac-induced eme- Cimetidine has been proposed as an antidote for acetami- sis (97). Another level-1b study looked at the difference nophen poisoning (78,114–116). It has the advantage of being between activated charcoal with sorbitol and activated charcoal available as an over-the-counter (OTC) medication. One pro- without sorbitol but found no significant difference in efficacy spective (level 1b) trial in overdose patients presenting more as measured by AUC (102).
than 8 hours after ingestion found no added benefit (as mea- Two studies found activated charcoal to be ineffective in sured by liver function tests) from cimetidine when it was reducing acetaminophen absorption. One was a simulated added to acetylcysteine treatment (116). One nonrandomized, overdose trial in volunteers (level 2b) that found no difference controlled trial in healthy adults with simulated overdoses in AUC between controls and those receiving 25 g of acti- found that cimetidine, given orally for 2 days prior to acetami- vated charcoal 15 minutes after ingestion (110). A retrospec- nophen, decreased the overall clearance of acetaminophen, tive cohort (level 2b) study in children with actual overdoses implying some benefit to its administration in overdoses (78).
found no difference in 4-hour serum acetaminophen concen- Three case reports (level 4) of its use had inconclusive out- trations between the activated charcoal and no decontamina- comes (70,115,117).
tion cohorts (54).
Two articles (level 2b and level 4) reported on the use of general gastric decontamination measures but did not specify Detoxification of Acetaminophen Metabolite (NAPQI) the specific method investigated (51,55).
The pharmaceutical formulation of acetylcysteine (but not Studies indicate that the use of decontamination measures the OTC tablet formulation) has been tested and found to have the potential to interfere with the effectiveness of acetyl- reduce or prevent liver injury following acetaminophen inges- cysteine. For example, ipecac syrup induces vomiting that can tion (17,118). There were no randomized controlled (level 1b) interfere with the administration of oral acetylcysteine. Acti- trials evaluating the efficacy of acetylcysteine in the out-of- vated charcoal binds acetylcysteine (111) and reduces its bio- hospital setting. Many observational studies reported the use of availability (112), although the clinical importance of these acetylcysteine in the out-of-hospital setting but did not explic- findings is unknown (113).
itly give information on its effectiveness and so they are notspecifically addressed here (3,44,51,53,54,67,72,119,120). In Body Position addition, multiple case reports and case series (level 4) were One randomized, controlled trial (level 1b) of simulated reported in which the efficacy of acetylcysteine could not be overdose found that the acetaminophen AUC was significantly OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING Retrospective cohort (level 2b), prospective cohort (level the loss of efficacy as time to administration increases indicate 2b), and case-control (level 3b) analyses have reported that that acetylcysteine is effective.
acetylcysteine, either in its usual oral or intravenous dosage, oras an unspecified dosage or route of administration, is effective Role of Different Acetaminophen Formulations
at reducing mortality or at reducing the subsequent incidence Acetaminophen is available in extended-release formula- and severity of liver injury after acetaminophen overdose tions that contain more acetaminophen (650 mg/tablet), are released over a longer period than the usual "extra strength" The degree of acetylcysteine efficacy also appears to formulations, and are intended for use three times per day.
depend on the time after overdose at which it is given. Read et Case reports and case series (level 4) indicate that a patient's al. (50) found that patients with serum acetaminophen concen- serum acetaminophen concentration might cross the Rumack- trations above the treatment line receiving acetylcysteine Matthew nomogram lines at times much later than anticipated.
within 16 hours (dose and route not specified) had a survival Six articles addressing extended-release acetaminophen rate of 94% (18 of 19) compared to 0% (none of seven) in an overdose were identified (27,28,125–128). Two studies were untreated cohort (level 2b). Prescott et al. reported that intrave- randomized, controlled (level 1b) pharmacokinetic compari- nous infusion of acetylcysteine more than 10 hours after ace- sons with regular extra-strength acetaminophen in healthy vol- taminophen ingestion in 15 patients was associated with more unteers taking simulated overdoses. In one study, both the peak severe liver damage than was associated with earlier adminis- serum acetaminophen concentration and the AUC were signifi- tration (level 4) (16,122). Smilkstein et al. (17) found that the cantly lower for extended-release formulation compared with 72-hour oral acetylcysteine regimen was most effective if similar doses of the extra-strength formulation. Time-to-peak given within 8 hours of ingestion. It was still effective, albeit concentration was not significantly longer (27). In the second less so, if administered up to 24 hours after ingestion (level 4).
