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Critical Care Explorations www.ccejournal.org 1
Critical Care
Explorations
Crit Care Expl 2020; 2:e0245
DOI: 10.1097/CCE.0000000000000245
1Department of Pharmacy, Scripps Memorial Hospital La Jolla, La Jolla, CA.
2Department of Pharmaceutical Services, University of California, San
Francisco Medical Center, San Francisco, CA.
3Department of Clinical Pharmacy, Touro University California College of
Pharmacy, Vallejo, CA.
4Department of Anesthesiology, University of North Carolina, Chapel Hill, NC.
5Department of Health Informatics, University of California, San Francisco
Medical Center, San Francisco, CA.
6Department of Physiological Nursing, University of California, San Francisco
School of Nursing, San Francisco, CA.
7Department of Anesthesia and Perioperative Care, University of California,
San Francisco Medical Center, San Francisco, CA.
Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc.
on behalf of the Society of Critical Care Medicine. This is an open-access
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sible to download and share the work provided it is properly cited. The work
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the journal.
Observational Study
Effects of a Clonidine Taper on
Dexmedetomidine Use and Withdrawal in
Adult Critically Ill Patients—A Pilot Study
Krupa Bhatt, PharmD, BCCCP1; Ashley ompson Quan, PharmD, BCCCP2;
Laura Baumgartner, PharmD, BCPS, BCCCP3; Shawn Jia, MD4; Rhiannon Croci, BSN, RN-BC5;
Kathleen Puntillo, RN, PhD, FAAN, FCCM6; James Ramsay, MD7; Rima H Bouajram, PharmD, BCCCP2
Objectives: Prolonged use of dexmedetomidine has become
increasingly common due to its favorable sedative and anxiolytic
properties. Hypersympathetic withdrawal symptoms have been
reported with abrupt discontinuation of prolonged dexmedetomi-
dine infusions. Clonidine has been used to transition patients off
dexmedetomidine infusions for ICU sedation. The objective of this
study was to compare the occurrence of dexmedetomidine with-
drawal symptoms in ICU patients transitioning to a clonidine taper
versus those weaned off dexmedetomidine alone after prolonged
dexmedetomidine infusion.
Design: This was a single-center, prospective, double cohort obser-
vational study conducted from November 2017 to December 2018.
Setting: Medical-surgical, cardiothoracic, and neurosurgical ICUs in
a tertiary care hospital.
Patients: We included adult ICU patients being weaned off dexme-
detomidine after receiving continuous infusions for at least 3 days.
Interventions: Patients were either weaned off dexmedetomidine
alone or with a clonidine taper at the discretion of the providers.
Measurements and Main Results: The primary outcome was the
incidence of at least two dexmedetomidine withdrawal symptoms
during a single assessment within 24 hours of dexmedetomidine
discontinuation. Time on dexmedetomidine after wean initiation and
difference in medication cost were also evaluated. Forty-two patients
were included in this study: 15 received clonidine (Group C) and 27
weaned off dexmedetomidine alone (Group D). There was no signifi-
cant difference in the incidence of two or more withdrawal symptoms
between groups (73% in Group C vs 59% in Group D; p = 0.51).
Patients in Group C spent less time on dexmedetomidine after wean
initiation compared with patients in Group D (19 vs 42 hr; p = 0.02).
An average cost savings of $1,553.47 per patient who received
clonidine was observed. No adverse effects were noted.
Conclusions: Our study demonstrated that patients receiving cloni-
dine were able to wean off dexmedetomidine more rapidly, with a
considerable cost savings and no difference in dexmedetomidine
withdrawal symptoms, compared with patients weaned off dexme-
detomidine alone. Clonidine may be a safe, effective, and practical
option to transition patients off prolonged dexmedetomidine infusions.
