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## Complete Summary

#### GUIDELINE TITLE

Management of alcohol withdrawal delirium. An evidence-based practice
guideline.

#### BIBLIOGRAPHIC SOURCE(S)

Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill
A, Jara G, Kasser C, Melbourne J. Management of alcohol withdrawal
delirium. An evidence-based practice guideline. Arch Intern Med 2004 Jul
12;164(13):1405-12. \[70 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15249349)

#### 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)

Alcohol withdrawal delirium (AWD)

#### GUIDELINE CATEGORY

Evaluation\
Management\
Treatment

#### CLINICAL SPECIALTY

Critical Care\
Emergency Medicine\
Family Practice\
Internal Medicine\
Neurology\
Pharmacology\
Psychiatry

#### INTENDED USERS

Advanced Practice Nurses\
Nurses\
Physician Assistants\
Physicians\
Substance Use Disorders Treatment Providers

#### GUIDELINE OBJECTIVE(S)

To assist physicians and other health care professionals in providing
appropriate treatment for all patients with alcohol withdrawal delirium
(AWD)

#### TARGET POPULATION

Patients with alcohol withdrawal delirium (AWD)

This guideline does *[not]{.underline}* include patients with
uncomplicated alcohol withdrawal syndrome.

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Pharmacologic Treatment**

1.  Benzodiazepines and other sedative-hypnotic agents as primary
    therapy

2.  Neuroleptic agents in combination with benzodiazepines

3.  Beta-adrenergic antagonists in combination with benzodiazepines

4.  Magnesium

5.  Thiamine

6.  Neuroleptic agents as sole pharmacologic therapy, ethyl alcohol, and
    any other pharmacologic agent for which published data on its use in
    patients with alcohol withdrawal delirium (AWD) could be located.

**Evaluation/Management**

1.  Medical evaluation

2.  Close nursing monitoring

3.  Vitals sign measurement

4.  Cardiac monitoring and oximetry

5.  Environmental cues

6.  Physical restraints

7.  Intravenous fluids and medications

8.  Endotracheal intubation and ventilatory support as needed

#### MAJOR OUTCOMES CONSIDERED

-   Mortality rate

-   Duration of delirium

-   Time required for control of agitation

-   Adequate control of delirium

-   Treatment complications

-   Costs

### 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

Searches of the English-language medical literature were conducted
through MEDLINE using the key words \"substance withdrawal syndrome and
alcohol,\" \"alcohol withdrawal delirium,\" and \"delirium tremens\"
from the initial entries in MEDLINE (January 1, 1966, through September
30, 2001). Articles were selected if they involved human subjects and
included new clinical data on the management of alcohol withdrawal
delirium (AWD) (ranging from a single case report to a prospective
randomized trial). References from the selected articles, including
those from before 1966, from review articles, and from textbooks were
also examined and included when appropriate.

#### NUMBER OF SOURCE DOCUMENTS

Forty-three articles were reviewed

#### 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

**Levels of Evidence**

**Level I studies**: Randomized trials with low false-positive and low
false-negative errors

**Level II studies**: Randomized trials with high false-positive or high
false-negative errors

**Level III studies**: Nonrandomized, concurrent cohort comparisons

**Level IV studies**: Nonrandomized, historical cohort comparisons

**Level V studies**: Case series without controls

#### METHODS USED TO ANALYZE THE EVIDENCE

Meta-Analysis of Randomized Controlled Trials\
Systematic Review with Evidence Tables

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

Members of the working group, using a structured data collection form,
abstracted all articles meeting the initial inclusion criteria. Articles
identified as prospective controlled trials with patients meeting
explicit inclusion criteria, including the basic elements of the
Diagnostic and Statistical Manual of Mental Disorders, 4^th^ edition
(DSM-IV) criteria for alcohol withdrawal delirium (AWD), underwent
further independent review by a second member, with abstraction of data
for meta-analysis. Any differences of interpretation were resolved by
consensus. Meta-analysis was performed when possible using the logit
method.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

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

Recommendations based on the evidence were drafted and graded according
to a published system. In several areas, it was recognized that a single
recommendation could not be formulated to guide the treatment of all
patients but that the decisions should be guided by a series of clinical
considerations. In such areas, the level of evidence supporting these
considerations was identified. In formulating recommendations, greater
weight was given to studies with higher grades of evidence. When no
evidence from controlled studies was available, expert opinion was
considered. Among outcomes, greatest value was given to patient safety,
followed by patient comfort, and then cost. Given the seriousness of the
outcomes involved, it was believed that there would be little or no
variation in patient preference for treatment and that patients would
prefer improved medical outcomes (decreased mortality, shorter duration
of delirium, etc).

