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Alcohol Withdrawal Syndrome:
Improving Outcomes Through
Early Identification And
Aggressive Treatment Strategies
Associate Editor-In-Chief
Kaushal Shah, MD, FACEP
Associate Professor, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, New
York, NY
Editorial Board
William J. Brady, MD
Professor of Emergency Medicine
and Medicine, Chair, Medical
Emergency Response Committee,
Medical Director, Emergency
Management, University of Virginia
Medical Center, Charlottesville, VA
Calvin A. Brown III, MD
Director of Physician Compliance,
Credentialing and Urgent Care
Services, Department of Emergency
Medicine, Brigham and Women's
Hospital, Boston, MA
Mark Clark, MD
Assistant Professor of Emergency
Medicine, Program Director,
Emergency Medicine Residency,
Mount Sinai Saint Luke's, Mount
Sinai Roosevelt, New York, NY
Peter DeBlieux, MD Professor of Clinical Medicine,
Interim Public Hospital Director
of Emergency Medicine Services,
Louisiana State University Health
Science Center, New Orleans, LA
Joseph H. Yanta, MD
Medical Toxicology Fellow, Division of Medical Toxicology, Dept. of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
Greg S. Swartzentruber, MD
Medical Toxicology Fellow, Division of Medical Toxicology, Dept. of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
Associate Professor, Division of Medical Toxicology, Dept. of Emergency
Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
Alcoholism is a prevalent medical and psychiatric disease, and,
consequently, alcohol withdrawal is encountered frequently in
the emergency department. This issue reviews the pathophysiology of the alcohol withdrawal syndrome, describes the 4 manifestations of alcohol withdrawal, and looks at the available evidence
for optimal treatment of alcohol withdrawal in its diverse presentations. Patients commonly manifest hyperadrenergic signs
and symptoms, necessitating admission to the intensive care unit,
intravenous benzodiazepines, and, frequently, adjunctive pharmacotherapy. An aggressive front-loading approach with benzodiazepines is proposed and the management of benzodiazepineresistant disease is addressed.
Andy Jagoda, MD, FACEP
Professor and Chair, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, Medical
Director, Mount Sinai Hospital, New
York, NY
Authors
Anthony F. Pizon, MD
Abstract
Editor-In-Chief
June 2015
Volume 17, Number 6
Peer Reviewers
Gillian A. Beauchamp, MD
Medical Toxicology Fellow, Dept. of Emergency Medicine, Oregon Health
& Science University, Portland, OR
Adarsh K. Srivastava, MD
Assistant Professor, Division of Critical Care Medicine, Dept. of
Emergency Medicine, University of Cincinnati Academic Health Center,
Cincinnati, OH
CME Objectives
Upon completion of this article, you should be able to:
1.
2.
3.
Summarize the pathophysiology of alcohol withdrawal.
Describe the indications for inpatient and outpatient treatment of
alcohol withdrawal.
Apply common therapies used in the treatment of alcohol withdrawal.
Prior to beginning this activity, see “Physician CME Information”
on the back page.
of Emergency Medicine, Vanderbilt
Research Editors
University Medical Center, Nashville, TN Michael Guthrie, MD
Emergency Medicine Residency,
Charles V. Pollack Jr., MA, MD,
Stephen H. Thomas, MD, MPH
Icahn School of Medicine at Mount
FACEP
George Kaiser Family Foundation
Sinai, New York, NY
Professor and Chair, Department of
Professor & Chair, Department of
Emergency Medicine, Pennsylvania
Michael A. Gibbs, MD, FACEP
Emergency Medicine, University of
Federica Stella, MD
Hospital, Perelman School of
Professor and Chair, Department
Oklahoma School of Community
Emergency Medicine Residency,
Medicine, University of Pennsylvania,
of Emergency Medicine, Carolinas
Medicine, Tulsa, OK
Giovani e Paolo Hospital in Venice,
Philadelphia, PA
Medical Center, University of North
University of Padua, Italy
David M. Walker, MD, FACEP, FAAP
Carolina School of Medicine, Chapel Michael S. Radeos, MD, MPH
Director, Pediatric Emergency
Hill, NC
Assistant Professor of Emergency
International Editors
Services, Division Chief, Pediatric
Medicine, Weill Medical College
Steven A. Godwin, MD, FACEP
Emergency Medicine, Elmhurst
Peter Cameron, MD
of Cornell University, New York;
Professor and Chair, Department
Hospital Center, New York, NY
Academic Director, The Alfred
Research Director, Department of
of Emergency Medicine, Assistant
Emergency and Trauma Centre,
Ron M. Walls, MD
Emergency Medicine, New York
Dean, Simulation Education,
Monash University, Melbourne,
Professor and Chair, Department of
Hospital Queens, Flushing, NY
University of Florida COMAustralia
Emergency Medicine, Brigham and
Jacksonville, Jacksonville, FL
Ali S. Raja, MD, MBA, MPH
Women's Hospital, Harvard Medical Giorgio Carbone, MD
Vice-Chair, Emergency Medicine,
Gregory L. Henry, MD, FACEP
School, Boston, MA
Chief, Department of Emergency
Massachusetts General Hospital,
Clinical Professor, Department of
Medicine Ospedale Gradenigo,
Boston, MA
Emergency Medicine, University
Critical Care Editors
Torino, Italy
of Michigan Medical School; CEO,
Robert L. Rogers, MD, FACEP,
William A. Knight IV, MD, FACEP
Amin Antoine Kazzi, MD, FAAEM
Medical Practice Risk Assessment,
FAAEM, FACP
Associate Professor of Emergency
Associate Professor and Vice Chair,
Inc., Ann Arbor, MI
Assistant Professor of Emergency
Medicine and Neurosurgery, Medical
Department of Emergency Medicine,
Medicine, The University of
John M. Howell, MD, FACEP
Director, EM Midlevel Provider
University of California, Irvine;
Maryland School of Medicine,
Clinical Professor of Emergency
Program, Associate Medical Director,
American University, Beirut, Lebanon
Baltimore, MD
Medicine, George Washington
Neuroscience ICU, University of
Hugo Peralta, MD
University, Washington, DC; Director Alfred Sacchetti, MD, FACEP
Cincinnati, Cincinnati, OH
Chair of Emergency Services,
of Academic Affairs, Best Practices,
Assistant Clinical Professor,
Scott D. Weingart, MD, FCCM
Hospital Italiano, Buenos Aires,
Inc, Inova Fairfax Hospital, Falls
Department of Emergency Medicine, Associate Professor of Emergency
Argentina
Church, VA
Thomas Jefferson University,
Medicine, Director, Division of ED
Philadelphia, PA
Dhanadol
Rojanasarntikul, MD
Shkelzen Hoxhaj, MD, MPH, MBA
Critical Care, Icahn School of Medicine
Attending Physician, Emergency
Chief of Emergency Medicine, Baylor Robert Schiller, MD
at Mount Sinai, New York, NY
Medicine,
King Chulalongkorn
College of Medicine, Houston, TX
Chair, Department of Family Medicine,
Memorial Hospital, Thai Red Cross,
Senior Research Editors
Beth Israel Medical Center; Senior
Eric Legome, MD
Thailand; Faculty of Medicine,
Faculty, Family Medicine and
Chief of Emergency Medicine,
James Damilini, PharmD, BCPS
Chulalongkorn University, Thailand
Community Health, Icahn School of
King’s County Hospital; Professor of
Clinical Pharmacist, Emergency
Medicine at Mount Sinai, New York, NY
Suzanne Y.G. Peeters, MD
Clinical Emergency Medicine, SUNY
Room, St. Joseph’s Hospital and
Emergency Medicine Residency
Downstate College of Medicine,
Scott Silvers, MD, FACEP
Medical Center, Phoenix, AZ
Director, Haga Teaching Hospital,
Brooklyn, NY
Chair, Department of Emergency
Joseph D. Toscano, MD
The Hague, The Netherlands
Medicine, Mayo Clinic, Jacksonville, FL
Keith A. Marill, MD
Chairman, Department of Emergency
Research Faculty, Department of
Medicine, San Ramon Regional
Corey M. Slovis, MD, FACP, FACEP
Emergency Medicine, University
Medical Center, San Ramon, CA
Professor and Chair, Department
Nicholas Genes, MD, PhD
Assistant Professor, Department of
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, New
York, NY
of Pittsburgh Medical Center,
Pittsburgh, PA
Case Presentations
While seemingly straightforward, the diagnosis
of AWS is often missed, or its signs and symptoms
are erroneously attributed to another cause, such as
sepsis or drug intoxication. The differential diagnosis is broad. There is no single laboratory or imaging test that can diagnose AWS, and the criteria are
strictly historical and clinically based.8
An understanding of risk factors for progression to severe AWS as well as basic knowledge of
the pathophysiology of alcohol withdrawal will aid
the emergency clinician in the prompt recognition
of AWS. Recognition of risk factors will allow for
early empiric treatment as well as optimal choices
for therapeutic interventions. In turn, unnecessary
hospital and ICU admissions can be avoided and
hospital lengths of stay shortened when alcohol
withdrawal is recognized promptly and aggressive
treatment is initiated early. This review will evaluate
the limited available literature regarding the management of AWS in the emergency department (ED).
