S YS T E M AT I C R E V I E W P R O T O C O L

Dexmedetomidine as adjunctive therapy for the treatment

of alcohol withdrawal syndrome: a systematic review
protocol
Marco Fiore 1  Giacomo Torretta 1  Maria Beatrice Passavanti 1  Pasquale Sansone 1  Maria Caterina Pace 1 
Aniello Alfieri 1  Caterina Aurilio 1  Vittorio Simeon 2  Paolo Chiodini 2  Vincenzo Pota 1
1
Department of Women, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy, 2Department of Public,
Clinical and Preventive Medicine, Medical Statistics Unit, University of Campania Luigi Vanvitelli, Naples, Italy

ABSTRACT

Objective: The purpose of this review is to evaluate the effectiveness and safety of dexmedetomidine as adjunctive
therapy to the standard of care (benzodiazepines) compared to either the standard of care or other adjunctive
treatment approaches (e.g. benzodiazepines plus propofol) for the treatment of alcohol withdrawal syndrome (AWS).
Introduction: Benzodiazepines have been the cornerstone of AWS therapy, but in some patients, AWS is refractory
to high doses. Moreover, benzodiazepine use is burdened by excessive sedation, confusion and respiratory
depression. Options for management of refractory AWS include the addition of phenobarbital, propofol and, more
recently, dexmedetomidine to benzodiazepines therapy. The possible advantage of dexmedetomidine compared to
benzodiazepines is that it does not cause respiratory depression, thus reducing the risk of intubation and
hospitalization in the intensive care unit.
Inclusion criteria: This review will consider studies including patients who are 18 years or older and are diagnosed
with AWS. The exclusion criteria are a history of psychoactive substances or withdrawal states and/or severe
neurologic disorder (e.g. traumatic brain injury, acute stroke, severe dementia, seizure disorder).
Methods: This review will include only studies published in English, with no restrictions on the year of publication.
Both randomized controlled trials and observational studies (including cohort and case-control studies) assessing
the drug effectiveness and safety will be included. The databases utilized will include: PubMed, Embase and
Cochrane Central Register of Controlled Trials. In addition, the trial registers to be searched will include: World Health
Organization International Clinical Trials Registry Platform (ICTRP), U.S. National Library of Medicine Drug Information
Portal and ClinicalTrials.gov.
Systematic review registration number: PROSPERO CRD42018084370
Keywords Adrenergic alpha-2 receptor agonists; alcohol withdrawal syndrome; benzodiazepines; delirium
tremens; dexmedetomidine
JBI Database System Rev Implement Rep 2019; 17(10):2159–2164.

Introduction symptoms include insomnia, anxiety, nausea, head-

lcohol is the second most commonly abused
A drug after nicotine.1 Approximately 20% of
patients who access medical care have an alcohol
use disorder.2 Alcohol withdrawal syndrome (AWS)
occurs when, after abrupt alcohol discontinuation,
the patient becomes symptomatic. Minor AWS
Correspondence: Marco Fiore, marco.fiore@unicampania.it
The authors declare no conflict of interest.
DOI: 10.11124/JBISRIR-2017-003949
ache and palpitations. If AWS is effectively pre-
vented, these symptoms will resolve within one to
two days after the alcohol discontinuation. Major
AWS symptoms include seizures and delirium tre-
mens (DTs). The seizures are usually singular and
resolve spontaneously. Delirium tremens is the most
dangerous complication of AWS, and it can result
from under-treatment or lack of treatment of the
preceding AWS symptoms. The overall mortality of
DTs is reported to be 8%.3 The incidence of DTs in
patients in the intensive care unit (ICU) is