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

**Grade A**: Supported by level I studies or by a meta-analysis in which
the lower limit of the confidence interval for the effect of treatment
exceeds the minimally clinically significant benefit

**Grade B**: Supported by level II studies or by a meta-analysis in
which the estimate of treatment effect exceeds the minimal clinically
significant benefit but the lower limit of the confidence interval does
not

**Grade C**: Supported by data other than prospective controlled trials,
including secondary analyses of level I or II studies

#### COST ANALYSIS

Acquisition costs were determined by averaging wholesale prices listed
in the *2001 Red Book*.

Costs can vary greatly depending on the selected drug and the route of
administration. For example, the average wholesale costs of different
agents in oral form at approximately equivalent dosages are as follows:
chlordiazepoxide, 25 mg, \$0.07; diazepam, 5 mg, \$0.10; and lorazepam,
1 mg, \$0.80. Intravenous (IV) medication, which is usually needed for
adequate control of alcohol withdrawal delirium (AWD), is often more
than 3 times as expensive as oral medication. For example, the average
wholesale costs of these agents in equivalent dosages are as follows:
diazepam, 10 mg, \$2.40; lorazepam, 2 mg, \$2.74; pentobarbital, 350 mg,
\$4.90; and midazolam, 5 mg, \$5.60. (Midazolam would need continuous
infusion, with published doses at 0.75 to 10.0 micrograms/kg per minute,
or \$3.36 to \$47.04 per hour for a 70-kg person, although prices are
expected to decrease as the generic form becomes available.) Some
practitioners have described the use of continuous infusion of
short-acting benzodiazepines, such as lorazepam or midazolam. Such
infusions can require very large amounts of medication over several
hours or days. Direct drug costs (excluding costs of preparation,
administration, and monitoring) of \$50,335 for a 25-hour infusion of
midazolam were reported for 1 patient, and a hospital stay costing
\$26,045 was reported for another patient. Furthermore, there are no
trials reporting comparative risks and benefits of intermittent vs.
continuous IV administrations, and no evidence could be identified
documenting an advantage for continuous infusion.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The draft guideline was sent for review to first authors of articles
from the past 10 years that met the inclusion criteria and to
representatives of organizations of medical interest (drawn from the
list published by the American Medical Association) for whom this
guideline may have been of interest. The American Society of Addiction
Medicine Board of Directors approved the final version in October 2002,
with review and revision scheduled for November 2007, unless new
information warrants revision before then.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Levels of recommendation (A-C) and Levels of Evidence (I-V) are defined
at the end of the \"Major Recommendations\" field.

**Choice of Pharmacologic Agent**

The initial therapeutic goal in patients with alcohol withdrawal
delirium (AWD) is control of agitation, the symptom that should trigger
use of the medication regimens described in this guideline. Rapid and
adequate control of agitation reduces the incidence of clinically
important adverse events. Sedative-hypnotic drugs are recommended as the
primary agents for managing AWD (**grade A recommendation**). These
drugs reduce mortality, reduce the duration of symptoms, and are
associated with fewer complications compared with neuroleptic agents in
controlled trials.

Current evidence does not clearly indicate that a specific
sedative-hypnotic agent is superior to others or that switching from one
to another is helpful. Benzodiazepines are most commonly used and
recommended by addiction specialists because of a favorable
therapeutic/toxic effect index. Examples of commonly used regimens are
shown in the original guideline document. However, reported clinical
experience indicates that barbiturates may be considered an option.
Owing to difficulties in administration and titration of dose,
paraldehyde is not recommended (**grade A recommendation**). Choice
among benzodiazepines may be guided by the following considerations: (1)
agents with rapid onset control agitation more quickly, for example,
oral or intravenous (IV) diazepam has a more rapid onset than other
agents (**level II evidence**); (2) agents with long duration of action
(e.g., diazepam) provide a smooth treatment course with less
breakthrough symptoms; (3) agents with shorter duration of activity
(e.g., lorazepam) may have lower risk when there is concern about
prolonged sedation, such as in patients who are elderly or who have
substantial liver disease or other serious concomitant medical illness
(**level III evidence**); and (4) the cost of different benzodiazepines
can vary considerably.

