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## Complete Summary

#### GUIDELINE TITLE

Valproic acid poisoning: an evidence-based consensus guideline for
out-of-hospital management.

#### BIBLIOGRAPHIC SOURCE(S)

Manoguerra AS, Erdman AR, Woolf AD, Chyka PA, Caravati EM, Scharman EJ,
Booze LL, Christianson G, Nelson LS, Cobaugh DJ, Troutman WG. Valproic
acid poisoning: an evidence-based consensus guideline for out-of
hospital management. Washington (DC): American Association of Poison
Control Centers; 2006. 23 p. \[85 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Valproic acid poisoning

**Note**:

-   This guideline applies to the acute ingestion and acute-on-chronic
    ingestion of immediate-release and extended-release dosage forms of
    valproic acid, divalproex, and valproate sodium alone. Co-ingestion
    of additional substances could require different referral and
    management recommendations depending on the combined toxicities of
    the substances.

-   This review focuses on the ingestion of more than a single
    therapeutic dose and the effects of an overdose. Although
    therapeutic doses of valproic acid can cause adverse effects in
    adults and children, some idiosyncratic and some dose-dependent,
    these cases are not considered.

#### GUIDELINE CATEGORY

Evaluation\
Management\
Risk Assessment

#### CLINICAL SPECIALTY

Emergency Medicine\
Family Practice\
Internal Medicine\
Obstetrics and Gynecology\
Pediatrics

#### INTENDED USERS

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

#### GUIDELINE OBJECTIVE(S)

To assist poison center personnel in the appropriate out-of-hospital
triage and initial out-of-hospital management of patients with a
suspected ingestion of valproic acid by:

-   Describing the process by which an ingestion of valproic acid might
    be managed

-   Identifying the key decision elements in managing cases of valproic
    acid ingestion

-   Providing clear and practical recommendations that reflect the
    current state of knowledge

-   Identifying needs for research

#### TARGET POPULATION

Children and adults (including pregnant women) with suspected valproic
acid poisoning

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Evaluation**

1.  Assessment of key decision elements for triage

    -   Patient intent

    -   Dose and formulation

    -   Presence of symptoms

    -   Time of ingestion

**Management**

1.  Referral to an emergency department

2.  Activated charcoal administration by health professionals

3.  Evaluation of pregnant women by their obstetrician

4.  Naloxone

5.  Benzodiazepines administered by emergency medical services (EMS)
    personnel

6.  Home observation

**Note**: The following measure was considered but not recommended:
induction of emesis.

#### MAJOR OUTCOMES CONSIDERED

-   Signs and symptoms of toxicity

-   Mortality

-   Toxic dose

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

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

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Search Strategy**

Literature searches for relevant articles were performed by a single
investigator. The National Library of Medicine\'s PubMed database was
searched (through March 2006) using valproic acid as a Medical Subject
Headings (MeSH) term with the subheadings poisoning or toxicity, limited
to humans. The PubMed database was further searched using valproic acid,
valproate, and divalproex as textwords (title, abstract, MeSH term, CAS
registry) plus either poison\* or overdos\* or intox\* or toxic\*,
limited to humans. This process was repeated in International
Pharmaceutical Abstracts (1970--March 2006, excluding abstracts of
meeting presentations), Science Citation Index (1977--March 2006),
Database of Abstracts of Reviews of Effects (accessed March 2006),
Cochrane Database of Systematic Reviews (accessed March 2006), and
Cochrane Central Register of Controlled Trials (accessed March 2006).
Reactions (1980--March 2006), the valproic acid poisoning management in
Poisindex, and the bibliographies of recovered articles were reviewed to
identify previously undiscovered articles. Furthermore, North American
Congress of Clinical Toxicology (NACCT) abstracts published in the
Journal of Toxicology Clinical Toxicology (1995--2004) and Clinical
Toxicology (2005) were reviewed for original human data.