Key Words: adrenergic alpha-2 receptor agonists; clonidine;
dexmedetomidine; hypnotics and sedatives; substance withdrawal
syndrome; symptom assessment
Dexmedetomidine, an alpha-2 adrenergic agonist, is Food
and Drug Administration-approved for sedation in the
ICU for up to 24 hours of continuous infusion (1). Its
safety and ecacy have been demonstrated in studies for up to 5
days of use (2, 3), with bradycardia and hypotension being the most
frequently cited adverse eects (1). In practice, dexmedetomidine
is oen used for prolonged periods of time due to its favorable
sedative, anxiolytic, and analgesic characteristics (4–9). Recent
data, however, suggest that abrupt discontinuation of prolonged
2020
Bhatt et al
2 www.ccejournal.org 2020 • Volume 2 • e0245
dexmedetomidine infusions may be associated with withdrawal
symptoms such as agitation, tachycardia, hypertension, and other
hypersympathetic conditions (10–22). Previous studies have
dened prolonged dexmedetomidine infusion as infusion greater
than 72 hours, aer which withdrawal symptoms have been cited
with dexmedetomidine wean (15, 16). In a preliminary study con-
ducted by our research team, the incidence of withdrawal symp-
toms when weaning o prolonged dexmedetomidine infusions
was as high as 64% (22). Given this potential risk for withdrawal,
gradual weaning of dexmedetomidine may preclude transfer out
of the ICU and increase overall healthcare costs for some patients
due to ICU level of care and high drug acquisition cost (23).
Clonidine, another alpha-2 adrenergic agonist, has been used
in recent years to transition patients o of dexmedetomidine
infusions (24–28). Although dexmedetomidine and clonidine
share similar pharmacologic properties, clonidine’s high oral
bioavailability, longer half-life, ease of administration, and lower
medication cost provide a convenient and tolerable taper option
for patients on prolonged dexmedetomidine infusions (29, 30).
However, no studies have specically assessed the eect of cloni-
dine on the incidence of dexmedetomidine withdrawal symptoms
aer prolonged exposure to dexmedetomidine in adult critically
ill patients. e objective of this study was to compare the inci-
dence of dexmedetomidine withdrawal symptoms in ICU patients
transitioning to a clonidine taper versus those weaned o dexme-
detomidine alone aer at least 3 days of continuous infusion.
MATERIALS AND METHODS
is was a single-center, prospective, double cohort study con-
ducted from November 2017 to December 2018. All adult patients
in the medical-surgical, cardiothoracic, or neurosurgical ICUs
that were being weaned o dexmedetomidine aer at least 3 days
of continuous infusion were considered for study enrollment. A
minimum of 3 days of dexmedetomidine administration was used
based on previous denitions of prolonged infusion and based
on the time aer which withdrawal symptoms have been cited
in previous reports (15, 16). Exclusion criteria included patients
with active substance or medication withdrawal and patients
with primary neurologic disease which could interfere with the
assessments. is study protocol was approved by the Institutional
Review Board prior to initiation of the study.
Patients were divided into two groups: those who received cloni-
dine in order to transition o of dexmedetomidine (Group C) and
those who were weaned o dexmedetomidine alone (Group D).
e decision to use clonidine was at the discretion of the medical
team and was not inuenced by study investigators. Of note, cloni-
dine was used o-label in this context for ICU sedation (24–29).
e standard clonidine taper used at our institution is outlined in
Appendix A (Supplemental Digital Content 1, http://links.lww.
com/CCX/A391) based on a previous study by Gagnon et al (24).
is includes a standard decrease in dexmedetomidine rate by 25%
with each clonidine dose. Adjustments to the clonidine taper could
be initiated by the medical team based on sedative response and
hemodynamic eects and were consistent with adjustments made
in the previous study by Gagnon et al (24). Immediate-release cloni-
dine was the only formulation used in our study due to previous
data supporting equivalent pharmacokinetics via enteral and sub-
lingual route (31). Patients without enteral access were administered
clonidine via sublingual route to ensure continuity of dosing. For
patients weaning o dexmedetomidine alone, nurses weaned dex-
medetomidine as clinically able based on each patient’s Richmond
Agitation-Sedation Scale (RASS) goal and in alignment with our
institutional dexmedetomidine guide (Appendix B, Supplemental
Digital Content 2, http://links.lww.com/CCX/A392).