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SYSTEMATIC REVIEW PROTOCOL
approximately 10%.4 Delirium tremens is an inde-
pendent predictor of length of ICU and hospital stay
with an increased duration of invasive ventilation.
The related ICU costs are mainly due to room
occupancy and mechanical ventilation, yet recently
another driver of ICU cost was identified to be
mortality before ICU discharge.5
The AWS symptoms occur when blood alcohol
concentrations decline rapidly, within the first four
to 12 hours after alcohol consumption has been
stopped or reduced. The symptoms reach peak inten-
sity on the second day and improve by the fourth or
fifth day of alcohol suspension.6 The onset of DTs is
typically three to five days after the last alcohol
consumption.7 Symptoms include severe agitation,
tremor, disorientation, hallucinations and exacerba-
tion of autonomic symptoms. The symptoms may
persist up to one week, and DTs duration is associ-
ated with an increased risk of mortality and cogni-
tive dysfunction. According to evidence, early
diagnosis and effective management of DTs results
in reduced mortality.2
The goal of treatment for an agitated patient with
AWS is sedation. Benzodiazepines (BZDs) have been
the cornerstone of therapy for prevention and man-
agement of AWS and its complications. Unfortu-
nately, some patients exhibit refractory AWS
when given high doses of BZDs. Moreover, the use
of BZDs is burdened by excessive sedation, ataxia,
confusion, memory impairment and respiratory
depression.8 Options for management of refractory
AWS include the addition to BZD therapy of pheno-
barbital, propofol or, more recently, dexmedetomi-
dine. Dexmedetomidine is an alpha-2 agonist that
decreases the release of norepinephrine. It is eight
times more potent that clonidine with a rapid onset
of action (15 minutes) and short half-life (two hours).
The agonist action on alpha-2 receptors is responsible
for anxiolytic and sedative effects, decreasing the
sympathetic tone.9 The possible advantage of dexme-
detomidine compared to BZDs is that it does not
cause respiratory depression, so the risk of intubation
and hospitalization in the ICU should be reduced. The
most common adverse drug events (ADEs) of dexme-
detomidine are hypotension and bradycardia.10
This review will analyze the effectiveness of dex-
medetomidine in comparison to BZDs, or BZDs
adjunctive therapy (benzodiazepines plus propofol),
as propofol may be useful in patients who do not
clinically respond to first-line therapy with BZDs.11
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M. Fiore et al.
Our systematic review differs from relatively
recent ones. Firstly, the systematic review conducted
by Woods et al.12 analyzed the effectiveness of
dexmedetomidine only in comparison to benzodia-
zepines in ICU patients. In this proposed systematic
review, the population will not be restricted to ICU
patients. Furthermore, the outcome was measured
by Woods et al.12 using the Clinical Institute With-
drawal Assessment Score - Revised (CIWA), the
Ramsey scale, the Richmond Agitation-Sedation
Scale (RASS) and the Confusion Assessment Method
for the ICU (CAM-ICU). Instead, this review has
pragmatic outcomes (respiratory depression requir-
ing endotracheal intubation and ICU admission)
rather than a score (CIWA, RASS, CAM-ICU),
which does not provide concrete data on the effec-
tiveness of the therapy related to augmented costs for
ICU length of stay. Additionally, Woods et al.12 did
not analyze the treatment safety of the most common
dexmedetomidine-related ADEs. These ADEs are
harmful and unintended consequences of medica-
tions; therefore, the reporting of ADEs is essential
for monitoring and providing research on drug
safety, although it has not been internationally
standardized.13
In this systematic review, we will analyze dexme-
detomidine safety and ADEs as secondary outcomes
reporting the onset of the most common dexmede-
tomidine ADEs (bradycardia and hypotension).10
Other systematic reviews that assessed the effective-
ness of dexmedetomidine in the treatment of AWS
were conducted by consulting a single database
(MEDLINE).10,11,14 Furthermore, some systematic
reviews evaluating the role of dexmedetomidine in
AWS management concluded that further studies are
needed to develop evidence-based recommenda-
tions.15,16 Therefore, a systematic review, including
several databases that also identify the most recent
studies, is necessary to establish the role of dexme-
detomidine in the treatment of AWS. The Cochrane
Database of Systematic Reviews, the JBI Database of
Systematic Reviews and Implementation Reports
and PubMed were searched to identify previously
published reviews on a similar topic.
Review objective
The purpose of this review is to evaluate the effec-
tiveness and safety of dexmedetomidine as adjunc-
tive treatment to the standard of care (BZD)
compared to either the standard of care or other
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adjunctive treatment approaches (BZD plus propo-
fol) used in the treatment of AWS.
Inclusion criteria
Participants
This review will consider studies including patients
who meet the following criteria: 18 years or older