If a patient demonstrates agitation that is not controlled with
extremely large doses of benzodiazepines, use of pentobarbital or
propofol can be considered (**grade C recommendation**).

**Determination of Dose and Route of Administration**

It is recommended that the dose be determined specifically for each
individual patient and that medications be given in doses sufficient to
achieve and maintain light somnolence as the recommended therapeutic end
point (**grade C recommendation**). Light somnolence is characterized by
a state in which the patient is awake but tends to fall asleep unless
stimulated or is sleeping but easily aroused. The amount of medication
required for adequate sedation varies greatly from patient to patient
and over time in the same patient. Sedative-hypnotic drug doses needed
to suppress AWD are commonly much higher than doses used to treat severe
anxiety or to sedate patients presurgically. Tolerance, age, severity of
signs and symptoms, and medical comorbidity affect the quantity of
medication needed for adequate control. When using shorter-acting
agents, medication should be tapered carefully even after AWD resolves
to prevent the development of breakthrough symptoms or the occurrence of
withdrawal seizures.

The medication should be administered by a route that supports
achievement of rapid control of agitation and maintenance of appropriate
sedation (light somnolence). Intravenous administration has the quickest
onset compared with other routes. Intramuscular injection of most
benzodiazepines is not recommended owing to erratic absorption (**grade
C recommendation**). Lorazepam, however, is an option in patients with
stable cardiovascular status, as it has good intramuscular absorption.
Intermittent IV administrations of long-acting medications and
continuous IV infusion of short-acting medications seem effective and
thus are acceptable. However, continuous IV infusion is considerably
more expensive, and there is no existing evidence of therapeutic
superiority.

**Other Agents**

Neuroleptic agents are not recommended as the sole pharmacologic agents
in the treatment of AWD because they are associated with higher
mortality, longer duration of delirium, and more complications compared
with sedative-hypnotic agents in controlled trials (**grade A
recommendation**). Neuroleptic agents may be considered for use in
conjunction with benzodiazepines when agitation, perceptual
disturbances, or disturbed thinking are not adequately controlled by
benzodiazepine therapy (**grade C recommendation**).

Beta-adrenergic antagonists may be considered for use in conjunction
with benzodiazepines in selected patients for control of persistent
hypertension or tachycardia (**grade C recommendation**). They are not
recommended for routine use in all patients with AWD, however, as there
is no evidence that they improve outcomes in AWD, and beta-adrenergic
antagonists, particularly propranolol, may worsen delirium (**level V
evidence**).

Ethyl alcohol is not recommended because there are no controlled trials
and there are well-known adverse effects (**grade C recommendation**).

There is no evidence that magnesium therapy specifically benefits the
delirium in alcohol withdrawal. However, magnesium deficiency is common
in patients with AWD. Magnesium should be provided for demonstrated
hypomagnesemia, and it is also safe and reasonable to include it in IV
fluids given for volume repletion provided renal function is normal and
levels are monitored (**grade C recommendation**).

Parenteral administration of thiamine (100 mg daily for at least 3 days,
IV or intramuscularly) is recommended to prevent or treat
Wernicke-Korsakoff syndrome (**grade C recommendation**).

**[Settings and Services]{.underline}**

The following recommendations are based on the clinical experience of
recognized experts; they have not been the subject of controlled studies
(**grade C recommendations**).

**Evaluation**

On admission or transfer of a patient from one setting to another, a
thorough medical evaluation is needed to determine appropriate
diagnostic tests, monitoring, and medication. Elderly patients and those
with concurrent medical conditions, acute and chronic, are at higher
risk of complications. Concurrent medical conditions are common and may
include dehydration, unrecognized head trauma, electrolyte
abnormalities, infections (including meningitis), gastrointestinal
hemorrhage, pancreatitis, liver disease, and myocardial infarction.
These conditions may not be obvious or self-reported in delirious
patients.