Demographic and baseline characteristics were collected for
all patients, including age, sex, weight, Sequential Organ Failure
Assessment score, type of ICU, reason for ICU admission, median
baseline RASS score, time on dexmedetomidine prior to study
enrollment, and concomitant sedatives used prior to study enroll-
ment. Baseline RASS was dened as the median daily RASS score
2 days prior to wean initiation in eorts to control for failed wean
attempts in the 24 hours prior to enrollment.
Withdrawal assessments were conducted by study investigators
for all patients aer the rst dose of clonidine was administered for
patients in Group C and aer a dexmedetomidine wean was initi-
ated for patients in Group D (the beginning of the wean period).
Repeat assessments were conducted for each patient at least 3
hours apart at random until 24 hours aer dexmedetomidine dis-
continuation (the end of the wean period) to account for residual
eects with prolonged clearance (based on dexmedetomidine’s
half-life). Informed consent was waived for this study, as signs of
medication withdrawal, pain, and sedation are regularly assessed
at our institution in our critically ill patients. Simultaneous with-
drawal assessments were performed by a subset of investigators
to evaluate inter-rater reliability during withdrawal assessments.
e primary outcome was the incidence of at least two dex-
medetomidine withdrawal symptoms during a single assessment
within 24 hours of dexmedetomidine discontinuation. In the
absence of a validated instrument for iatrogenic withdrawal in the
hospital setting, withdrawal symptoms included in this study were
chosen based on previous literature describing dexmedetomidine
withdrawal (10–22). e endpoint of two or more symptoms was
deemed to be clinically signicant given the presence of these
symptoms would prompt an increase in dexmedetomidine infu-
sion rate or prevention of wean in clinical practice at our insti-
tution. e ve withdrawal symptoms evaluated were as follows:
(1) agitation as per a RASS greater than +1, (2) delirium as per a
positive Confusion Assessment Method for the ICU assessment,
(3) withdrawal as per a Withdrawal Assessment Tool Version 1
(WAT-1) score greater than 2, (4) tachycardia dened as heart
rate (HR) greater than 90 beats per minute (beats/min), and
(5) hypertension dened as systolic blood pressure (SBP) greater
than 140 mm Hg or mean arterial pressure greater than 90 mm Hg.
Although the WAT-1 (Appendix C, Supplemental Digital Content 3,
http://links.lww.com/CCX/A393) is only validated to evaluate
opioid and benzodiazepine withdrawal in pediatric patients, it
includes several hypersympathetic symptoms that overlap with
dexmedetomidine withdrawal in adult patients and has been suc-
cessfully used to evaluate dexmedetomidine withdrawal in pedi-
atric studies (17, 21, 26, 32, 33). Secondary outcomes included
incidence of individual withdrawal symptoms, incidence of pain
(as dened by a Numerical Pain Rating Scale ≥ 4 for patients able
Observational Study
Critical Care Explorations www.ccejournal.org 3
to self-report or a Critical Care Pain Observation Tool ≥ 3 for those
who were not), oral morphine equivalents (OMEs) administered
during the wean period (calculated based on our institutional stan-
dard equivalency chart for all opiates, described in Appendix D,
Supplemental Digital Content 4, http://links.lww.com/CCX/A394),
use of concomitant propofol, antipsychotics, benzodiazepines,
and ketamine during the wean period, average daily dexmedeto-
midine infusion rate throughout the total infusion duration, time
to successful dexmedetomidine discontinuation, dierence in
drug cost using average wholesale price, time to transfer out of the
ICU, and incidence of hypotension (SBP < 90 mm Hg) or brady-
cardia (HR < 60 beats/min) at any time during the wean period.