study, peak acetaminophen concentrations were significantly Bray et al. (123) reported that survival in a cohort treated with lower for the extended-release product, but AUC and time to acetylcysteine within 24 hours of ingestion was 65% vs. 38% peak were not different from the typical extra-strength product for an untreated cohort (level 2b). In another level-2b study, Bray et al. (38) noted that survival was 67% in patients treated The other articles were case reports or case series (level 4) Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 within 8–12 hours compared to 7% in untreated controls. In a of overdoses with extended-release acetaminophen in which level-2b study, Makin et al. (42) showed that survival was bet- several patients were noted to have serum acetaminophen con- ter in patients treated with intravenous acetylcysteine within 24 centrations that crossed the nomogram line despite initially hours (80%) and that patients treated after 24 hours were still nontoxic serum concentrations (126–128). Hepatotoxicity more likely (78%) to survive than untreated controls (48%).
developed in one patient who ingested a handful of extended- Other studies have supported the concept that an increase in release acetaminophen and did not present to an emergency the interval between acetaminophen ingestion and acetylcys- department until 19 hours after the ingestion where she was teine administration is associated with a higher rate of liver treated with acetylcysteine (125).
injury (2,33,46,52,82,83,121). In a large cohort analysis (level Acetaminophen is also available in a formulation containing 2b), Schmidt et al. (47) found that mortality after acute ace- diphenhydramine. In overdose, diphenhydramine could theoreti- taminophen overdose depended on time to acetylcysteine treat- cally decrease gastrointestinal motility and slow absorption of ment, with mortality rates for the 0–12, 12–24, 24–48, and acetaminophen. One case report (level 4) described a patient more than 48 hour groups of 0.4%, 6%, 13%, and 19%, respec- who had acutely ingested 46 g of acetaminophen plus 2.3 g tively. One study (level 2b) found no difference in survival diphenhydramine and developed a serum acetaminophen con- between small treated and untreated cohorts (43).
centration that crossed the nomogram line for possible toxicity at Few studies have examined the efficacy of acetylcysteine in 10.5 hours despite earlier measurements that were below the line patients with RSTI. Makin et al. (42) included 45 patients with (129). The patient developed mild liver function abnormalities.
RSTI; however, the study did not specifically address the effi- Although unusual, some exposures to acetaminophen occur cacy of acetylcysteine in this subgroup (level 2b). Several case by rectal suppositories. The panel concluded that the out-of- reports (level 4) of its use in patients with RSTI were located, hospital management of patients with rectal exposure should but no assessment of benefit from acetylcysteine could be be assessed in the same manner as those who have ingested gleaned from them (63,64,86–88,124). No studies were found that directly compared different routes or dosages of acetylcys-teine. Spiller et al. (108) found that activated charcoal did notinterfere with acetylcysteine efficacy as measured by liver Poison Center Referral of Patients to Healthcare Facilities
function abnormalities (level 2b).
The acetaminophen nomogram is used by plotting a serum The acetylcysteine data suffer from the same limits as acetaminophen concentration at the time after ingestion that it cohort and case-control studies for decontamination. However, was drawn. The blood sample should be drawn at 4 hours after the volume of information available about acetylcysteine and ingestion or as soon as possible thereafter. For many children, R. C. DART ET AL.
the ingestions are discovered soon after they occur, raising the acetaminophen toxicity (alcoholism, isoniazid use, prolonged issue of when patients should be referred to healthcare facili- fasting) should be obtained.
ties for further evaluation. If patients are referred immediately,they could arrive more than 3 hours before their blood sample Patient Age and Intent is to be drawn. This could allow for the administration of a All patients in whom suicidal or malicious intent (e.g., child decontamination method such as ipecac syrup or activated abuse or neglect) is known or suspected should be referred to charcoal, but could also produce long waiting times and con- emergency departments for medical evaluation. Adults with sume emergency department resources.
definite unintentional ingestion or children less than 6 years ofage in whom neither self-harm nor abuse are suspected can be Time of Referral considered for out-of-hospital management.