**Monitoring**

-   Close monitoring by nursing personnel is critical in providing
    protection for the patient and for maintaining accurate information
    to guide ongoing medical management. In many cases, continuous,
    one-to-one observation and monitoring may be required to ensure safe
    and adequate management of agitated and disoriented patients.

-   Vital signs should be monitored regularly in all patients. The
    appropriate frequency of monitoring depends on the frequency of
    medication administration, concurrent medical conditions, and the
    degree of abnormality of the vital signs.

When high doses of benzodiazepines are needed, or when continuous
infusions of medication are used, or when patients have significant
concurrent medical conditions, cardiac monitoring and oximetry should be
in place and resuscitative equipment should be readily available.

**Management**

-   A quiet room with good lighting and environmental cues (e.g., a
    clock and a calendar) may help reduce confusion.

-   Physical restraints may be needed temporarily to protect agitated
    patients from injuring themselves and to protect staff. Guidelines
    have been formulated on the appropriate use of restraints to ensure
    patient safety. If patients cannot take oral medications or maintain
    adequate oral intake, or if more rapid sedation is needed, IV fluids
    and medications are recommended. Fluid and electrolyte balance
    should be maintained, and monitoring of fluid input and output and
    laboratory variables may be required. Occasionally, endotracheal
    intubation and ventilatory support may be required.

**[Definitions]{.underline}**:

**Strength of the Recommendations**

**Grade A**: Supported by level I studies or by a meta-analysis in which
the lower limit of the confidence interval for the effect of treatment
exceeds the minimally clinically significant benefit

**Grade B**: Supported by level II studies or by a meta-analysis in
which the estimate of treatment effect exceeds the minimal clinically
significant benefit but the lower limit of the confidence interval does
not

**Grade C**: Supported by data other than prospective controlled trials,
including secondary analyses of level I or II studies

**Levels of Evidence**

**Level I studies**: Randomized trials with low false-positive and low
false-negative errors

**Level II studies**: Randomized trials with high false-positive or high
false-negative errors

**Level III studies**: Nonrandomized, concurrent cohort comparisons

**Level IV studies**: Nonrandomized, historical cohort comparisons

**Level V studies**: Case series without controls

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is stated for selected recommendations
(see the \"Major Recommendations\" field).

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Appropriate treatment for all patients with alcohol withdrawal
    delirium (AWD)

-   Control of patient agitation

-   Maintenance of light somnolence for the duration of the delirium

-   Prevention of morbidity and mortality

Sedative-hypnotic drugs reduce mortality, reduce the duration of
symptoms, and are associated with fewer complications compared with
neuroleptic agents in controlled trials.

#### POTENTIAL HARMS

**Overall Harms**

Complications of treatment

**Specific Harms**

-   *Benzodiazepines and other sedative-hypnotic agents*: In the study
    comparing rectal paraldehyde use and intravenous (IV) diazepam use,
    2 of 17 patients in the paraldehyde group developed respiratory
    arrest requiring resuscitation. In another study, 1 patient treated
    with pentobarbital developed lethargy progressing to coma. In the
    remainder of the studies, significant complications related to
    treatment were not observed. It has also been demonstrated in
    patients undergoing alcohol withdrawal, but not in those with
    alcohol withdrawal delirium (AWD), that shorter-acting agents have a
    higher incidence of rebound symptoms and may be associated with the
    occurrence of withdrawal seizures if discontinued too rapidly.

-   Several case series have reported on the use of other
    sedative-hypnotic agents in managing AWD, including chlormethiazole,
    lorazepam, flunitrazepam, pentobarbital, propofol, and midazolam.
    Chlormethiazole and flunitrazepam are not available in the United
    States. The shorter-acting agents-propofol, pentobarbital,
    lorazepam, and midazolam-were thought to be advantageous owing to
    ease of titration and lower risk of excess sedation. However, there
    are no controlled trials comparing short- and longer-acting agents
    in AWD.