with AWS diagnosed using the International Classi-
fication of Diseases, Ninth Revision, Clinical Modi-
fication (ICD-9-CM) or Diagnostic and Statistical
Manual of Mental Disorders (DSM–4) criteria.17,18
The exclusion criteria will include a history of use
of other psychoactive substances or withdrawal
states and/or severe neurologic disorder (e.g. trau-
matic brain injury, acute stroke, severe dementia,
seizure disorder).
Intervention
This review will evaluate the effectiveness of dexme-
detomidine in the treatment of AWS. The range of
dexmedetomidine dose will be 0.2–1.4 mcg/kg/h as
registered in the medication package insert.
Comparator
The comparator will be management of AWS
with BZDs alone, or association between BZDs
and propofol.
Outcomes
The primary outcome will be the effectiveness of
dexmedetomidine on the occurrence of respiratory
depression (requiring endotracheal intubation) and/
or ICU admission, compared to the other treatments.
The secondary outcome will be the occurrence of
ADEs: hypotension (systolic blood pressure < 90
mmHg) and/or bradycardia (heart rate < 50 bpm),
compared to the other treatments.
Types of studies
This review will include both randomized controlled
trials and observational studies (including cohort
and case-control studies) to assess the drug effective-
ness and safety.
Methods
The proposed systematic review will be conducted in
accordance with JBI methodology for systematic
reviews of effectiveness evidence.19 The review pro-
tocol was registered on PROSPERO (International
Prospective Register of Systematic Reviews, Regis-
tration Number CRD42018084370).20
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M. Fiore et al.
Search strategy
The search strategy will consist of three steps, with
the aim to find both published and unpublished
studies.
Firstly, we will perform a search on MEDLINE
and CINAHL, examining the text words contained
in the title and abstract, and the index terms used to
describe the articles. A search strategy, which will be
adapted for each information source, will be devel-
oped. A proposed search strategy for PubMed is
detailed in Appendix I. A second search will be
conducted using all recognized keywords and index
terms through all included databases. Searching for
additional studies from gray literature from govern-
ment departments, international agencies and aca-
demics institution repositories or websites will be
conducted using similar keywords from the search
strings. Thirdly, the reference list of all identified
reports and articles will be searched for additional
eligible studies. Studies published in English will be
considered for inclusion in this review. We will not
set a year limit to avoid the exclusion of pre-regis-
tration studies. If pre-registration studies are found,
a sub-analysis will be conducted between pre-regis-
tration versus post-registration studies.
The searches will be completed a second time
before the final analyses and additional studies
retrieved for inclusion.
Information sources
The databases utilized will include PubMed,
EMBASE and Cochrane Central Register of Con-
trolled Trials (CENTRAL). Also, the trial registers to
be searched will include: World Health Organization
International Clinical Trials Registry Platform
(ICTRP), U.S. National Library of Medicine and
ClinicalTrials.gov.
The search for unpublished studies will include
Conference Proceedings Citation Index via Web of
Science, ProQuest Dissertations and Theses, Google
Scholar, Networked Digital Library of Theses and
Dissertations, OpenDOAR and OpenGrey. The bib-
liography of all identified reports and articles will be
searched for additional studies; this will include the
use of backward and forward citation tracking.
Study selection
Following the search, all identified citations will be
loaded into EndNote VX8.0 (Clarivate Analytics,
PA, USA) and duplicates removed. Two authors (GT
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and AA) will independently evaluate the titles and
abstracts of potentially eligible studies. Data will be
extracted independently according to the Meta-anal-
ysis Of Observational Studies in Epidemiology
(MOOSE) guideline, and the results will be cross-
checked.21 Any disagreements on study eligibility or
data extraction will be resolved with a third reviewer
(MF).
Potentially relevant studies will be retrieved in full
and their citation details will be imported into the JBI
System for the Unified Management, Assessment
and Review of Information (JBI SUMARI; Joanna
Briggs Institute, Adelaide, Australia).19
The full text of selected citations will be assessed
in detail against the inclusion criteria by two inde-
pendent reviewers (GT and AA). Reasons for exclu-
sion of full-text studies that do not meet the inclusion
criteria will be recorded and reported in the system-
atic review. Any disagreements that arise between
the reviewers at each stage of the study selection
process will be solved through discussion or with a
third reviewer (MF). The results of the search will be
reported in full in the final report and the data will be
presented in a Preferred Reporting Items for System-
atic Reviews and Meta-Analyses (PRISMA) flow
diagram.22
Assessment of methodological quality