Descriptive statistics were used to summarize baseline demo-
graphic information. Analysis of the primary outcome and other
categorical variables was performed using the chi-square or Fisher
exact test. Secondary continuous outcomes were assessed using
either the Student t test or Wilcoxon rank-sum test. Inter-rater
reliability during simultaneous assessments was analyzed using
the Krippendor alpha score. All p values less than or equal to 0.05
were considered signicant using an alpha value of 0.05. All sta-
tistical analyses were conducted using Stata Version 15 (StataCorp
LP, College Station, TX).
RESULTS
Out of the 738 patients screened, 42 patients were included in the
nal analysis: 15 in Group C and 27 in Group D (Fig. 1). Baseline
characteristics are shown in Table1. Of note, patients in Group C
had a higher median daily RASS score 2 days prior to wean initia-
tion (0 vs –1; p = 0.04) and were more likely to have received anti-
psychotics prior to study enrollment (8 vs 2 patients; p = 0.005).
Table 2 presents outcomes in both groups. ere was no
statistically signicant dierence between groups in the inci-
dence of at least two dexmedetomidine withdrawal symp-
toms during a single assessment within the wean period
(73% in Group C vs 59% in Group D; p = 0.27). In the sub-
set of patients with simultaneous withdrawal assessments,
inter-rater reliability was good (0.89) between assessors.
A total of 54 simultaneous assessments were performed.
In evaluating individual withdrawal symptoms (Fig. 2),
patients in Group C exhibited more agitation per a RASS greater
than +1 compared with patients in Group D (40% vs 11%; p = 0.05).
ere was no statistically signicant dierence in positive
WAT-1 scores between groups. Across both groups, the most
common symptoms recorded from the WAT-1 tool were loose
stools, fever, and agitation. Notably, patients in Group C had a
higher median number of withdrawal assessments conducted
than patients in Group D (3.7 vs 2.7; p < 0.01).
ere was no dierence in the incidence of signicant pain
scores between groups (47% in Group C vs 41% in Group D;
p = 0.75). However, patients in Group D had a trend toward higher
OME use in the 48 hours prior to wean initiation as well as during
the rst and second days of the wean as compared to patients in
Group C, although this was not statistically signicant (Table3).
ere was no dierence between groups in the use of propofol,
antipsychotics, benzodiazepines, or ketamine during the wean
period. Patients in Group C had a higher average daily dexme-
detomidine rate in microgram/kilogram/hr (µg/kg/hr) compared
with patients in Group D. Total infusion dose in µg/hr was not
signicantly dierent between groups.
Patients in Group C spent signicantly less time on dexme-
detomidine aer wean initiation
compared with patients in Group D
(19 vs 43 hr; p = 0.02). Furthermore,
93% of patients in Group C were able
to discontinue dexmedetomidine
within 24 hours of clonidine initia-
tion. is dierence in time on dex-
medetomidine resulted in an average
drug cost savings of $1,553.47 per
patient who received clonidine when
taking into account the medica-
tion cost of dexmedetomidine and
clonidine alone. Costs of nursing
titration and monitoring were not
included in this assessment. Patients
in Group C had a trend toward lon-
ger median ICU length of stay than
patients in Group D, although this
was not statistically signicant (22.7
vs 17 d; p = 0.3). ere was no dif-
ference in time to ICU discharge aer
wean initiation (7.2 in Group C vs 7 d
in Group D; p = 0.69). ere were
no reported events of bradycardia or
hypotension during the wean period
for all patients in either group.
Figure 1. Patient flowchart. Group C = patients administered clonidine taper, Group D = patients weaned off
dexmedetomidine alone.
Bhatt et al
4 www.ccejournal.org 2020 • Volume 2 • e0245
DISCUSSION
is is the rst study to evaluate the eect of clonidine on dexme-
detomidine withdrawal symptoms in adults being weaned o of
prolonged dexmedetomidine infusions. Given there was no dier-
ence in the incidence of two or more withdrawal symptoms with
the use of clonidine versus when weaning o dexmedetomidine
alone, clonidine can be considered an eective alternative to dex-
medetomidine for sedation wean aer prolonged dexmedetomi-
dine infusion.