-   *Neuroleptic Agents*: Neuroleptic agents have the potential to cause
    a variety of serious adverse effects, particularly when used in very
    high doses, which may be required to control severe agitation.
    Chlorpromazine, promazine, and other low-potency typical
    antipsychotic agents have been reported to have the greatest effect
    on lowering seizure threshold. Chlorpromazine and thioridazine are
    the most common offenders for causing hypotension, and thioridazine
    may also prolong the QTc interval, increasing risk for torsade de
    pointes and sudden death. All neuroleptic agents are thought to have
    the potential for causing neuroleptic malignant syndrome, and cases
    have been reported in patients with alcohol withdrawal syndrome
    (AWD) who have received neuroleptic drugs. No studies were
    identified describing the use of newer \"atypical\" antipsychotic
    agents, such as risperidone, olanzapine, and quetiapine, for AWD.
    These agents are at least as efficacious as typical antipsychotic
    agents for other indications and have a preferable adverse effect
    profile.

-   *Beta-adrenergic Antagonists*: Delirium is a known adverse effect of
    beta-adrenergic blocker therapy, and in at least 1 controlled study
    of propranolol in alcohol withdrawal syndrome, there was an
    increased incidence of delirium.

**Patients Most Likely to Experience Harm**

Elderly patients and those with concurrent medical conditions, acute and
chronic, are at higher risk of complications.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   This guideline is not a substitute for the experience and judgment
    of a physician. It has been developed to enhance the physician\'s
    ability to practice evidence-based medicine. Presented authors\'
    opinions are not necessarily representative of the agencies for
    which they work.

-   This guideline does not address the management of uncomplicated
    alcohol withdrawal syndrome or the prevention of alcohol withdrawal
    syndrome as these topics are covered in a previously published
    guideline.

-   American Society of Addiction Medicine practice guidelines are
    intended to assist physicians in making clinical decisions. The
    ultimate judgment regarding any specific treatment must be made by
    the physician with consideration of the pertinent scientific and
    patient information and in light of the diagnostic and treatment
    options available.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

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

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill
A, Jara G, Kasser C, Melbourne J. Management of alcohol withdrawal
delirium. An evidence-based practice guideline. Arch Intern Med 2004 Jul
12;164(13):1405-12. \[70 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15249349)

#### ADAPTATION

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

#### DATE RELEASED

2004 Jul 12

#### GUIDELINE DEVELOPER(S)

American Society of Addiction Medicine - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Supported by the American Society of Addiction Medicine and a grant from
the Stepping Stones Foundation, Bedford Hills, NY

#### GUIDELINE COMMITTEE

Working Group on the Management of Alcohol Withdrawal Delirium

American Society of Addiction Medicine, Practice Guidelines Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Working Group Members*: Michael F. Mayo-Smith, MD, MPH, Primary Care
Service, Veterans Administration Medical Center, Manchester, NH; Lee H.
Beecher, MD, St. Louis Park, Minn; Timothy L. Fischer, DO, Tri County
Commission on Alcohol and Drug Abuse, Orangebury, SC; David A. Gorelick,
MD, PhD, Intramural Research Program, National Institute on Drug Abuse,
Baltimore, Md; Jeanette L. Guillaume, MA, American Society of Addiction
Medicine, Chevy Chase, Md; Arnold Hill, MD, Marlboro Medical Center,
Marlborough, Mass; Gail Jara, BA, American Society of Addiction
Medicine, Chevy Chase, Md; Chris Kasser, MD, Kasser & Associates,
Cordova, Tenn; John Melbourne, MD, Conifer Park Rehabilitation Center,
Scotia, NY

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The guideline authors have no relevant financial interest in this
article.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the American Society of Addiction
Medicine (ASAM) Web site:

-   [HTML
    Format](http://archinte.ama-assn.org/cgi/content/full/164/13/1405)

-   [Portable Document Format
    (PDF)](http://archinte.ama-assn.org/cgi/reprint/164/13/1405.pdf)

Print copies: Available from ASAM, 4601 North Park Ave, Arcade Suite
101, Chevy Chase, MD 20815.

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on April 26, 2005. The
information was verified by the guideline developer on May 20, 2005.

#### COPYRIGHT STATEMENT

For reproduction of the guideline for purposes other than personal use,
please contact the ASAM national office.

### DISCLAIMER

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Date Modified: 11/3/2008