This is the current release of the guideline.

Acetaminophen poisoning

Note: This guideline applies to ingestion of acetaminophen alone. Co-ingestion of additional substances could require different referral and management recommendation depending on the combined toxicities of the substances.

Evaluation
Management
Risk Assessment

Emergency Medicine
Family Practice
Internal Medicine
Pediatrics

Advanced Practice Nurses
Allied Health Personnel
Emergency Medical Technicians/Paramedics
Nurses
Pharmacists
Physicians

To assist U.S. poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of acetaminophen by:

• Describing the process by which an ingestion of acetaminophen might be managed
• Identifying the key decision elements
• Providing clear and practical recommendations that reflect the current state of knowledge
• Identifying needs for research

Children under 6 years of age and older children and adults with acute and repeated ingestion of acetaminophen

Evaluation

1. Assessment of key decision elements for triage
   • Patient intent
   • Patient's age
   • Pattern of ingestion (single or multiple)
   • Dose and formulation of the acetaminophen product ingested
   • Duration of ingestion
   • Conditions that might increase acetaminophen toxicity (alcoholism, isoniazid use, prolonged fasting) and co-ingestants
2. Serum acetaminophen concentration measurements

Management

1. Referral to an emergency department
2. Activated charcoal when appropriate
3. Detoxification with acetylcysteine if the emergency department is far away

   Note: The dietary supplement tablet form of acetylcysteine has not been tested as an antidote for acetaminophen toxicity, therefore only the pharmaceutical product should be used.

4. Home observation
5. Cimetidine as an antidote (considered, but not recommended)

• Mortality
• The threshold dose for the development of toxicity after acute and repeated acetaminophen ingestion
• Signs and symptoms of toxicity

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Literature Search

The National Library of Medicine's MEDLINE database was searched (1966 to January 2003) using acetaminophen as a Medical Subject Heading (MeSH) term with the subheadings poisoning (po) or toxicity (to), limited to humans. MEDLINE and PreMEDLINE (1966 to January 2003) were searched using acetaminophen or paracetamol as textwords (title, abstract, MeSH term, CAS registry) plus either poison* or overdos*, limited to humans. This same process was repeated in International Pharmaceutical Abstracts (1970 to January 2003, excluding abstracts of meeting presentations), Science Citation Index (1977 to January 2003), Database of Abstracts of Reviews of Effects (accessed Jan 2003), Cochrane Database of Systematic Reviews (accessed Jan 2003), and Cochrane Central Register of Controlled Trials (accessed Jan 2003). A similar search was conducted in EMBASE using both acetaminophen and paracetamol as primary search terms. Index Medicus was hand-searched (1960-1965) using the term "analgesics and antipyretics" through 1964 and "acetaminophen" for 1965. Reactions (1980 to January 2003), the acetaminophen poisoning management in POISINDEX, the Cochrane systematic review of interventions for acetaminophen overdoses, and the chapter bibliographies in four major toxicology textbooks were reviewed for citations of additional articles with original human data. The bibliographies of recovered articles were reviewed to identify previously undiscovered articles.

Article Selection

The recovered citations were entered into an EndNote library and duplicate entries were eliminated. The abstracts of these articles were reviewed, looking specifically for those that dealt with 1) estimations of mg/kg or ingested doses with or without subsequent signs or symptoms, and 2) management techniques that might be suitable for out-of-hospital use (e.g., gastrointestinal decontamination). The panel agreed that acetylcysteine therapy could be considered for initiation in the prehospital setting. Articles excluded were those that did not meet either of the preceding criteria, did not add new data (e.g., some reviews and editorials), described inpatient-only procedures (e.g., dialysis), or described treatments that were unlikely to be used (e.g., methionine).

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Articles were assigned level-of-evidence scores based on the Grades of Recommendation table developed by the Centre for Evidence-Based Medicine at Oxford University. Single case reports were classified along with case series as level 4.

Systematic Review with Evidence Tables

Expert Consensus (Delphi)

An expert consensus panel was established to oversee the guideline development process (see Appendix 1 of the original guideline document). The American Association of Poison Control Centers (AAPCC), the American Academy of Clinical Toxicology (AACT), and the American College of Medical Toxicology (ACMT) appointed members of their organizations to serve as panel members. To serve on the expert consensus panel, an individual had to have an exceptional track record in clinical care and scientific research in toxicology, board certification as a clinical or medical toxicologist, significant U.S. poison center experience, and be an opinion leader with broad esteem. Two Specialists in Poison Information were included as full panel members to provide the viewpoint of the end-users of the guideline.