Before inclusion in the review, the quantitative
papers will be assessed by two independent reviewers
(GT and AA) for methodological validity using the
standardized critical appraisal instruments from
JBI.19 The authors of papers will be contacted to
request missing or additional data, where clarifica-
tion is required. Disagreements between the two
reviewers will be resolved through discussion or with
a third reviewer (MF). The results collected by the
critical appraisal will be reported in narrative form
and a table. Following critical analysis, studies that
do not meet a certain quality threshold will be
excluded. The decision to exclude will be based on
cut-off scores of less than 70% of the items assessed
for all JBI critical appraisal tools. This represents the
following checklist amount of ‘‘yes’’ answers: fewer
than six out of nine for quasi-experimental studies;
fewer than nine out of 13 for randomized controlled
trials; fewer than eight out of 11 for cohort studies;
fewer than seven out of 10 for case-control studies
and fewer than five out of eight for analytical cross-
sectional studies.19
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M. Fiore et al.
Data extraction
The collected data will be extracted independently
by two reviewers (GTand AA), and the results will be
cross-checked.
Quantitative data will be extracted from manu-
scripts included in the review using the standardized
data extraction tool from JBI. The data extracted
will include the authors, year of study enrollment,
country of origin, outcome analyzed in the individ-
ual studies, details about the populations, methods
and interventions.
Data synthesis
Data extracted from the included studies will, where
possible (e.g. studies using uniform case definitions,
the same measures of outcome, context and
approaches), be pooled in a statistical meta-analysis
using STATA v14 (StataCorp LLC, Texas, USA) or
any other relevant software.
Risk differences will be used as the meta-analytic
measure of association between the addition of dex-
medetomidine and the requiring of tracheal intubation.
For each study, the proportion of patients requiring
tracheal intubation will be used to calculate risk dif-
ference and corresponding 95% confidence interval
using a 2x2 table. The proportion of patients requiring
intubation also will be calculated for each study.
Heterogeneity between studies will be assessed by
using Q statistic and I2, which is the proportion of
total variance observed between the studies attributed
to the differences between studies rather than to sam-
pling error. I2 values of 25%, 50%, and 75% corre-
spond to cut-off points for low, moderate, and high
degrees of heterogeneity. A P-value of Q statistic less
than 0.10 will be considered significant. If overall
heterogeneity is significant, a random-effect model will
be used; otherwise, a fixed-effect model will be used.
Subgroup analyses will be conducted, if appropri-
ate, based on these items: i) pre-registration studies
versus post-registration; ii) standard of care therapy
(BZD) versus adjunctive standard of care therapy
(BZD plus other sedative drugs). Furthermore, sen-
sitivity analysis will be performed, in case of strong
heterogeneity, excluding single studies from the final
evaluation. A funnel plot will be generated to evalu-
ate publication bias; if 10 or more studies are found,
a meta-analysis will be conducted. Statistical tests
for funnel plot asymmetry (Egger test, Begg test,
Harbord test) will be performed, where appropriate.
If statistical pooling is not possible, the results will be
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presented in a narrative form including tables and
figures to aid in data presentation. The tables will
report the authors, the year of study enrollment, the
country of origin and the outcome analyzed in the
individual studies.
Assessing certainty in the findings
The Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) approach
will be used for grading the certainty of evidence,
and a Summary of Findings (SoF) will be created
using GRADEPro software (McMaster University,
ON, Canada).23 The SoF will present the following
information where appropriate: the absolute risks
for the treatment and control, the estimates of rela-
tive risk, a ranking of the quality of the evidence
based on the risk of bias, the directness, the hetero-
geneity, the precision and the risk of publication bias
of the review results. All primary outcomes will be
included in the SoF.
Acknowledgments
The authors would like to thank Dr. Anna Battimelli
and Dr. Alessia Gatani from the University of Cam-
pania Luigi Vanvitelli for providing excellent biblio-
graphic service and assistance.
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Appendix I: Search strategy for PubMed

Search conducted on 11 November 2018

Search Query Records retrieved

#1 (‘‘Alcohol Withdrawal Delirium’’[Mesh] OR ‘‘Delirium’’[Mesh] 625
OR ‘‘Alcohol Withdrawal Delirium’’[Text Word] OR ‘‘Delir-
ium’’[Text Word] OR ‘‘alcohols’’[MeSH] OR ‘‘alcohol’’[Title/
Abstract]) AND (‘‘Dexmedetomidine’’[Mesh] OR ‘‘Dexmedeto-
midine’’[Text Word])
Filter: English Language 573

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