Six major toxicology textbooks were reviewed for recommendations on the
management of valproic acid poisonings and for citations of additional
articles with original human data in the chapter bibliographies. The
Toxic Exposure Surveillance System (TESS) maintained by the American
Association of Poison Control Centers was searched for deaths resulting
from valproic acid poisoning. These cases were abstracted for review by
panel members. All United States poison control centers were surveyed in
2006 to ascertain their out-of-hospital management and triage practices
for valproic acid poisonings.

**Criteria Used to Identify Applicable Studies**

The recovered citations were entered into an EndNote library and
duplicate entries were eliminated. The abstracts of these articles were
reviewed, searching specifically for those that dealt with estimations
of doses with or without subsequent signs or symptoms of toxicity and
management techniques that might be suitable for out-of-hospital use
(e.g., gastrointestinal decontamination). Articles that did not meet
either of the preceding criteria, did not add new data (e.g., reviews,
editorials), or that exclusively described inpatient-only procedures
(e.g., dialysis) were excluded.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

 

  ------------------------------------------------------------------------
  **Level of   **Description of Study Design**
  Evidence**   
  ------------ -----------------------------------------------------------
  1a           Systematic review (with homogeneity) of randomized clinical
               trials

  1b           Individual randomized clinical trials (with narrow
               confidence interval)

  1c           All or none (all patients died before the drug became
               available, but some now survive on it; or when some
               patients died before the drug became available, but none
               now die on it.)

  2a           Systematic review (with homogeneity) of cohort studies

  2b           Individual cohort study (including low quality randomized
               clinical trial)

  2c           \"Outcomes\" research

  3a           Systemic review (with homogeneity) of case-control studies

  3b           Individual case-control study

  4            Case series, single case reports (and poor quality cohort
               and case control studies)

  5            Expert opinion without explicit critical appraisal or based
               on physiology or bench research

  6            Abstracts
  ------------------------------------------------------------------------

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Data Extraction Process**

All articles that were retrieved from the original search were reviewed
by a single trained physician abstractor. The complete paper was
reviewed for original human data regarding the toxic effects of valproic
acid or original human data directly relevant to the out-of-hospital
management of patients with valproic acid toxicity or overdose. Relevant
data (e.g., dose, effects, time of onset of effects, therapeutic
interventions or decontamination measures provided, efficacy or results
of any interventions, and overall patient outcome) were compiled into a
table and a brief description of each article was written. This evidence
table is available at
[http://www.aapcc.org/DiscGuidelines/valproic%20acid%20evidence%20table%202006-6-8.pdf](http://www.aapcc.org/DiscGuidelines/valproic acid evidence table 2006-6-8.pdf).

The table of all abstracted articles was then forwarded to the panel
members for review and consideration in developing the guideline. Every
attempt was made to locate foreign language articles and have their
crucial information extracted, translated, and tabulated. A written
summary of the data was created and distributed by the abstractor.
Copies of all of the abstracted articles were made available for reading
by the panel members on a secure American Association of Poison Control
Centers (AAPCC) website.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Delphi)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

An expert consensus panel was established to develop the guideline (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 record in clinical care and scientific research in
toxicology, board certification as a clinical or medical toxicologist,
significant US poison control 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 lead 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, anonymously copied into a table of comments, and submitted to
the lead author for response. The lead 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 lead author, the draft
was prepared for the external review process.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

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

  -----------------------------------------------------------------------
  **Grade of Recommendation**                          **Level of\
                                                       Evidence**
  ---------------------------------------------------- ------------------
  A                                                    1a

                                                       1b

                                                       1c

  B                                                    2a

                                                       2b

                                                       2c

                                                       3a

                                                       3b

  C                                                    4

  D                                                    5

  Z                                                    6
  -----------------------------------------------------------------------

#### COST ANALYSIS

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

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

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 in the
original guideline document). Comments were submitted via a discussion
thread on the AAPCC web site or privately through email 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 lead author. The lead
author responded to each comment in the table and his responses and
subsequent changes in the guideline were reviewed and accepted by the
panel.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

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

1.  All patients with suicidal intent, intentional abuse, or in whom a
    malicious intent is suspected (e.g., child abuse or neglect) should
    be referred to an emergency department **(Grade D)**.