The data in human volunteers indicate that ipecac-induced emesis and activated charcoal are both effective in reducing the Dose and Pattern of Acetaminophen Ingestion serum concentration of acetaminophen (130). However, sev- Acetaminophen may be ingested over a short period (acute eral factors discourage use of these treatments in children.
ingestion) or a longer period (RSTI). Most adult patients with First, the incidence of serious toxicity from the acute ingestion single acute ingestions of acetaminophen have attempted self- of acetaminophen by children is very low (3). Second, the harm. Patients 6 years of age or older with demonstrated unin- effectiveness of either ipecac syrup or activated charcoal is tentional acetaminophen ingestion of at least 10 g or 200 mg/ reduced as time elapses (130). Finally, an effective antidote kg (whichever is lower) over a period of less than 8 hours war- (acetylcysteine) is widely available. However, one study (level rant prompt medical evaluation in an emergency department.
2b) indicated that early activated charcoal administration might For patients under the age of 6 years, an acute single ingestion reduce the number of patients that require acetylcysteine treat- (ingestion period of less than 8 hours) of 200 mg/kg or more ment (109). The panel determined that if activated charcoal of acetaminophen warrants evaluation in an emergency could be administered within 2 hours of a significant acetami- nophen ingestion, it would be appropriate to do so.
Liver toxicity following acetaminophen RSTI is likely to be The panel concluded that in the case of a single uninten- related to both dose and duration of exposure. Therefore, con- Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 tional ingestion by a child without suspicious circumstances, cern for liver injury increases as the dosage increases and as the child should be referred to arrive in time to have a stat the duration of ingestion exceeds 24 hours. For patients 6 years serum acetaminophen concentration determined at 4 hours of age and older, the panel concluded that referral to an emer- after ingestion. Thus, the specialist in poison information will gency department is warranted for those, who ingest at least 10 need to ascertain the travel time for the patient and the poten- g or 200 mg/kg/day (whichever is less) over a single 24-hour tial delay at the receiving facility.
period, or at least 6 g or 150 mg/kg/day (whichever is less) per24-hour period for 48 hours or longer. For children less than 6 Type of Healthcare Facility years of age, the following referral thresholds for repeated There were no studies found that addressed the issue of the ingestion were created: 200 mg/kg or more over a period of 8– type of healthcare facility that would be suitable for managing 24 hours, 150 mg/kg or more per 24-hour period for the pre- an acetaminophen overdose. The panel concluded that patients ceding 48 hours, and 100 mg/kg or more per 24-hour period for should be referred to emergency departments that have the the preceding 72 hours or longer.
ability to measure serum concentrations of acetaminophen and Although the data are uncertain, pregnant patients and those either aspartate aminotransferase (AST) or alanine aminotrans- with histories of prolonged fasting, chronic ethanol ingestion, ferase (ALT) in a timely manner.
or chronic isoniazid ingestion should probably be evaluated ifmore than 4 g/day or 100 mg/kg/day (whichever is less) of ace- taminophen are consumed, particularly if signs consistent with There were no studies that addressed the frequency or type acetaminophen hepatotoxicity are present (e.g., repeated vom- of out-of-hospital follow-up for any type of ingestion.
iting, marked anorexia, jaundice).
Potential Out-of-Hospital Management Techniques
Key Decision Elements
to Prevent or Ameliorate Acetaminophen Toxicity
The panel identified the patient's age, intent, the pattern of ingestion, as well as the dose and formulation of the acetami- nophen product ingested as critical information that would be The consensus panel concluded that activated charcoal needed in order to make a sound triage decision. In addition, administration reduced acetaminophen absorption but the specific information about conditions that might increase potential risks and overall benefits could not be determined.
OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING Therefore, the use of decontamination cannot be routinely form conclusions on several issues due to the lack of informa- advocated. However, the panel recognized that the use of acti- tion available. These included the mode of transportation to vated charcoal should be guided by the individual poison cen- emergency departments, the effects of circadian rhythm on ter's assessment of the circumstances, the local policies for toxicity, the role of patient gender, and the body position for prehospital care in their service area, and potential benefit-to- transport. The use of an acetaminophen serum concentration to risk analysis in their service area. Exceptions should be made determine the need for acetylcysteine therapy was not on a case-by-case basis. For example, activated charcoal addressed by the panel because it is not applied in the out-of- administration could be appropriate for patients who might have ingested large doses of acetaminophen and who arelocated several hours from an emergency department.
These recommendations are provided in chronological order Inhibition of Acetaminophen Metabolism of likely clinical use. The grade of recommendation is pro- The panel concluded that the available literature indicates vided in parentheses.
that cimetidine inhibits the metabolism of acetaminophen.