It will also address the underlying pathophysiology
of AWS and the treatment modalities available to
emergency clinicians. Finally, it will introduce adjunctive and controversial therapeutic interventions.
A 56-year-old alcoholic woman presents to the ED seeking
detoxification from alcohol. Her reported consumption is
750 mL of vodka daily. Her last drink was 15 hours prior,
at 4:30 PM the previous afternoon. Upon presentation to
the ED, she is found to be tachycardic, with a heart rate
of 139 beats/min; and hypertensive, with blood pressure
of 172/84 mm Hg. She is diaphoretic and has a severe
tremor. She is unable to hold a glass of water without
spilling its contents. The patient denies any history of illicit drug use and states that she has no history of alcohol
withdrawal seizures or delirium tremens. She receives
1 liter of intravenous normal saline and an intravenous
dose of 5 mg of diazepam. Fifteen minutes later, her
tremor is worsening and her vital signs have failed to
improve. What treatment modalities should you choose for
her worsening symptoms?
As you are returning to her room, a nurse asks for
your assistance in an adjacent room where EMS has
brought in a 62-year-old man with agitated delirium. You
find a disheveled, malnourished-appearing man being
restrained by 2 security guards. He is tachycardic, with a
heart rate of 162 beats/min; and hypertensive, with blood
pressure of 165/92 mm Hg. He is attempting to sit up in
the stretcher and appears to be miming turning a key in
a car ignition, repeating over and over, “I have to go.”
He does not attend to you or the staff, and he appears to
look off into space, tracking objects that are not there. He
is diaphoretic and tremulous. The paramedics tell you
they know him as a local alcoholic. He has a history of
pancreatitis, and his wife told the paramedics that he has
complained of abdominal pain and has been vomiting for
the past 2 or 3 days. The paramedics were initially called
for seizure-like activity. What are your priorities in the
initial diagnosis and management of this patient?
Critical Appraisal Of The Literature
Relevant primary literature was identified by a
search of the Cochrane Database of Systematic Reviews, PubMed, and Ovid MEDLINE®. Search terms
included alcohol withdrawal syndrome, alcohol withdrawal seizure, alcoholic hallucinosis, alcoholic hallucinations, and delirium tremens. We reviewed only reports
available in the English language and excluded
outpatient studies. Using the same search terms,
relevant review literature was identified. Select case
reports and case series were utilized where clinical
trial literature was lacking. The bibliographies of
major toxicology textbooks9,10 and review articles11-20
were also queried to ensure relevant literature was
not overlooked.
A total of 87 randomized controlled studies
of drug-versus-drug trials or drug-versus-placebo
trials were identified. However, there was a paucity
of trials pertaining directly to the ED management
of AWS.21 The settings of most clinical trials were
inpatient psychiatric alcohol detoxification units,
predominantly in Europe, and the numbers of participants in these studies were small. In addition, the
patient populations in these inpatient detoxification
unit trials did not necessarily parallel the patient
population seen in the ED with acute, severe alcohol withdrawal. The challenges of research directly
pertaining to the ED diagnosis and management of
AWS are numerous and include difficulty in obtaining informed consent (especially in the setting of
delirium) and the lack of homogeneity of alcohol
withdrawal. While the underlying principles of the
Introduction
Alcohol withdrawal syndrome (AWS) is a major
cause of morbidity and mortality among alcoholics,
and, for many medical centers, it creates a significant burden on resource utilization. Several studies
have reported that alcohol withdrawal increases the
morbidity and mortality of coexisting illness and
prolongs the duration of hospital admissions.1-3
Alcohol withdrawal has been recognized since
ancient times.4 Marked strides in recognition and
management have occurred over the past century.
The mortality rate of delirium tremens (DT), the
most severe manifestation of AWS, was 52% in 1912,
and had decreased to 10% to 12% by the 1930s.5
Mortality due to DT is now estimated to be 2% to
3%.6 Nonetheless, complications due to alcohol
abuse remain important clinical problems, accounting for 21% of medical intensive care unit (ICU) admissions at one urban hospital.7 Alcohol withdrawal
was the most common of these diagnoses.
Copyright © 2015 EB Medicine. All rights reserved.
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www.ebmedicine.net • June 2015
formational change of the receptor subunits. This
alteration of receptor structure and function results
in resistance to the antagonistic effects of ethanol,
requiring higher blood alcohol levels to achieve
similar effect. In acute ethanol withdrawal, a hyperexcitable state exists due to the loss of GABA inhibitory effect and potentiation of NMDA-mediated
excitatory neurotransmission. This is the underlying
pathophysiologic mechanism of acute AWS and the
CNS hyperexcitable state.
By mechanisms not completely understood,
repeated episodes of AWS lead to increasingly
difficult-to-treat withdrawal symptoms known as
“kindling.” Data suggest that these GABA receptor alterations may become permanent, leading to
benzodiazepine resistance.23
management of the 4 stages of AWS are similar,
studies focusing on a single presentation (such as
alcohol withdrawal seizure) cannot necessarily be
applied to alcohol withdrawal as a whole.
Etiology And Pathophysiology
AWS represents a complex collection of signs
and symptoms that occur as a direct result of the
acute cessation or reduction of alcohol intake. The
syndrome is best understood as a state of central
nervous system (CNS) hyperexcitation, with clinical manifestations ranging from mild tremor to DT,
seizure, severe autonomic dysfunction, and death.
Ethanol Pharmacology
Following ingestion, ethanol is rapidly absorbed
and distributed, with a volume of distribution near
that of total body water (VD 0.6 L/kg). Under typical
conditions, approximately 90% of ingested alcohol is
absorbed by 60 minutes, though this may be delayed
by food in the stomach or co-ingestants. Absorption
may also be prevented by the action of gastric mucosal alcohol dehydrogenase (ADH) which oxidizes
ethanol and decreases the amount available for
absorption.22
The liver is the primary means of elimination of
ethanol, though small amounts are excreted unchanged in the kidneys, lungs, and sweat. Ethanol
is metabolized primarily by ADH to form acetaldehyde and, secondarily, by aldehyde dehydrogenase
(ALDH) to form acetate.22 Acetate is then converted
to acetyl coenzyme A (acetyl-CoA), which enters the
Krebs cycle in a thiamine-dependent conversion,
where it is metabolized to carbon dioxide and water.
Although there is wide individual variation (especially among alcoholics), ethanol is generally metabolized with a clearance rate of approximately 20
mg/dL/h, based on a study of patients presenting to
the ED.22 There are additional minor hepatic metabolic pathways that are involved in ethanol metabolism, but these are of little clinical significance.
Differential Diagnosis
For patients presenting to the ED with signs and
symptoms of acute alcohol withdrawal, correct identification of the diagnosis is critical. A wide differential diagnosis must be considered when entertaining
alcohol withdrawal as the primary diagnosis. It is imperative that evaluation for alternate or concomitant
diagnoses begins at the time of presentation, because
coexisting illness may precipitate alcohol withdrawal,
and delay in diagnosing the primary pathology may
cause significant morbidity or mortality.
The differential diagnosis for alcohol withdrawal is extensive. Table 1 highlights many of the toxicologic and nontoxicologic diagnoses to consider. The
diagnosis of alcohol withdrawal is primarily historical and is supported by physical examination findings including tachycardia, hypertension, tremor,
diaphoresis, and neuromuscular excitation. Commonly, there is underlying disease, and both may
cause a patient to present to the ED and lead to the
cessation of alcohol consumption. Thus, the emergency clinician must also investigate why the patient
has stopped consuming alcohol. Often, underlying
pancreatitis or severe gastritis should be considered
and treated appropriately.