2.  Patients who are symptomatic (more than somnolence or exhibiting
    coma or seizures) after a valproic acid ingestion should be referred
    to an emergency department **(Grade C)**.

3.  Asymptomatic patients with an unintentional acute ingestion of 50
    mg/kg or more or asymptomatic patients who are taking the drug
    therapeutically and who take an additional single acute ingestion of
    50 mg/kg or more of any valproic acid formulation should be referred
    to an emergency department for evaluation **(Grade C)**.

4.  Patients with unintentional ingestions of immediate-release valproic
    acid formulations, who are asymptomatic, and more than 6 hours has
    elapsed since the time of ingestion, can be observed at home
    **(Grade C)**.

5.  Patients with unintentional ingestions of delayed-release or
    extended-release formulations of valproic acid who are asymptomatic,
    and more than 12 hours has elapsed since the time of ingestion, can
    be observed at home **(Grade C)**.

6.  Pregnant women who ingest below the dose for emergency department
    referral and do not have other referral conditions should be
    directed to their primary care obstetrical provider for evaluation
    of potential maternal and fetal risk. Routine referral to an
    emergency department for immediate care is not required **(Grade
    D)**.

7.  Do not induce emesis **(Grade C)**.

8.  Activated charcoal can be administered to asymptomatic patients who
    have ingested valproic acid within the preceding hour **(Grade C)**.
    Prehospital activated charcoal administration, if available, should
    only be carried out by health professionals and only if no
    contraindications are present. Poison centers should follow local
    protocols and experience with its use. Do not delay transportation
    in order to administer activated charcoal **(Grades D)**.

9.  In patients who have ingested valproic acid and who are comatose,
    naloxone can be considered for prehospital administration in the
    doses used for treatment of opioid overdose, particularly if the
    patient has respiratory depression **(Grade C)**.

10. A benzodiazepine can be administered by emergency medical services
    (EMS) personnel if convulsions are present and if authorized by EMS
    medical direction, expressed by written treatment protocol or
    policy, or if there is direct medical oversight **(Grade C)**.

**Definitions**:

**Grades of Recommendation and Levels of Evidence**

  ----------------------------------------------------------------------------
  **Grade of         **Level of\  **Description of Study Design**
  Recommendation**   Evidence**   
  ------------------ ------------ --------------------------------------------
  A                  1a           Systematic review (with homogeneity) of
                                  randomized clinical trials

                     1b           Individual randomized clinical trials (with
                                  narrow confidence interval)

                     1c           All or none (all patients died before the
                                  drug became available, but some now survive
                                  on it; or when some patients died before the
                                  drug became available, but none now die on
                                  it.)

  B                  2a           Systematic review (with homogeneity) of
                                  cohort studies

                     2b           Individual cohort study (including low
                                  quality randomized clinical trial)

                     2c           \"Outcomes\" research

                     3a           Systemic review (with homogeneity) of
                                  case-control studies

                     3b           Individual case-control study

  C                  4            Case series, single case reports (and poor
                                  quality cohort and case control studies)

  D                  5            Expert opinion without explicit critical
                                  appraisal or based on physiology or bench
                                  research

  Z                  6            Abstracts
  ----------------------------------------------------------------------------

#### CLINICAL ALGORITHM(S)

An algorithm is provided in Appendix 4 of the original guideline
document for triage for acute and single acute-on-chronic valproic acid
poisoning.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

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

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate out-of-hospital triage and initial out-of-hospital
management of patients with suspected valproic acid poisoning

#### POTENTIAL HARMS

Not stated

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   This guideline has been developed for the conditions prevalent in
    the United States. While the toxicity of valproic acid 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 might be at variance with this
    guideline and are the prerogative of the patient and the health
    professionals providing care, considering all of the circumstances
    involved. This guideline does not substitute for clinical judgment.