However, the literature does not convincingly demonstrate that 1. The initial history obtained by the specialist in poison infor- it improves outcome.
mation should include the patient's age and intent (GradeB), the specific formulation and dose of acetaminophen, the Detoxification of Acetaminophen Metabolite (NAPQI) ingestion pattern (single or multiple), duration of ingestion The panel agreed that acetylcysteine is an effective treat- (Grade B), and concomitant medications that might have ment for acetaminophen poisoning, but that there are no pub- been ingested (Grade D).
lished data regarding the out-of-hospital use of acetylcysteine.
2. Any patient with stated or suspected self-harm or who is the The panel concluded that acetylcysteine therapy could poten- recipient of a potentially malicious administration of ace- tially be initiated in the prehospital environment, especially in taminophen should be referred to an emergency department situations in which the emergency department is far away. The immediately regardless of the amount ingested. This refer- dietary supplement tablet form of acetylcysteine has not been ral should be guided by local poison center procedures Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 tested as an antidote for acetaminophen toxicity and, therefore, only the pharmaceutical product should be used.
3. Activated charcoal can be considered if local poison center policies support its prehospital use, a toxic dose of acetami-nophen has been taken, and fewer than 2 hours have elapsed Role of Unusual Formulations of Acetaminophen
since the ingestion (Grade A). Gastrointestinal decontamina- The panel concluded that knowledge of the extended- tion could be particularly important if acetylcysteine cannot release nature of a product would not affect the out-of-hospital be administered within 8 hours of ingestion.
management of a patient. Concomitant ingestion of other sub-stances should be investigated in all patients so that an addi-tional poisoning does not go unrecognized.
Acute, Single, Unintentional Ingestion of Acetaminophen
1. Any patient with signs consistent with acetaminophen poi- Time of Emergency Department Referral
soning (e.g., repeated vomiting, abdominal tenderness inthe right upper quadrant or mental status changes) should Patients in whom suicidal, homicidal, or abuse intent is be referred to an emergency department for evaluation suspected should be referred to an emergency department immediately regardless of the dose ingested or the time since 2. Patients less than 6 years of age should be referred to an ingestion. When the time of ingestion is known accurately emergency department if the estimated acute ingestion and suicidal, homicidal, or abuse intent is not involved, the amount is unknown or is 200 mg/kg or more. Patients can patient with acetaminophen ingestion alone should be be observed at home if the dose ingested is less than 200 instructed to arrive at the emergency department in time to mg/kg (Grade B).
have their stat serum acetaminophen concentration drawn at 4 3. Patients 6 years of age or older should be referred to an hours after ingestion. Based on the available evidence, a emergency department if they have ingested at least 10 g or serum acetaminophen concentration before 4 hours cannot be 200 mg/kg (whichever is lower) or when the amount ingested is unknown (Grade D).
4. Patients referred to an emergency department should Other Issues
arrive in time to have a stat serum acetaminophen con- The panel concluded that poison centers should follow local centration determined at 4 hours after ingestion or as procedures for follow-up frequencies. The panel chose not to soon as possible thereafter. If the time of ingestion is R. C. DART ET AL.
unknown, the patient should be referred to an emergency 2. Further information regarding the effect of a child's age and department immediately (Grade D).
the relation to intent is needed.
5. If the initial contact with the poison center occurs more than 3. Further investigation is needed to determine whether any 36 hours after the ingestion and the patient is well, the subgroup of adult or pediatric patients has increased sus- patient does not require further evaluation for acetami- ceptibility to acetaminophen. If this effect exists, it is cru- nophen toxicity (Grade D).
cial to determine the threshold dose for liver injury in thesespecial populations.
4. Research is needed about out-of-hospital management of Repeated Supratherapeutic Ingestion of
acetaminophen ingestions in pregnant patients.
5. The feasibility, effectiveness, and safety of the out-of-hospi- 1. Patients under 6 years of age should be referred to an emer- tal use of acetylcysteine should be investigated (including gency department immediately if they have ingested: the use of OTC products).
• 200 mg/kg or more over a single 24-hour period, or 6. The feasibility, effectiveness, and safety of the out-of-hospi- tal use of activated charcoal for acetaminophen poisoning • 150 mg/kg or more per 24-hour period for the preced- should be investigated.
7. Although the phenomenon of RSTI is increasingly recog- • 100 mg/kg or more per 24-hour period for the preced- nized, there is little information available concerning it.
ing 72 hours or longer (Grade C).