No studies have evaluated clonidine’s impact on dexmedeto-
midine withdrawal symptoms in adult patients. Lardieri et al
(26) used the WAT-1 assessment to evaluate the eect of cloni-
dine on dexmedetomidine withdrawal in pediatric patients. ey
found no dierence in WAT-1 scores between groups, although
patients in the clonidine group displayed a trend toward fewer
elevated WAT-1 scores while weaning from dexmedetomidine.
Our study also found no dierence in WAT-1 scores or its com-
ponents between groups. Notably, several components of the
WAT-1 assessment were not seen at all in this study, suggesting
that the WAT-1 may not be an accurate measure of dexmedeto-
midine withdrawal in adult ICU patients. Since the completion of
our study, Capilnean et al (34) conrmed this nding when they
evaluated the validity and reliability of the WAT-1 in critically ill
adults and found that it was not a valid tool for assessing iatro-
genic withdrawal syndrome in this patient population. In a post
hoc analysis of our data excluding WAT-1, we found no dierence
in the incidence of two or more withdrawal symptoms between
groups (p = 0.56), further suggesting the WAT-1 may not be a nec-
essary component of future withdrawal assessments.
A few studies have assessed the safety and ecacy of transi-
tioning from dexmedetomidine to clonidine for ICU sedation
aer short-term use of dexmedetomidine (< 48 hr). Terry et al
(25) conducted a retrospective assessment of 26 adult patients
and found that over 65% of patients were able to safely discon-
tinue short-term dexmedetomidine as early as 8 hours aer ini-
tiating clonidine for ICU sedation. Gagnon et al (24) conducted
a prospective study of 20 adult patients and found that 75% of
patients were able to successfully transition from short-term
TABLE 1. Demographics and Baseline Characteristics
Variables
Patients Administered
Clonidine Taper
(n = 15)
Patients Weaned Off
Dexmedetomidine
Alone (n = 27) p
Age (yr), median (IQR) 58 (43–66) 54 (45–66) 0.93
Male sex, n (%) 11 (73) 16 (60) 0.73
Weight (kg), median (IQR) 86.9 (67.3–94.1) 91.6 (78.9–101.1) 0.19
Sequential Organ Failure Assessment score, median (IQR) 9.5 (7–12) 10 (8.5–14) 0.19
Type of ICU, n (%)
Medical/surgical 10 (67) 13 (48) 0.34
Cardiovascular 3 (20) 8 (30) 0.72
Neurologic 2 (13) 6 (22) 0.69
Reason for ICU admission, n (%)
Respiratory 7 (47) 9 (33) 0.51
Cardiac surgery 1 (7) 5 (19) 0.4
Cardiovascular 2 (13) 4 (15) 1
Abdominal surgery 2 (13) 3 (11) 1
Infection/sepsis 3 (20) 3 (11) 0.65
Neurologic 0 2 (7) 0.53
Trauma 0 1 (4) 1
Median daily Richmond Agitation-Sedation Scale
score 2 d prior to wean initiation, median (IQR) 0 (–1 to 0.5) –1 (–2 to –0.25) 0.04
Time on dexmedetomidine prior to first assessment (hr), median (IQR) 167.1 (115–217.1) 113.5 (91.1–204) 0.60
Propofol used within 2 d prior to wean initiation, n (%) 9 (60) 12 (44.4) 0.35
Antipsychotics used within 2 d prior to wean initiation, n (%) 8 (53.3) 2 (7.4) 0.005
Benzodiazepines used within 2 d prior to wean initiation, n (%) 2 (13.3) 2 (7.4) 0.58
Ketamine used within 2 d prior to wean initiation, n (%) 1 (6.7) 6 (22.2) 0.15
IQR = interquartile range.