As there is no diagnostic imaging or laboratory
test to confirm AWS, it should be considered a diag-
Pathophysiology Of Alcohol Withdrawal
Though there is no specific ethanol receptor, ethanol
produces generalized CNS depression by multiple
and incompletely understood mechanisms. Ethanol
potentiates the effect of gamma-aminobutyric acid
(GABA), an inhibitory neurotransmitter, at GABAA
receptors and antagonizes the effect of glutamate,
an excitatory amino acid, at N-methyl-D-aspartate
(NMDA) receptors. Chronic ethanol potentiation of
GABA activity results in conformational changes
to the GABAA receptor and desensitization of the
GABAA receptor to ethanol. A similar phenomenon
occurs at the NMDA receptor; chronic NMDA
receptor antagonism by ethanol leads to either an
upregulation in the number of receptors or a conJune 2015 • www.ebmedicine.net
Table 1. Differential Diagnoses Of Alcohol
Withdrawal Syndrome
3
Toxicologic Differential
Medical Differential
• Sympathomimetic syndrome
(cocaine, amphetamines, etc)
• Antimuscarinic syndrome
• Sedative-hypnotic withdrawal
• Severe alcohol intoxication
• Serotonin syndrome
• Neuroleptic malignant syndrome
•
•
•
•
•
•
Thyrotoxicosis
Encephalitis
Acute psychosis
Hypoglycemia
Trauma (head injury)
Sepsis and septic shock
Reprints: www.ebmedicine.net/empissues
nosis of exclusion. Drug intoxication, predominantly
sympathomimetic or antimuscarinic syndromes,
should be considered and ruled out either historically, clinically, or by laboratory confirmation. Importantly, severe alcohol intoxication can mimic alcohol
withdrawal. Severe alcohol intoxication can lead to
confusion, delirium, tachycardia, and diaphoresis.
A serum ethanol level may be considered in cases
where the history is inconclusive. There is no single
ethanol level at which withdrawal is impossible;
however, withdrawal does become increasingly
unlikely at higher ethanol levels. Alcoholics may experience ethanol withdrawal at serum ethanol levels
that are intoxicating to the naïve drinker.
native diagnosis. Patients who have had an abrupt
cessation in alcohol consumption may experience
a more severe withdrawal syndrome than patients
who simply decrease their daily intake. In addition,
previous episodes of severe withdrawal, including
withdrawal seizures or DT, typically portend future
episodes of severe withdrawal.
History
There is no reliable indicator to predict which
alcoholic patient is at high risk for alcohol withdrawal, and this is an active area of research.
Table 2 describes risk factors for the development
of alcohol withdrawal. The most important risk
factor is a previous history of alcohol withdrawal.
Determining which patients may go on to develop DT is even more difficult, and emergency
clinicians must rely on their clinical judgment
and history-taking skills, as a prior history of
severe withdrawal (seizures or DT) portends a
more severe course than clinical judgment alone.
Commonly, patients will state that they ceased or
reduced alcohol consumption due to a willingness
to quit, inability to acquire alcohol, or because of
underlying medical complaints such as abdominal
pain and nausea. Symptoms of withdrawal can
develop within as little as 6 hours of cessation or
reduction in alcohol consumption.
Prehospital Care
The overall goal for the prehospital care of patients with alcohol withdrawal is rapid transport
to an appropriate facility while preventing injury
to the patient or prehospital care provider. Recognition that alcohol withdrawal is an underlying
medical disorder rather than a primary psychiatric
disease is paramount. The presence of abnormal
vital signs or severe agitation should prompt the
prehospital care provider to transport the patient
to a medical facility rather than a psychiatric facility. Agitation due to suspected alcohol withdrawal
should be treated with benzodiazepines, when
available, in the prehospital setting. Lorazepam,
diazepam, or midazolam should all be effective.
Midazolam is an ideal intramuscular option. There
are no data regarding the prehospital administration of sedatives to patients with alcohol withdrawal. Antipsychotics should be avoided, as
these may lower the seizure threshold.
Drug intoxication from overdose can be difficult
to differentiate from alcohol withdrawal, and due to
the complex receptor pharmacology of antipsychotic
agents, benzodiazepines are a safer choice until a
more complete toxicologic workup can be completed.
Appropriate consideration of other causes of agitated
delirium should be considered. (See Table 1, page 3.)
If trauma is suspected, appropriate immobilization
and transport to a trauma center are indicated.
Physical Examination
The clinical manifestations of AWS range from mild
tremor or anxiety to a severe hyperadrenergic state,
seizures, and death. The Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5)
notes criteria for diagnosing alcohol withdrawal
that occurs following the reduction or cessation of
alcohol use that had previously been heavy and prolonged.8 The diagnostic criteria are clinical and historical; there are no laboratory tests to confirm this
diagnosis. According to the DSM-5 criteria, alcohol
withdrawal may be diagnosed in patients exhibiting
Table 2. Risk Factors For The Development
Of Alcohol Withdrawal
Emergency Department Evaluation
• Personal history of AWS or DT24
• Family history of AWS or DT24
• Metabolic derangements (ALT > 50 units/L, serum chloride < 96
mEq/L, and serum potassium < 3.6 mEq/L)25
• Serum ethanol concentration > 150 mg/dL on admission26
The underlying pathophysiology of AWS is CNS
hyperexcitation. As such, tachycardia and hypertension are manifestations of the underlying pathology
and these conditions generally respond to standard
therapies targeting CNS hyperexcitation. If a patient’s symptoms and objective parameters fail to
improve with escalating doses of GABAA receptor
agonists (ie, benzodiazepines or barbiturates), the
patient’s worsening condition may be due to benzodiazepine-resistant alcohol withdrawal or an alterCopyright © 2015 EB Medicine. All rights reserved.
Note: Factors for development of severe alcohol withdrawal are
poorly identified; no single characteristic or combination of the above
characteristics can reliably predict development of severe withdrawal
or DT.
Abbreviations: ALT, alanine aminotransferase; AWS, alcohol withdrawal syndrome; DT, delirium tremens.
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or developing 2 or more of the 8 signs or symptoms
that are not attributable to other medical conditions
or mental disorders. The 8 signs include:
• Autonomic hyperactivity
• Tremor
• Insomnia
• Nausea/vomiting
• Hallucinations
• Psychomotor agitation
• Anxiety
• Seizures
Delirium Tremens
DT represents the most severe form of AWS. The
signs and symptoms of DT are a continuation of the
symptoms of milder forms of alcohol withdrawal
but they are accompanied by alteration in mentation,
including inattention or disorientation. As mentioned
previously, it is imperative to evaluate for other
causes of delirium, especially in a patient population
that is at high risk for coexisting pathology.
Autonomic Hyperactivity
Almost invariably, patients with moderate or
severe alcohol withdrawal will exhibit autonomic
hyperexcitability evidenced by tachycardia, hypertension, and diaphoresis. These effects may be
blunted in patients taking sympatholytics, such as
beta-adrenergic blockers or alpha-2 adrenergic agonists, for hypertension, migraine, anxiety, musculoskeletal disorders (tizanidine), or attention deficit
disorder (clonidine, guanfacine).
There are no particular diagnostic studies that
will show a patient is in withdrawal from alcohol.
Rather, AWS is a clinical diagnosis of exclusion. Diagnostic studies are useful to rule out other causes of
tremor, tachycardia, hypertension, seizures, hallucinations, and delirium.
All patients with suspected moderate or severe
alcohol withdrawal should have basic laboratory
studies obtained, including basic serum chemistries
and a complete blood count (CBC). The CBC may
show leukocytosis, which may be indicative of a
hyperadrenergic state or underlying infection. An
elevated mean corpuscular volume (MCV) may
be indicative of pernicious anemia secondary to
vitamin B12 deficiency. Serum pH and osmolality
tests may be indicated based on the results of the
patient’s chemistries; alcoholic ketoacidosis may
present with an elevated anion gap. The serum pH
may be low or normal due to concomitant ketoacidosis and contraction alkalosis. Alcoholics commonly have severe electrolyte abnormalities including hypokalemia, hypomagnesemia, hyponatremia,
and alcoholic ketoacidosis.
A urine immunoassay for drugs of abuse is
usually indicated. There are limitations to the basic
urine drug screen, but the presence of cocaine or
amphetamines may provide diagnostic clues to the
patient’s hyperadrenergic state. Serum salicylate and
acetaminophen levels are indicated in cases where
the history of present illness may suggest drug overdose. Abdominal pain in an alcoholic should prompt
evaluation for pancreatitis.
Obtaining an ethanol level is also recommended;
as severe alcohol intoxication can mimic alcohol
withdrawal in some individuals. Additionally,
individuals who have alcohol withdrawal with an
elevated ethanol level are more likely to develop
severe alcohol withdrawal.26 In cases where laboratory studies are being obtained, a serum ethanol
level is preferred; however, in cases of mild alcohol
withdrawal (ie, alcoholic tremor with normal vital
signs) measurement of the expired ethanol in breath
(breathalyzer) will suffice.