Research into its pathophysiology and management is 2. Patients 6 years of age or older should be referred to an emergency department if they have ingested: • at least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period, or Dr. Dart is employed by Denver Health, which provides • at least 6 g or 150 mg/kg (whichever is less) per 24- professional services to many pharmaceutical companies, hour period for the preceding 48 hours or longer.
including McNeil Consumer and Specialty Pharmaceuticals.
There are no other potential conflicts of interest reported by the Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 3. In patients with conditions purported to increase susceptibil- expert consensus panel or project staff regarding this guideline.
ity to acetaminophen toxicity (alcoholism, isoniazid use,prolonged fasting), the dose of acetaminophen consideredas RSTI should be greater than 4 g or 100 mg/kg (which-ever is less) per day (Grade D).
Watson WA, Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, Youniss J, 4. Gastrointestinal decontamination is not needed (Grade D).
Reid N, Rouse WG, Rembert RS, Borys D. 2003 Annual report of theAmerican Association of Poison Control Centers Toxic Exposure Sur-veillance System. Am J Emerg Med 2004; 22:335–404.
Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337:1112–1117.
Bond GR, Hite LK. Population-based incidence and outcome of ace- 1. The out-of-hospital management of extended-release ace- taminophen poisoning by type of ingestion. Acad Emerg Med 1999; taminophen or multi-drug combination products containing acetaminophen is the same as an ingestion of acetaminophen Daly FF, O'Malley GF, Heard K, Bogan GM, Dart RC. Prospective eval- alone (Grade D). However, the effects of other drugs might uation of repeated supratherapeutic acetaminophen (paracetamol) inges-tion. Ann Emerg Med 2004; 44:393–398.
require referral to an emergency department in accordance Bond GR, Novak JE. The human and economic cost of paracetamol (ace- with the poison center's normal triage criteria.
taminophen) overdose. Pharmacoeconomics 1995; 8:177–181.
2. The use of cimetidine as an antidote is not recommended Benson BE, Smith CA, McKinney PE, Litovitz TL, Tandberg WD. Do poison center triage guidelines affect healthcare facility referrals? J Toxi-col Clin Toxicol 2001; 39:433–438.
3. These recommendations are summarized in Appendices 4 Bond GR, Wiegand CB, Hite LK. The difficulty of risk assessment for hepatic injury associated with supra-therapeutic acetaminophen use. VetHum Toxicol 2003; 45:150–153.
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APPENDIX 1
Expert Consensus Panel Members
Lisa L. Booze, Pharm.D.
Certified Specialist in Poison InformationMaryland Poison CenterUniversity of Maryland School of PharmacyBaltimore, Maryland E. Martin Caravati, M.D., M.P.H., F.A.C.M.T., F.A.C.E.P.
Professor of Surgery (Emergency Medicine)University of UtahMedical DirectorUtah Poison CenterSalt Lake City, Utah Gwenn Christianson, R.N., M.S.N.
Certified Specialist in Poison InformationIndiana Poison CenterIndianapolis, Indiana Peter A. Chyka, Pharm.D., F.A.A.C.T., D.A.B.A.T.
Professor, Department of PharmacyUniversity of Tennessee Health Science CenterMemphis, Tennessee R. C. DART ET AL.
Richard C. Dart, M.D., Ph.D.
DirectorRocky Mountain Poison and Drug Center, Denver HealthProfessor of Surgery (Emergency Medicine)University of Colorado Health Sciences CenterDenver, Colorado Daniel C. Keyes, M.D., M.P.H.
Medical DirectorPine Bluff Chemical Demilitarization FacilityAssociate Professor, Southwestern Toxicology Training ProgramDallas, Texas Anthony S. Manoguerra, Pharm.D., D.A.B.A.T., F.A.A.C.T.
Professor of Clinical Pharmacy and Associate DeanSchool of Pharmacy and Pharmaceutical SciencesUniversity of California San DiegoFormer Director, California Poison Control System, San Diego DivisionSan Diego, California Kent R. Olson, M.D., F.A.C.E.P., F.A.A.C.T., F.A.C.M.T.
Medical DirectorCalifornia Poison Control System, San Francisco DivisionClinical Professor of Medicine & PharmacyUniversity of California, San Francisco Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 San Francisco, California Elizabeth J. Scharman, Pharm.D., D.A.B.A.T., B.C.P.S., F.A.A.C.T.