**Limitations of the Literature**

Unfortunately, the data on acute valproic acid poisoning generally
suffered from a number of limitations: 1) much of the data was
determined by retrospective observations and based on estimates of dose
provided by patients or family members, raising questions about the
accuracy of the dose estimates; 2) the dose-effect information was
confounded in many cases by the presence of co-ingestants, differences
in treatment measures provided, and concurrent medical conditions that
could have altered the clinical presentation or outcome; 3) as there are
several formulations of valproic acid and divalproex products, many
authors failed to report exactly which product was involved; 4) among
larger case series, many of the patients remained asymptomatic, and
product formulations, ingestion doses, and frequency and severity of
effects were typically reported as ranges of values, percentages, or
means, so individual doses resulting in specific effects could not be
determined; and 5) among the few prospective trials available, valproic
acid was administered in therapeutic doses, which would be expected to
be much smaller than doses likely to be seen in an overdose or
poisoning.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness\
Timeliness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Manoguerra AS, Erdman AR, Woolf AD, Chyka PA, Caravati EM, Scharman EJ,
Booze LL, Christianson G, Nelson LS, Cobaugh DJ, Troutman WG. Valproic
acid poisoning: an evidence-based consensus guideline for out-of
hospital management. Washington (DC): American Association of Poison
Control Centers; 2006. 23 p. \[85 references\]

#### ADAPTATION

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

#### DATE RELEASED

2006 Dec 22

#### GUIDELINE DEVELOPER(S)

American Association of Poison Control Centers - Professional
Association

#### SOURCE(S) OF FUNDING

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

#### GUIDELINE COMMITTEE

Not stated

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: Anthony S. Manoguerra, PharmD; Andrew R. Erdman, MD;
Alan D. Woolf, MD, MPH; Peter A. Chyka, PharmD; E. Martin Caravati, MD,
MPH; Elizabeth J. Scharman, PharmD; Lisa L. Booze, PharmD; Gwenn
Christianson, MSN; Lewis S. Nelson, MD; Daniel J. Cobaugh, PharmD;
William G. Troutman, PharmD

*Expert Consensus 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 Control Center, Salt
Lake City, Utah; Gwenn Christianson, RN, MSN, Certified Specialist in
Poison Information, Indiana Poison Center, Indianapolis, Indiana; Peter
A. Chyka, PharmD, DABAT, FAACT, Professor, Department of Clinical
Pharmacy, College of Pharmacy, University of Tennessee Health Science
Center, Knoxville, Tennessee; Daniel J. Cobaugh, PharmD, FAACT, DABAT,
Director of Research, ASHP Research and Education Foundation, Bethesda,
Maryland, Former Associate Director, American Association of Poison
Control Centers; 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; Lewis S. Nelson, MD, FACEP, FACMT,
FACCT, Associate Professor of Emergency Medicine, New York University
School of Medicine, Associate Medical Director, New York City Poison
Control Center, New York, New York; 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, Attending
Toxicologist, University of Texas Southwestern Medical Center, Dallas,
Texas; Alan D. Woolf, MD, MPH, FACMT, Director, Program in Environmental
Medicine, Children\'s Hospital, Boston, Associate Professor of
Pediatrics, Harvard Medical School, Boston, Massachusetts

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. Booze\'s husband is employed by AstraZeneca.

Dr. Erdman was employed by AstraZeneca at the time of his work on this
guideline.

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

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[American Association of Poison Control
Centers](http://www.aapcc.org/FinalizedPMGdlns/Valproic Acid Poisoning Final.pdf).

Print copies: Available from the American Association of Poison Control
Centers, 3201 New Mexico Avenue NW, Suite 330, Washington, DC 20016

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI Institute on December 18, 2007.
The information was verified by the guideline developer on January 14,
2008.

#### COPYRIGHT STATEMENT

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

### DISCLAIMER

#### NGC DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008