A chest x-ray is indicated in cases where hypoxia
or fever is present. Computed tomography of the
head is warranted in cases with alteration in mental
Diagnostic Studies Alcoholic Tremor
Tremor represents the mildest form of alcohol withdrawal, and it is easily identified on physical examination as a coarse muscle tremor in outstretched
hands or protruding tongue. Patients may feign
the extended hand tremor in an attempt to obtain
treatment with benzodiazepines or other sedativehypnotic agents; however, the tongue tremor is more
difficult to feign and is probably a more sensitive
confirmation of alcoholic tremor.
Alcoholic Hallucinosis
Hallucinations (visual, auditory, or tactile) develop in
7% to 8% of patients with AWS.27 The hallucinations
are most often tactile, but they may be visual. The
sensorium remains otherwise normal, which distinguishes alcoholic hallucinosis from DT. While hallucinations may portend impending DT, a very small
percentage of patients with alcoholic hallucinosis
progress to DT.
Seizures
Alcohol withdrawal seizures occur most commonly
within 24 hours after cessation of alcohol consumption. Typically, alcohol withdrawal seizures are
isolated, of short duration, and with little to no
postictal period. Status epilepticus is rare and complicates < 3% of alcohol withdrawal seizures.14 Since
alcoholics are at increased risk for multiple CNS
problems, including infection, subdural hemorrhage,
and metabolic derangements, additional diagnoses
should be entertained in patients presenting to the
ED with AWS, and alternative causes of seizures and
status epilepticus must be considered.
June 2015 • www.ebmedicine.net
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status, seizure, or delirium, as alcoholics are at high
risk for subdural hematoma and other traumatic
neurologic insults.
treatment. Intravenous administration allows for
rapid titration. Intravenous benzodiazepines should
always be used in the treatment of severe alcohol
withdrawal due to their rapid onset of action and
ease of rapid titration.
There is much debate regarding the optimal
benzodiazepine for AWS. One must balance the ease
of dose titration and the duration of action to control
symptoms quickly with avoiding unnecessary and
prolonged sedation. With intravenous administration, lorazepam reaches peak cerebrospinal fluid
(CSF) concentration in 7 minutes, whereas diazepam
reaches peak CSF concentration in 3.7 minutes.30 The
time to effects of diazepam occur in 1 to 5 minutes,
whereas the time to effects of lorazepam occur in 5
to 20 minutes.20 The more rapid achievement of peak
concentrations (and thus peak effect) of diazepam
allows for easy, rapid titration and avoidance of
dose-stacking. Dose-stacking is the administration of
additional medication doses before previous doses
have reached peak effect. This clinical scenario often
results in oversedation.
There is no correlation between CSF concentration and clinical effect for AWS, but experience and
consensus recommend diazepam for these reasons.
For AWS refractory to 200 mg of diazepam in 4
hours or requiring a single dose of diazepam ≥ 40
mg, escalating doses of 20 mg, 50 mg, and 100 mg
per dose every 15 minutes is recommended and supported by case-control literature.31 While there is no
randomized controlled trial comparing the efficacy
of diazepam versus lorazepam for early control of
alcohol withdrawal symptoms, case series and case
control literature support the use of escalating diazepam dosing over lorazepam.
Other pharmacokinetic factors of diazepam
make it ideal for the expected clinical course of alcohol withdrawal. Table 3 compares the pharmacoki-
Treatment
GABAA Agonists
Benzodiazepines
The cornerstone of the management of AWS is administration of sedative-hypnotic xenobiotics, most notably, benzodiazepines. The use of sedative-hypnotics
in AWS is logical, given the psychomotor agitation
that develops with severe symptoms. As central
GABAA agonists, benzodiazepines directly address
the underlying pathophysiology of the GABAA receptor driving alcohol withdrawal. A landmark study
in 1969 compared chlordiazepoxide, hydroxyzine,
thiamine, chlorpromazine, and placebo. Chlordiazepoxide was associated with the lowest incidence of
DT and alcohol withdrawal seizures.28 Two Cochrane
reviews concluded that benzodiazepines are effective
in the management of alcohol withdrawal.11,12
The first-line pharmaceutical class for the
management of mild, moderate, and severe alcohol
withdrawal symptoms is benzodiazepines. They
have stood the test of time. Multiple studies have
promoted one xenobiotic after another against
benzodiazepines, but no other drug class has been
demonstrated to be superior. A 1997 meta-analysis
further supported the use of benzodiazepines as
first-line agents over alternative regimens, showing
decreased withdrawal severity, decreased rates of
delirium, and decreased incidence of seizure.29
Benzodiazepines are effective for the management of early alcohol withdrawal in oral, intramuscular, and intravenous forms.12,16 Oral therapy
affords the advantages of avoiding intravenous
access as well as the potential option of outpatient
Table 3. Pharmacologic Properties Of Diazepam, Lorazepam, Midazolam, And
Chlordiazepoxide9,20,37
Drug
Properties
Lipid
Solubility
VD (L/kg)
Time to Onset
Active
Metabolites?
Initial Dose*
Formulations
Diazepam
++++
0.9
1-5 min IV
Yes
10-20 mg IV
10-20 mg PO
•
•
•
•
Lorazepam
+++
1.3
5-20 min IV
No
2-4 mg IV
2-4 mg PO
• 2 mg/mL and 4 mg/mL injectable
• 0.5 mg, 1 mg, and 2 mg tablets
• 2 mg/mL oral solution
Midazolam
+++
0.8
2-5 min IM/IV
Yes
2-4 mg IM/IV
• 1 mg/mL and 5 mg/mL injectable
• 2 mg/mL oral syrup
Chlordiazepoxide
+++
0.3
2-3 hours PO
Yes
50-100 mg PO
• 5 mg, 10 mg, and 25 mg capsules
5 mg/mL injectable
Rectal gel 5 mg/mL
2 mg, 5 mg, and 10 mg tablets
1 mg/mL, 5 mg/mL oral solution
*For 70 kg adult, for alcohol withdrawal syndrome.
Abbreviations: IM, intramuscular; IV, intravenous; PO, by mouth; VD, volume of distribution.
Copyright © 2015 EB Medicine. All rights reserved.
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netic and pharmacodynamic properties of diazepam,
lorazepam, and midazolam. Diazepam has a long
half-life of 48 hours and has active metabolites,
including nordazepam and oxazepam, which extend
the duration of the desired sedating effects.32 Treatment of AWS is much more than the prevention and treatment of seizures. In fact, seizures
in alcohol withdrawal are exceptionally uncommon. Though accumulation of active metabolites is
detrimental in many instances of xenobiotic use in
the medical management of illness, metabolite accumulation provides a unique advantage in alcohol
withdrawal. The natural course of alcohol withdrawal hyperexcitation can last for 5 to 7 days, with
peak symptoms around days 3 or 4. The early accumulation of active metabolites allows for prolonged
agonism of the GABA receptor and a self-tapering
effect, potentially mitigating the need for additional
benzodiazepines or other pharmacotherapy later in
the course of withdrawal. Chlordiazepoxide, which is only available in
oral form, offers similar advantages to diazepam
with active metabolites; however, its slow onset of
action and restriction to oral use limit it to the outpatient setting or for treatment of mild symptoms.
Intramuscular diazepam is not advised due to its
lipophilicity and, thus, unreliable systemic absorption.33 Lorazepam is predictably absorbed via the
intramuscular route34,35 and is recommended when
a parenteral option is preferred but no intravenous
access is available. Midazolam given intramuscularly is similarly and predictably absorbed, but it is
generally not utilized due to its short duration of action. Intramuscular midazolam may be useful in the
initial control of agitation while intravenous access
is obtained and more definitive therapy is initiated.