Guideline Writing and Review

A guideline draft was prepared by the primary author. The draft was submitted to the expert consensus panel for comment. Using a modified Delphi process, comments from the expert consensus panel members were collected, copied into a table of comments, and submitted to the primary author for response. The primary author responded to each comment in the table and, when appropriate, the guideline draft was modified to incorporate changes suggested by the panel. The revised guideline draft was again reviewed by the panel and, if there was no strong objection by any panelist to any of the changes made by the primary author, the draft was prepared for the external review process.

The rating scheme for the strength of the recommendation (A-D, Z) is directly tied to the level of evidence supporting the recommendation.

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

External review of the second draft was conducted by distributing it electronically to American Association of Poison Control Centers (AAPCC), American Academy of Clinical Toxicology (AACT), and American College of Medical Toxicology (ACMT) members and the secondary review panel. The secondary review panel consisted of representatives from the federal government, public health, emergency services, pediatrics, pharmacy practice, and consumer organizations (see Appendix 3 of the original guideline). Comments were submitted via a discussion thread on the AAPCC Web site or privately through e-mail communication to AAPCC staff. All submitted comments were stripped of any information that would identify their sources, copied into a table of comments, and reviewed by the expert consensus panel and the primary author. The primary author responded to each comment in the table and his responses and subsequent changes in the guideline were reviewed and accepted by the panel. Following a meeting of the expert consensus panel, the final revision of the guideline was prepared.

Grades of recommendation (A-D, Z) and levels of evidence (1a-6) are defined at the end of the "Major Recommendations" field.

Note: These recommendations are provided in chronological order of likely clinical use. The grade of recommendation is provided in parentheses.

1. The initial history obtained by the specialist in poison information should include the patient's age and intent (Grade B), the specific formulation and dose of acetaminophen, the ingestion pattern (single or multiple), duration of ingestion (Grade B), and concomitant medications that might have been ingested (Grade D).
2. Any patient with stated or suspected self-harm or who is the recipient of a potentially malicious administration of acetaminophen should be referred to an emergency department immediately regardless of the amount ingested. This referral should be guided by local poison center procedures (Grade D).
3. Activated charcoal can be considered if local poison center policies support its prehospital use, a toxic dose of acetaminophen has been taken, and fewer than 2 hours have elapsed since the ingestion (Grade A). Gastrointestinal decontamination could be particularly important if acetylcysteine cannot be administered within 8 hours of ingestion.

Acute, Single, Unintentional Ingestion of Acetaminophen

1. Any patient with signs consistent with acetaminophen poisoning (e.g., repeated vomiting, abdominal tenderness in the right upper quadrant, or mental status changes) should be referred to an emergency department for evaluation (Grade D).
2. Patients less than 6 years of age should be referred to an emergency department if the estimated acute ingestion amount is unknown or is 200 mg/kg or more. Patients can be observed at home if the dose ingested is less than 200 mg/kg (Grade B).
3. 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 lower) or when the amount ingested is unknown (Grade D).
4. Patients referred to an emergency department should arrive in time to have a stat serum acetaminophen concentration determined at 4 hours after ingestion or as soon as possible thereafter. If the time of ingestion is unknown, the patient should be referred to an emergency department immediately (Grade D).
5. If the initial contact with the poison center occurs more than 36 hours after the ingestion and the patient is well, the patient does not require further evaluation for acetaminophen toxicity (Grade D).

Repeated Supratherapeutic Ingestion of Acetaminophen (RSTI)

1. Patients under 6 years of age should be referred to an emergency department immediately if they have ingested:
   • 200 mg/kg or more over a single 24-hour period, or
   • 150 mg/kg or more per 24-hour period for the preceding 48 hours, or
   • 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer (Grade C).
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
   • at least 6 g or 150 mg/kg (whichever is less) per 24-hour period for the preceding 48 hours or longer.

   In patients with conditions purported to increase susceptibility to acetaminophen toxicity (alcoholism, isoniazid use, prolonged fasting), the dose of acetaminophen considered as RSTI should be greater than 4 g or 100 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 acetaminophen or multi-drug combination products containing acetaminophen is the same as an ingestion of acetaminophen alone (Grade D). However, the effects of other drugs might require referral to an emergency department in accordance with the poison center's normal triage criteria.
2. The use of cimetidine as an antidote is not recommended (Grade A).

Definitions:

Grades of Recommendation and Levels of Evidence

Algorithms are provided in Appendices 4 and 5 of the original guideline document for out-of-hospital management of acute acetaminophen ingestion and out-of-hospital management of repeated supratherapeutic acetaminophen ingestion.