Director, West Virginia Poison CenterProfessor, West Virginia University School of PharmacyDepartment of Clinical PharmacyCharleston, West Virginia Paul M. Wax, M.D., F.A.C.M.T.
Managing DirectorBanner Poison CenterProfessor of Clinical Emergency MedicineUniversity of Arizona School of MedicinePhoenix, Arizona Alan D. Woolf, M.D., M.P.H., F.A.C.M.T.
Director, Program in Environmental MedicineChildren's Hospital, BostonAssociate Professor of PediatricsHarvard Medical SchoolBoston, Massachusetts OUT-OF-HOSPITAL MANAGEMENT OF ACETAMINOPHEN POISONING APPENDIX 2
Grades of Recommendation and Levels of Evidence
Grade of Recommendation Level of Evidence Description of Study Design Systematic review (with homogeneity) of randomized Individual randomized clinical trials (with narrow confidence All or none (all patients died before the drug became available, but some now survive on it; or when some patients died before thedrug became available, but none now die on it.) Systematic review (with homogeneity) of cohort studies Individual cohort study (including low quality randomized "Outcomes" research Systemic review (with homogeneity) of case-control studies Individual case-control study Case series, single case reports (and poor quality cohort and case Expert opinion without explicit critical appraisal or based on physiol or bench research Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 APPENDIX 3
Secondary Review Panel Organizations
Ambulatory Pediatric Association
Department of Transportation American Academy of Breastfeeding Medicine Emergency Medical Services for Children American Academy of Emergency Medicine Emergency Nurses Association American Academy of Pediatrics Environmental Protection Agency American Association for Health Education European Association of Poisons Control Centres and Clinical American College of Clinical Pharmacy American College of Emergency Physicians Food and Drug Administration American College of Occupational and Environmental National Association of Children's Hospitals and Related Insti- American Public Health Association National Association of Emergency Medical Services American Society of Health-System Pharmacists Association of Maternal and Child Health Programs National Association of Emergency Medical Technicians Association of Occupational and Environmental Clinics National Association of School Nurses Association of State and Territorial Health Officials National Association of State Emergency Medical Services Canadian Association of Poison Control Centres Centers for Disease Control and Prevention—National Center National Safe Kids Campaign for Injury Prevention and Control Teratology Society Consumer Federation of America World Health Organization International Programme on Consumer Product Safety Commission R. C. DART ET AL.
APPENDIX 4
Algorithm for Out-of-Hospital Management of Acute Acetaminophen Ingestions
Is self-harm, suicidal, or malicious intent suspected? YES→ Refer to emergency department.
Does patient have signs of liver failure (e.g., repeatedvomiting, YES→ Refer to emergency department.
jaundice, right upper abdomen tenderness, mental changes)? Have more than 36 hours passed since the ingestion? YES → Toxicity unlikely to occur. No referralor treatment is needed.
Has the patient ingested a potentially toxic dose of acetaminophen YES→ Refer to emergency department to have stat (i.e., ≥200 mg/kg for patients <6 yr of age; ≥10 g or ≥200 mg/kg, serum acetaminophen concentration determined at whichever is less, for patients ≥6 yr of age)?* 4 hrafter ingestion.
No referral or treatment is needed.
* Activated charcoal should be considered if local poison center policies support its prehospital use, if a toxic dose of ace- Downloaded By: [Alerta - Chile 2005/2006 Consortium] At: 17:16 9 May 2007 taminophen has been taken and fewer than 2 hours have elapsed since the ingestion, or if acetylcysteine cannot be initiated within8 hours after the ingestion.
APPENDIX 5
Algorithm for Out-of-Hospital Management of Repeated Supratherapeutic Acetaminophen Ingestions (RSTI)
Is self-harm, suicidal, or malicious intent suspected? YES → Refer to emergency department. Has the patient ingested a potentially toxic dose of acetaminophen? YES → Refer to emergency department. For patients <6 yr of age: ≥200 mg/kg over 8–24 hours ≥150 mg/kg/day for 2 days ≥100 mg/kg/day for 3 days or longer For patients ≥6 yr of age:* ≥10 g or 200 mg/kg (whichever is less) over a single 24-hour period ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for 48 hours or longer No referral or treatment is needed.
*A referral dose of 4 g/day or 100 mg/kg/day (whichever is less) should be considered for patients with suspected risk fac-tors(e.g., alcoholism, isoniazid therapy, prolonged fasting).

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