Some clinicians prefer lorazepam to diazepam
due to the characteristics of its metabolism. As alluded to earlier, both diazepam and chlordiazepoxide
are hepatically metabolized to active metabolites.32,34
Thus, theoretically, in patients with severe liver
disease (which is common among alcoholics), the
effects of both drugs may be prolonged, leading to
a higher probability of dose-stacking and oversedation. Lorazepam is glucuronidated in the liver to an
inactive metabolite and eliminated by the kidneys.36
Because of this, in patients with severe liver disease,
an agent such as lorazepam (without active metabolites) may be the preferred choice.
chlordiazepoxide given at discharge were equivalent
to phenobarbital given in the ED and placebo given
at discharge.38 For DT, a Dutch study comparing
phenobarbital to diazepam found the 2 treatments
equivalent; however, there was a slightly higher rate
of respiratory depression in the phenobarbital group
(4% vs 1%).39 A 2013 study showed that a single 10
mg/kg dose of intravenous phenobarbital decreased
the probability of ICU admission in a population
admitted for alcohol withdrawal.40
Barbiturates have a distinct binding site on the
GABAA receptor. While phenobarbital increases
chloride influx by prolonging channel opening in
the presence of GABA, at high doses, it does not
require the presence of GABA for chloride channel
opening and chloride influx.41 Escalating doses of
65 mg, 130 mg, and 260 mg intravenously every 20
to 30 minutes are often effective, and are well below
the status epilepticus dose of 15 mg/kg (about 1000
mg in a 70-kg adult).31 Care must be taken to avoid
dose-stacking, as the peak effects of intravenous
phenobarbital are seen in 20 to 40 minutes.42
Ethanol
Ethanol has been reported as a potential treatment
for AWS.43 It seems logical to replace what is missing; at first glance, ethanol appears as the perfect
treatment for alcohol withdrawal. However, the
use of ethanol (oral or intravenous) in the hospital is fraught with difficulties, including the need
for frequent monitoring of blood alcohol levels,
potential for hepatic injury, hypoglycemia, caustic
vascular injury when administered intravenously,
and possible adverse effects on wound healing. Due
to these shortcomings, most studies have deemed
this an ineffective means of managing acute alcohol
withdrawal.15,44,45 Ethanol has an exceedingly narrow and variable therapeutic index, and it is difficult
to titrate due to zero-order elimination kinetics. The
use of ethanol for the treatment of acute alcohol
withdrawal is strongly discouraged.
Treating Uncomplicated Alcohol Withdrawal
The ED management of AWS begins with an assessment of the severity of alcohol withdrawal. This occurs promptly after the initial assessment of airway,
breathing, and circulation. The emergency clinician may obtain an excellent sense of withdrawal
severity from simple observation. The presence of
tachycardia, hypertension, diaphoresis, agitation,
and/or seizure activity (or history) suggests severe
withdrawal. Patients deemed to have severe alcohol withdrawal should be treated with intravenous
benzodiazepines to control symptoms and prevent
progression to life-threatening withdrawal.
Patients with mild withdrawal symptoms are
candidates for ED discharge. (See the “Disposition”
section, page 15.) Outpatient management of mild
Barbiturates
Phenobarbital has been used both in uncomplicated
alcohol withdrawal and in DT. Studies regarding its
use are limited. One study compared lorazepam/
chlordiazepoxide and phenobarbital for the management of patients with uncomplicated withdrawal
who were discharged from the ED. The authors
found that lorazepam given in the ED and oral
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alcohol withdrawal is cost-effective and has similar
success rates to inpatient treatment.46 Patients who
are not intoxicated, have no history of complicated
AWS (withdrawal seizures or DT), no significant underlying medical or psychiatric comorbidities, and
a Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) score of < 8 can be safely managed
as outpatients, provided close outpatient follow-up
with an addiction specialist or an outpatient alcohol
detoxification program is available.13 See Figure 1
for links and QR codes for an online tool for administering the CIWA-Ar and a PDF of the CIWA-Ar.
Figure 2, page 9, displays the complete CIWA-Ar.
Oral benzodiazepines are appropriate for
this patient population. Chlordiazepoxide is an
ideal choice, as it is long-acting and has less abuse
potential than diazepam or lorazepam, due to its
slower onset of action. Reasonable chlordiazepoxide dosing would be 50 to 100 mg every 6 hours for
4 doses, then 25 to 50 mg every 6 hours. Patients
should be provided with only a short supply (2 to 3
days) due to the abuse potential of benzodiazepines
and to encourage follow-up. Diazepam and lorazepam are also suitable for outpatient management
in doses of 10 to 20 mg and 2 to 4 mg every 6 hours
as needed, respectively.
and the elderly. Bedside titration of benzodiazepines
by the treating clinician is strongly recommended in
order to prevent oversedation, especially when large
and frequent doses of benzodiazepines are used.
Alcohol Withdrawal Seizures
As with early alcohol withdrawal, the pharmacologic cornerstone of withdrawal seizure management is
benzodiazepines. Numerous studies have evaluated
the efficacy of antiepileptic drugs (AEDs) compared
to benzodiazepines or placebo for the prevention
of recurrent alcohol withdrawal seizures.21,47,48 In
the setting of significant alcohol withdrawal, AEDs
uniformly fail, compared to benzodiazepines.49
This is easily explained by the etiology of alcohol
withdrawal seizures, namely a neuroexcitatory state
due to decreased GABA tone and increased NMDA
tone. There is no role for traditional AEDs – except
benzodiazepines or barbiturates – in the prevention
of alcohol withdrawal seizure.
Alcohol withdrawal seizures are typically
self-limited. The presence of status epilepticus
would be highly unusual and concomitant pathology should be investigated in such cases. Thus, the
administration of benzodiazepines is for prevention
of recurrent seizure and for the treatment of active
withdrawal. There are insufficient data pertaining to
alcohol withdrawal seizure to recommend diazepam
over lorazepam. However, extrapolating from the
pharmacology literature, the electroencephalographic effects of a single dose of lorazepam may outlast
those of a single dose of diazepam.30
Treating More-Severe Withdrawal Symptoms
Management of more-severe alcohol withdrawal
symptoms should consist of aggressive early treatment. Initial attention to airway, breathing, and
circulation are mandatory. The emergency clinician
must also consider other disorders in the differential
diagnosis for alcohol withdrawal. Initial control of
symptoms is best done with intravenous benzodiazepines. As stated previously, intravenous diazepam
offers the advantages of rapid onset of action for
easy titration and long-acting metabolites, allowing
for self-tapering of the GABA-agonist effect.
Repeating escalating doses of intravenous diazepam (20 mg, 50 mg, 100 mg) or lorazepam (2 mg, 4
mg, 8 mg, 16 mg) are recommended until symptoms
are controlled. Escalating doses of diazepam can be
given every 10 to 15 minutes, while doses of lorazepam should be spaced out every 15 to 20 minutes
to avoid oversedation. Benzodiazepines should be
titrated based on the clinical appearance of the patient as well on correction of vital sign abnormalities.
For severe withdrawal, titration to a state of somnolence with arousal to minimal tactile stimulus is
ideal. The use of escalating diazepam dosing in this
fashion and diazepam front-loading has been shown
to reduce the frequency of a number of important
markers of alcohol withdrawal including seizure,
DT, and the need for mechanical ventilation.17,31
In the absence of coadministered sedatives (such
as opioids), benzodiazepines rarely interfere with respiratory drive except in the very young, the obese,
Copyright © 2015 EB Medicine. All rights reserved.
Alcoholic Hallucinosis
The management of alcoholic hallucinosis mimics
that of uncomplicated alcohol withdrawal. Benzodi-
Figure 1. Links To Clinical Institute
Withdrawal Of Alcohol Scale, Revised
(CIWA-Ar) Tools
Link to MDCalc.com online calculation tool:
http://www.mdcalc.com/ciwa-ar-for-alcohol-withdrawal/
Link to CIWA-Ar PDF:
https://umem.org/files/uploads/1104212257_CIWA-Ar.pdf
Scan QR code with an enabled smartphone or tablet.
8
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Figure 2. Clinical Institute Withdrawal Assessment Of Alcohol Scale, Revised (CIWA-Ar)
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Clinical
Pathway
For Emergency
Department
Management
Clinical
Pathway
For Emergency
Department
Management
Of Multiple
Of Alcohol Withdrawal
Shocks Syndrome
Patient presents with signs of AWS
• Autonomic hyperactivity
• Agitation
• Tremor
• Seizure
• Delirium
•
•
•
•
Send basic laboratory tests, including ethanol level
Obtain further workup as clinically indicated
Rule out other diagnoses
Administer IV fluids, thiamine, glucose, folate, as needed
Administer benzodiazepine:
Diazepam 10 mg IV
or
Lorazepam 2 mg IV
(Class I)
Re-evaluate in 10-15 min. Symptoms controlled?
(Normalization of vital signs, improvement of
tremor, resolution of agitation)
Administer escalating doses of benzodiazepines:
Diazepam 20 mg, 50 mg, 100 mg IV every 15 min
or
Lorazepam 4 mg, 8 mg, 16 mg IV every 20-30 min
(Class III)
NO
YES
Any of the following:
• History of complicated withdrawal?
• Severe underlying psychiatric or medical comorbidities?
• Clinical alcohol or drug intoxication?
• Initial CIWA-Ar score > 8 (or other comparable, validated
tool)?
Re-evaluate every 10-15 min.
Symptoms controlled?