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

• Appropriate out-of-hospital triage and initial management of patients with suspected ingestions of acetaminophen
• Optimized patient outcome
• Reduced costs
• Reduced disruption for patient and caregivers

Not stated

• This guideline has been developed for the conditions prevalent in the U.S. While the toxicity of acetaminophen is not expected to vary in a clinically significant manner in other nations, the out-of-hospital conditions could be much different. This guideline should not be extrapolated to other settings unless it has been determined that the conditions assumed in this guideline are present.
• This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment.
• The history of ingestion might be inaccurate because it is often obtained during a period of extreme emotional stress for both the patient and their family. Furthermore, there are often confounding factors such as co-ingestion of ethanol or other drugs that affect the central nervous system. In most reports available, the accuracy of the history was not addressed and the history was not confirmed by outside sources (e.g., family members) or objective evidence (e.g., empty product containers).
• The panel chose not to form conclusions on several issues due to the lack of information available. These included the mode of transportation to emergency departments, the effects of circadian rhythm on toxicity, the role of patient gender, and the body position for transport. The use of an acetaminophen serum concentration to determine the need for acetylcysteine therapy was not addressed by the panel because it is not applied in the out-of-hospital environment.

Limitations of Published Decontamination Data

Simulated overdose studies in volunteers might be a poor representation of what occurs in real acetaminophen overdoses, in which larger doses are ingested, patients are not fasting, and co-ingestants that affect gastrointestinal motility might be involved. Volunteer studies might underestimate the efficacy of decontamination if gastric emptying is delayed in overdoses or they might overestimate efficacy if the decontamination measures become less effective with massive acetaminophen doses (by stoichiometry), tablet bezoar formation, or because of activated charcoal binding to food or other co-ingestants rather than acetaminophen.

There are also challenges in the interpretation of cohort and case-control studies. There could be other differences between the cases and controls other than the variable being tested (e.g., ingested doses, times to treatment might differ, and use of acetylcysteine might differ). They also tend to rely on retrospective data-gathering, a process that produces its own unique disadvantages (e.g., decisions on treatment could have been based on some piece of history that was not recorded or recorded inaccurately in the medical record).

An implementation strategy was not provided.

Getting Better

Effectiveness
Timeliness

Not applicable: The guideline was not adapted from another source.

2005

American Association of Poison Control Centers - Professional Association

Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services

Not stated

Primary Authors: Richard C. Dart, MD; PhD, Andrew R. Erdman, MD; Kent R. Olson, MD; Gwenn Christianson, MSN; Anthony S. Manoguerra, PharmD; Peter A. Chyka, PharmD; E. Martin Caravati, MD, MPH; Paul M. Wax, MD; Daniel C. Keyes, MD, MPH; Alan D. Woolf, MD, MPH; Elizabeth J. Scharman, PharmD; Lisa L. Booze, PharmD; William G. Troutman, PharmD

Panel Members: Lisa L. Booze, PharmD, Certified Specialist in Poison Information, Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, Maryland; E. Martin Caravati, MD, MPH, FACMT, FACEP, Professor of Surgery (Emergency Medicine), University of Utah, Medical Director, Utah Poison Center, Salt Lake City, Utah; Gwenn Christianson, RN, MSN, Certified Specialist in Poison Information, Indiana Poison Center, Indianapolis, Indiana; Peter A. Chyka, PharmD. FAACT, DABAT, Professor, Department of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee; Richard C. Dart, MD, PhD, Director, Rocky Mountain Poison and Drug Center, Denver Health, Professor of Surgery (Emergency Medicine), University of Colorado Health Sciences Center, Denver, Colorado; Daniel C. Keyes, MD, MPH, Medical Director, Pine Bluff Chemical Demilitarization Facility, Associate Professor, Southwestern Toxicology Training Program, Dallas, Texas; Anthony S. Manoguerra, PharmD, DABAT, FAACT, Professor of Clinical Pharmacy and Associate Dean, School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, Former Director, California Poison Control System, San Diego Division, San Diego, California; Kent R. Olson, MD, FACEP, FAACT, FACMT, Medical Director, California Poison Control System, San Francisco Division, Clinical Professor of Medicine & Pharmacy, University of California, San Francisco, San Francisco, California; Elizabeth J. Scharman, PharmD, DABAT, BCPS, FAACT, Director, West Virginia Poison Center, Professor, West Virginia University School of Pharmacy, Dept. Clinical Pharmacy, Charleston, West Virginia; Paul M. Wax, MD, FACMT, Managing Director, Banner Poison Center, Professor of Clinical Emergency Medicine, University of Arizona School of Medicine, Phoenix, Arizona; Alan Woolf, MD, MPH, FACMT, Director, Program in Environmental Medicine, Children's Hospital, Boston, Associate Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts

Dr. Dart is employed by Denver Health, which provides professional services to many pharmaceutical companies, including McNeil Consumer and Specialty Pharmaceuticals.

There are no other potential conflicts of interest reported by the expert consensus panel or project staff regarding this guideline.

This is the current release of the guideline.

None available

None available

This NGC summary was completed by ECRI on October 31, 2005. The information was verified by the guideline developer on November 28, 2005.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.