YES
NO
• Continue high-dose benzodiazepines (Class I)
• Consider adjunct phenobarbital, 500 mg IV x 1 (Class I)
• Adjunctive ketamine 0.3 mg/kg IV bolus, 0.3 mg/kg/h
infusion (Class III)
YES
NO
Discharge with addiction or outpatient
detoxification follow-up (Class II)
Admit to ICU
• Monitored unit or inpatient detoxification admission
• Benzodiazepine administration (diazepam or lorazepam)
based on CIWA-Ar score (or other validated tool) (Class I)
Abbreviations: AWS, alcohol withdrawal syndrome; CIWA-Ar, Clinical Institute Withdrawal Assessment Of Alcohol Scale, Revised; ICU, intensive
care unit; IV, intravenous.
For class of evidence definitions, see page 11.
Copyright © 2015 EB Medicine. All rights reserved.
10
www.ebmedicine.net • June 2015
azepines are the mainstay of therapy. A paucity of
literature exists regarding the use of antipsychotics or other medications for hallucinosis. Because
the hallucinations associated with alcohol withdrawal are distinct from those typically associated
with schizophrenia (ie, visual or tactile rather
than auditory), the underlying pathophysiology is
likely different. There are limited data to suggest
antipsychotic use is actually detrimental in acute
alcohol withdrawal.28 However, patients with
alcohol withdrawal may also have underlying
psychiatric disease, and discerning hallucinations
from alcohol withdrawal or underlying psychiatric pathology is often difficult. Continuation of
home antipsychotics is advised, but benzodiazepines should remain first-line treatment of alcohol
withdrawal-related hallucinations.
In many cases, the agitation associated with
DT or respiratory failure from iatrogenic sedative
administration necessitates intubation and mechanical ventilation. After intubation, propofol is an ideal
adjunct. In addition to its GABA-agonist effects,
propofol is an NMDA antagonist, and it inhibits the
neuroexcitation from increased NMDA receptormediated glutamate activity.50-52 Propofol, however,
does have a narrow therapeutic index and can be
difficult to titrate in patients without a protected
airway.53,54 Prolonged use, especially at high doses,
is associated with metabolic derangements.55 While
the use of propofol for alcohol withdrawal has been
reported in the absence of mechanical ventilation,56
we strongly recommend the use of this drug only
in intubated patients, due to respiratory depression
and loss of airway protective reflexes. Dosing of propofol for ICU sedation is typically 1 to 6 mg/kg/h.57
Delirium Tremens And Benzodiazepine-Resistant
Alcohol Withdrawal
Despite optimal pharmacologic management, there is
a subset of patients who develop severe benzodiazepine-resistant alcohol withdrawal and DT. An early,
aggressive approach improves outcomes in these
cases. In one observational study, higher individual
and total doses of diazepam (86 mg vs 32 mg per dose
and 562 mg vs 248 mg, respectively) were associated
with a statistically significant decrease in the need
for mechanical ventilation, and trends were noted in
shorter ICU stays and a lower incidence of nosocomial pneumonia.31 In our experience, it is not unusual to
administer in excess of 400 to 500 mg of intravenous
diazepam over several hours for severe alcohol withdrawal without the need for mechanical ventilation.
For patients in whom extreme benzodiazepine
resistance is present, barbiturates (notably, phenobarbital) are reasonable adjuncts. Phenobarbital use
has been associated with a decrease in ICU admissions when given early in the course of disease40
and it has been associated with decreases in mechanical ventilation when administered to patients
in the ICU.31
Symptom-Driven Dosing Versus Fixed
Dosing
In many EDs, especially those directly associated
with psychiatric or inpatient alcohol detoxification
units, the management of alcohol withdrawal may
be prolonged while patients await inpatient bed assignment. In these instances, it becomes important
to understand benzodiazepine dosing beyond the
initial control of withdrawal symptoms. An increasing body of evidence suggests that symptom-driven
dosing of benzodiazepines based on validated withdrawal assessment tools is superior to fixed dosing.
With symptom-driven dosing of benzodiazepines,
less total benzodiazepines are administered, hospital
lengths of stay are shorter, and complication rates
are similar.58-60
Fixed-dosing regimens are often protocol-driven
and involve tapering a benzodiazepine, regardless of the severity of withdrawal symptoms or
consideration of the patient’s withdrawal history.
Symptom-driven therapy utilizes a validated withdrawal assessment tool (such as the CIWA-Ar), and
benzodiazepine dosing is based on a score achieved
Class Of Evidence Definitions
Each action in the clinical pathways section of Emergency Medicine Practice receives a score based on the following definitions.
Class I
Class II
• Always acceptable, safe
• Safe, acceptable
• Definitely useful
• Probably useful
• Proven in both efficacy and effectiveness
Level of Evidence:
Level of Evidence:
• Generally higher levels of evidence
• One or more large prospective studies
• Nonrandomized or retrospective studies:
are present (with rare exceptions)
historic, cohort, or case control studies
• High-quality meta-analyses
• Less robust randomized controlled trials
• Study results consistently positive and
• Results consistently positive
compelling
Class III
• May be acceptable
• Possibly useful
• Considered optional or alternative treatments
Level of Evidence:
• Generally lower or intermediate levels
of evidence
• Case series, animal studies, consensus panels
• Occasionally positive results
Indeterminate
• Continuing area of research
• No recommendations until further
research
Level of Evidence:
• Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2015 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.
June 2015 • www.ebmedicine.net
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in that assessment. For example, appropriate dosing
regimens may include diazepam 10 to 20 mg orally,
lorazepam 2 to 4 mg orally every 2 to 4 hours, or
chlordiazepoxide 50 to 100 mg orally every 6 hours
if CIWA-Ar scores are > 8 to 10.
The use of such assessment tools and the dosage
of benzodiazepines based on the patient’s score is
appropriate only for uncomplicated alcohol withdrawal. Patients with severe withdrawal symptoms,
seizures, or DT are best served by aggressive bedside administration of intravenous benzodiazepines,
ideally diazepam, using the front-loading technique,
until symptoms are adequately controlled.
hypomagnesemia may be present and should be
addressed with dextrose-containing fluids and judicious replacement of potassium and magnesium.
Alcoholic ketoacidosis is typically reversed with
glucose-containing intravenous fluids and thiamine.
Wernicke encephalopathy is a common cause of
altered mental status and gait disturbance among
alcoholics. Nystagmus, ataxia, and confusion are
the hallmark triad of Wernicke encephalopathy, or
dry beriberi.61 However, in the authors’ experience,
rarely are all 3 clinical findings seen concurrently.
It is imperative to have a low threshold to use high
thiamine doses if signs of Wernicke encephalopathy
are present, even in the absence of the classic clinical
triad. We suggest 500 mg of intravenous thiamine
every 8 hours. Intravenous thiamine is preferred, as
the absorption of oral thiamine is erratic.62 Depending upon the patient’s severity, symptoms may
slowly improve over several days to weeks, but
they may not improve at all. The convention that
thiamine ought to be administered before glucose
Adjunctive Therapy
Alcoholics frequently have significant metabolic
derangements on presentation, often with marked
electrolyte abnormalities. These patients are often
significantly dehydrated, requiring intravenous
fluid resuscitation. Electrolyte abnormalities (including alcoholic ketoacidosis and hypokalemia) and
Risk Management Pitfalls For Alcohol Withdrawal
(Continued on page 13)
1. “The patient was hallucinating, so I gave him
an antipsychotic.”
While antipsychotics are certainly indicated
for psychotic hallucinations, the use of
antipsychotics in alcohol withdrawal is
associated with poorer outcomes.91 It is best to
address the underlying pathophysiology of CNS
hyperexcitability and utilize a GABAA receptor
agonist such as a benzodiazepine.
4. “I thought the patient had straightforward alcohol withdrawal, so I didn’t check any labs.”
Alcoholics commonly present with a range of
metabolic derangements, some of which can
be life threatening. These generally stem from
malnutrition and dehydration. All intoxicated
patients or patients with altered mental status
should have a capillary glucose checked.
Alcoholic patients who require inpatient
admission (for withdrawal or otherwise) should
have basic chemistries performed (including
checking the magnesium level), and should
be checked for severe abnormalities such as
hyponatremia or alcoholic ketoacidosis.
2. “The patient’s withdrawal looked mild, so I
discharged her with benzodiazepines.”
There are criteria for safe discharge of an
alcoholic patient presenting with withdrawal or
requesting detoxification: CIWA-Ar score < 8,
no history of complicated alcohol withdrawal,
no clinical alcohol or drug intoxication, no
significant underlying medical or psychiatric
comorbidities. Even in patients who develop DT,
early symptoms may be mild.
5. “The patient presented with alcohol withdrawal and was confused, but looked okay, so I
admitted him to the floor.”
Even in the absence of agitation, the presence of
confusion in the setting of alcohol withdrawal
suggests DT and necessitates admission to
a higher level of care such as the ICU or, at
minimum, a step-down unit. Furthermore, the
treating emergency clinician should consider
Wernicke encephalopathy or an underlying
concomitant medical cause.
3. “The patient was tachycardic; I presumed it
was from alcohol withdrawal.”
Alcoholics are at high risk for multiple acute and
chronic medical comorbidities. Furthermore,
there is commonly an acute medical ailment
that causes an alcoholic patient to decrease or
cease alcohol consumption. Pulmonary embolus,
myocardial infarction, sepsis, dehydration, and a
number of other diagnoses should be considered
in the tachycardic alcoholic patient.
Copyright © 2015 EB Medicine. All rights reserved.
12
www.ebmedicine.net • June 2015
hol dependence.64-66 Ethanol is an NMDA receptor
antagonist, and chronic antagonism of the NMDA
receptor results in upregulation of neurotransmission.67 Like the GABAA receptor, this increase in neurotransmission is likely related to alteration of receptor subunits rather than an increase in the absolute
number of NMDA receptors.68 In the acute alcohol
withdrawal state, there is uninhibited NMDA receptor activity, resulting in CNS hyperstimulation. This
scenario offers a biologically plausible approach to
combating the underlying pathophysiology of CNS
hyperexcitability seen in alcohol withdrawal.
NMDA receptor antagonists have been studied
in alcohol-related disorders and have been shown to
decrease the severity of symptoms in AWS, prevent
ethanol withdrawal seizures, and sustain alcohol
abstinence after detoxification.69-71 Acamprosate is
one such NMDA receptor antagonist and GABAA
agonist studied extensively in alcohol-related disorders. It has been shown to be both safe and effective
in maintaining alcohol abstinence after detoxifica-
is pharmacologically illogical, as thiamine acts on
enzyme pathways (eg, as a cofactor in the conversion of pyruvate to acetyl-CoA) while the effects of
glucose are nearly immediate.63
The emergency clinician must be cognizant of alternative underlying pathology either masquerading
as or coexisting with alcohol withdrawal, including,
but not limited to, drug intoxication, trauma, or sepsis. External evidence or history of trauma should
prompt appropriate radiologic evaluation. The presence of fever and leukocytosis, while potentially due
to severe alcohol withdrawal, should be considered
infectious until proven otherwise.
Controversies And Cutting Edge
NMDA Receptor Antagonists
Receptors other than the GABAA receptors are affected by chronic alcohol consumption. The NMDA
receptor is a glutamatergic excitatory receptor that
is thought to be involved in the development of alco-
Risk Management Pitfalls For Alcohol Withdrawal
(Continued from page 12)
6. “The patient is an alcoholic; I assumed his
delirium was from alcohol withdrawal.”
Alcohol withdrawal is a diagnosis of exclusion;
there is no available test that confirms a
diagnosis of alcohol withdrawal delirium.
Consideration must be taken for other causes
of delirium including structural CNS pathology
(eg, stroke, intracranial hemorrhage), metabolic
derangements (eg, uremia, hyperammonemia),
infectious sources (eg, sepsis, meningitis), and
toxicologic causes (eg, antimuscarinic syndrome,
sympathomimetic syndrome).
antecedent trauma and subsequent intracranial
hemorrhage places that patient at high risk for
seizure. A seizure in an adult alcoholic without
a history of withdrawal seizures and without
other objective signs of withdrawal should
prompt a more complete neurologic workup and
cranial imaging.
9. “The patient told me he only drink 2 beers per
day, so I didn’t think his presentation could be
alcohol withdrawal.”
Alcoholics commonly minimize their alcohol
consumption, portraying to the clinician a vast
underestimation of actual alcohol consumption.
In the right clinical context, a social history
of daily drinking or periodic heavy alcohol
consumption should prompt the emergency
clinician to further consider alcohol withdrawal
in the presentation of the tachycardic tremulous
patient and/or new-onset seizure.
7. “I was afraid benzodiazepines would cause her
to stop breathing.”
In the absence of structural airway abnormalities
or drug co-intoxication, benzodiazepines should
not have a significant effect on ventilation. While
patients will become sedated with high-dose
benzodiazepines, their respiratory drive should
be maintained, provided they are not also toxic
on opioids or other sedating medications and
they are without obstructive upper airway
pathology.
10. “The patient was requesting detoxification, but
had no history of severe withdrawal and had
no symptoms in the ED, so I discharged her
with outpatient follow-up.”
Psychiatric comorbidities, including depression,
are common among alcoholics. Some drink
alcohol due to an underlying psychiatric
disorder, and others have a mood disorder
due to alcohol consumption. It is imperative
that patients presenting with alcohol-related
complaints are screened for suicidality.
8. “The patient is an alcoholic; I assumed the
seizure was from alcohol withdrawal.”
While alcohol withdrawal seizures are relatively
uncommon, alcoholics are at high risk for
structural CNS injury, putting them at high risk
for the development of epilepsy. Furthermore,
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Adrenergic Antagonists
tion in the outpatient setting.70,72-74 Krupitsky and
Krystal suggest that lamotrigine (an inhibitor of
glutamate release) and memantine are equally efficacious to benzodiazepines in treating AWS.71 The
authors’ institution has presented data previously
that support the use of intravenous subdissociative
ketamine as adjunctive therapy in treating severe
alcohol withdrawal in both the ED and the ICU.75
In light of these data suggesting uninhibited
NMDA receptor agonism in the acute alcohol withdrawal state, we initiated an institutional guideline
with intravenous subdissociative ketamine for
severe alcohol withdrawal. (Note: this is off-label
use.) In the authors’ clinical experience, ketamine
has been well tolerated, safe, and effective in reducing benzodiazepine requirements, normalizing vital
signs, and decreasing the duration of delirium. At
the present time, we utilize intravenous ketamine
only as adjunctive treatment for severe alcohol
withdrawal, most often after 200 mg of diazepam
or equivalent benzodiazepine has failed to control
symptoms or decrease delirium. Our recommended
dosing is 0.3 mg/kg IV bolus and an infusion of 0.3
mg/kg/h for 24 hours followed by 0.15 mg/kg/h
for 24 hours. Multiple studies in the chronic pain
literature suggest that oral ketamine is safe when
administered in the setting of a hospital guideline
or in the context of a research protocol. The authors
believe that in the future this may prove to be an essential component of treatment of AWS.76,77
Beta-adrenergic antagonists are effective in reducing the autonomic effects of ethanol withdrawal
syndrome. While this has not been extensively
studied, the selective treatment of tachycardia and
hypertension without treating CNS hyperexcitation is not expected to reduce delirium or prevent
convulsions.18,29 It is imperative to understand that
the underlying pathophysiology of AWS is a state of
CNS hyperactivity. Masking the peripheral effects
of this hyperactive state overlooks the underlying
pathological mechanism. Clonidine and dexmedetomidine, both centrally acting selective alpha-2
adrenergic agonists, may have an additive benefit
when used in conjunction with benzodiazepines, but
there is insufficient evidence to recommend using
these agents as primary treatments in controlling
alcohol withdrawal symptoms.83 Lofexidine, also
a selective alpha-2 adrenergic agonist, was used
as adjunctive treatment to chlordiazepoxide and
compared to placebo, but no benefit was identified
and lofexidine-treated patients experienced moresevere withdrawal symptoms and hypotension.84 A
prospective randomized placebo-controlled study
of dexmedetomidine as an adjunctive therapy for
patients in alcohol withdrawal did not decrease
long-term benzodiazepine exposure, and it was associated with bradycardia.85
Antiepileptic Agents
Antiepileptic agents are often used to treat AWS.
Carbamazepine is the most widely studied and has
been used extensively and effectively in Europe
because of availability of an intravenous formulation.
In a Cochrane review of anticonvulsants for alcohol
withdrawal published in 2010, only carbamazepine
showed a favorable outcome when compared to
benzodiazepines.86 However, the patients in the
carbamazepine studies had less-severe alcohol withdrawal, and extrapolating treatment to the ED patient
population is difficult. Carbamazepine may be a good
adjunct in the outpatient setting, but the authors do
not recommend its use in moderate to severe withdrawal in the ED patient due to the lack of evidence
and availability of better alternatives. Oxcarbazepine
performed no better than placebo in a randomized,
placebo-controlled trial published in 2007.87 Valproic
acid has been studied and is safe and effective in reducing auditory hallucinations.88 Comparison studies
between carbamazepine and valproic acid as adjunctive therapies showed slight benefit of valproic acid
over carbamazepine in the prevention of withdrawal
seizures.89 Multiple other studies demonstrate the
safety and efficacy of valproic acid in the treatment of
AWS. In spite of this, a Cochrane review found insufficient evidence to support the use of any antiepileptic
drug in the treatment of AWS.86
Neuromodulators
Gamma-hydroxybutyric Acid
Gamma-hydroxybutyric acid (GHB) is a GHB receptor and GABAB receptor agonist produced endogenously as a metabolite of GABA. It is also available
as an FDA-approved treatment for narcolepsy, and
it can be a drug of abuse. Multiple studies demonstrate the efficacy of GHB in the prevention and
treatment of alcohol withdrawal.78 Though GHB is
not commonly used in the United States, it appears
to be safe in the treatment of AWS.78-80
Baclofen
Baclofen is a GABAB receptor agonist that has been
studied in acute alcohol withdrawal.81 Data from
a prospective randomized controlled trial of patients with mild to moderate withdrawal demonstrated comparable efficacy between baclofen and
diazepam. A second study compared baclofen and
placebo in addition to standard therapy and found
a reduction in benzodiazepine requirements among
patients treated with low-dose baclofen.82 At this
time, though several studies have favorable results
with baclofen, there is insufficient evidence to recommend its routine use in ED patients with AWS.
Copyright © 2015 EB Medicine. All rights reserved.
14
www.ebmedicine.net • June 2015
Nonpharmacologic Therapies
diazepam 15 minutes later after she experiences no clinical improvement. The patient’s heart rate and tremor
failed to improve with these doses, so you gave her 100
mg of intravenous diazepam, which resulted in significant
improvement in her symptoms. One hour later, her tremor
increased significantly, her heart rate increased to 124
beats/min, and her subjective level of anxiety returned.
You gave her a second 100-mg dose of intravenous diazepam. After you gained initial control of her symptoms,
she was admitted to the ICU for further treatment of
severe AWS. She was administered folic acid, thiamine,
and multivitamins for nutritional replacement.
After receiving the history from EMS and evaluating the second patient, you suspected that his withdrawal was more severe and would be more difficult to
treat than your first patient. After intravenous access
is obtained, you sent blood to the lab for evaluation and
administered escalating doses of diazepam. After giving
270 mg of intravenous diazepam in 2 hours, you administered 260 mg of phenobarbital. The patient remained
Acupuncture as an adjunctive treatment90 and aromatherapy have been suggested as beneficial treatments of substance-related disorders. Neuroelectric
therapy involves administration of low-voltage currents to the patient’s head; at this time there is a lack
of evidence to recommend its use, especially in the
ED patient. Data related to these therapies are mixed
and we mention these only for information’s sake.
Disposition
As mentioned previously, AWS represents a spectrum of illness. Accurately identifying the patient’s
place on this spectrum is critical for determining the
treatment and level of care required. Patients with
AWS represent complicated clinical scenarios, and
a thorough understanding of the underlying pathophysiology, the typical progression of the disease,
and associated illnesses is required for effective
treatment. (See Table 4.)
Table 4. Disposition Criteria For Alcohol
Withdrawal
Must-Do Markers Of Quality Emergency
Department Care
• Early recognition of alcohol withdrawal based
on presentation and history
• Consideration of differential diagnoses, including head trauma, sepsis, and drug intoxication
• Early and aggressive titration of benzodiazepines
• Evaluation for and treatment of metabolic comorbidities
• Appropriate selection of level of care
Summary
AWS is a complex diagnosis that requires thorough
evaluation, given the risk of precipitating or coexisting illness. When the diagnosis is established, early
and aggressive front-loading with benzodiazepines
is appropriate. A stepwise approach to management of AWS will improve symptoms and decrease
morbidity and mortality. DT represents the most
severe form of AWS and merits aggressive therapy
and ICU admission. Several novel therapies such as
intravenous ketamine are being studied and warrant
consideration as adjunctive therapy in patients with
severe alcohol withdrawal. AWS represents a spectrum of illness, and accurately identifying a patient’s
place on the spectrum is imperative for determining
treatment and disposition of the patient.
Case Conclusions
After examining the first patient, you correctly diagnose
the patient with severe AWS. You decide to administer
20 mg of intravenous diazepam followed by 50 mg of
June 2015 • www.ebmedicine.net
Disposition
Criteria
Discharge with
detoxification
referral13
• Initial CIWA-Ar score < 8 (or equivalent
of other validated withdrawal assessment
tool)
• No clinical alcohol or drug intoxication
• No history of complicated AWS (seizures,
hallucinosis, DT)
• No significant underlying medical or psychiatric comorbidities
Inpatient detoxification or medical
unit30
• No underlying medical or surgical condition requiring ICU-level care
• Normalization or near-normalization of
vital signs with ED management
• Clear sensorium
• Responsive to 10-20 mg of diazepam or
equivalent
• Tolerates 2-4 hours between benzodiazepine doses
• Presence of medical or psychiatric condition requiring inpatient admission
Intensive care unit30
• Underlying medical or surgical condition requiring ICU-level care, including
mechanical ventilation
• Requires > 100-200 mg of diazepam or
equivalent to control symptoms in the ED
• Requires benzodiazepines more frequently than every 2 hours
• Requires use of phenobarbital or other
adjunctive therapy to control acute withdrawal
• Hyperthermia due to alcohol withdrawal
• Presence of altered sensorium or recurrent seizures
Abbreviations: AWS, alcohol withdrawal syndrome; CIWA-Ar, Clinical
Institute Withdrawal Assessment Of Alcohol Scale, Revised; DT, delirium tremens; ED, emergency department; ICU, intensive care unit.
15
Reprints: www.ebmedicine.net/empissues
agitated, with hypertension and tachycardia; he still did
not attend to you or follow commands. He continued to
mime turning a key in an ignition and voicing a desire
to leave. You administered a second bolus of phenobarbital 260 mg. The patient’s hypertension and tachycardia improved, but did not completely resolve. After 30
minutes, the patient’s vital signs again worsened, and
he was severely agitated and delirious. You wanted to
avoid intubation and its attendant complications, if
possible. You administered a ketamine bolus (0.3 mg/
kg IV) followed by initiation of a ketamine infusion at
0.3 mg/kg/h. The patient’s tachycardia and hypertension again improved, he became somnolent, with normal
respirations, and he was admitted to the ICU for further
treatment of DT.
4.
5.
6.
7.
8.
9.
10.
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www.ebmedicine.net • June 2015
CME Questions
4. Which of the following should be considered
in the differential diagnosis of alcohol withdrawal?
a. Head trauma
b.Psychosis
c.Encephalitis
d. Sympathomimetic toxicity
e. All of the above
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5. Patients with alcohol withdrawal seizures
a. Almost always present more than 24 hours after cessation of alcohol consumption
b. Often present with status epilepticus
c. Most often progress to DT
d. Should have a careful consideration for meningitis, head trauma, and metabolic derangements in addition to alcohol withdrawal
6. All of the following statements concerning DT
are true, EXCEPT:
a. DT is the most severe form of alcohol withdrawal
b. Patients with DT always have associated confusion
c. Patients with DT usually have hypotension and bradycardia
d. Patients with DT will require an ICU admission
1. In addition to GABAA receptors, what other
receptor is altered in chronic alcohol use and
may be a good source of pharmacotherapy for
alcohol withdrawal patients who are resistant
to large benzodiazepine doses?
a. Serotonin receptors
b.GABAB receptors
c.NMDA
d. Beta adrenergic receptors
7. Which of the following drugs is the least-preferred first-line treatment for alcohol withdrawal in the ED?
a.Midazolam
b.Lorazepam
c.Diazepam
d. Chlordiazepoxide
2. As used in the alcohol withdrawal literature,
“kindling” refers to which of the following?
a. Increasing difficulty treating alcohol
withdrawal symptoms with each subsequent episode of withdrawal
b. Increased tolerance to the effects of alcohol with prolonged alcohol consumption
c. Increased sedation with higher serum or blood alcohol levels
d. Ability to metabolize alcohol more quickly with chronic alcohol use
8. Which of the following is appropriate adjunctive therapy in patients with alcohol withdrawal?
a. Electrolyte replacement
b. Intravenous fluid hydration
c. Intravenous thiamine replacement
d. Parenteral glucose administration
e. All of the above
3. Which of the following statements concerning
the diagnosis of alcohol withdrawal is FALSE?
a. The diagnosis is often missed or signs and symptoms are erroneously attributed to another cause.
b. An elevated total creatinine kinase can be used to confirm the diagnosis.
c. Diagnostic criteria are strictly historical and clinical.
d. The differential diagnosis for alcohol withdrawal is broad.
June 2015 • www.ebmedicine.net
19
Reprints: www.ebmedicine.net/empissues
Physician CME Information
Date of Original Release: June 1, 2015. Date of most recent review: May 10, 2015.
Termination date: June 1, 2018.
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ANNOUNCEMENT
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