Observational Study
Critical Care Explorations www.ccejournal.org 5
dexmedetomidine to clonidine within 48 hours with no signi-
cant dierences in pain, sedation, or hemodynamic variables.
ese ndings are similar to those of our study, where patients
in Group C were able to transition o of dexmedetomidine in a
median of 19 hours, with no dierences in withdrawal symptoms
or adverse eects.
In terms of ecacy, there was a higher incidence of elevated
RASS scores in Group C when compared with Group D. is
TABLE 2. Withdrawal Symptoms, Sedatives Administered, and Patient Length of Stay
Variables
Patients Administered
Clonidine Taper
(n = 15)
Patients Weaned Off
Dexmedetomidine Alone
(n = 27) p
Incidence of ≥ 2 withdrawal symptoms, n (%) 11 (73) 16 (59) 0.51
Individual withdrawal symptoms, n (%)
Heart rate > 90 beats/min 12 (80) 20 (74) 1
Confusion Assessment Method for the ICU + 11 (73) 17 (63) 0.73
Systolic blood pressure > 140 mm Hg 6 (40) 8 (30) 0.55
RASS > +1 6 (40) 3 (11) 0.05
WAT-1 > 2 2 (13) 1 (4) 0.29
Individual WAT-1 components, n (%)
Pre stimulus
RASS > 0 6 (40) 4 (15) 0.13
Loose/watery stools 3 (20) 13 (48) 0.1
Temperature > 37.8°C 3 (20) 8 (29) 0.72
Vomiting 1 (7) 2 (7) 1
Diaphoresis 1 (7) 3 (11) 1
Moderate-severe repetitive movements 0 1 (4) 1
Moderate-severe tremor 0 0
Yawning or sneezing 0 0
Post stimulus
Moderate-severe startle to touch 0 0
Increased muscle tone 0 0
2+ min to return to calm state 0 0
5+ min to return to calm state 0 0
Number of assessments conducted per patient, mean ± sd 3.7 ± 1.2 2.7 ± 0.8 <0.01
Incidence of pain during the wean period, n (%) 7 (47) 11 (41) 0.75
Propofol used during the wean period, n (%) 5 (33) 8 (30) 1
Antipsychotics used during the wean period, n (%) 9 (60) 10 (37) 0.2
Benzodiazepines used during the wean period, n (%) 3 (20) 3 (11) 0.34
Ketamine used during the wean period, n (%) 1 (7) 4 (15) 0.64
Average daily dexmedetomidine ratea (µg/hr), mean ± sd 75 ± 28.1 66.5 ± 30 0.37
Average daily dexmedetomidine ratea (µg/kg/hr), mean ± sd 0.9 ± 0.3 0.7 ± 0.3 0.03
Time on dexmedetomidine after wean initiation (hr), median (IQR) 19 (9.5–23) 43 (14–74.7) 0.02
ICU length of stay (d), median (IQR) 22.7 (16.3–35) 17 (10.7–33.5) 0.3
Time to ICU discharge after dexmedetomidine wean
initiation (d), median (IQR) 7.2 (4–20) 7 (3.1–20) 0.69
IQR = interquartile range, RASS = Richmond Agitation-Sedation Scale, WAT-1 = Withdrawal Assessment Tool 1.
aAverage daily dexmedetomidine rate was calculated based on the infusion rate throughout the total infusion duration (not limited to the wean period).
Bhatt et al
6 www.ccejournal.org 2020 • Volume 2 • e0245
may be in part due to the higher median RASS scores in Group
C prior to dexmedetomidine wean initiation, also reected by the
greater antipsychotic use at baseline in this group. Additionally,
patients in Group C had a higher average daily dexmedetomidine
dose administered of 0.9 µg/kg/hr compared with 0.7 µg/kg/hr
in Group D. In a previous analysis by our research team, we found
a greater risk for withdrawal symptoms in patients receiving peak
dexmedetomidine doses greater than 0.8 µg/kg/hr and cumulative
daily doses of dexmedetomidine greater than 12.9 µg/kg/d (22).
e higher RASS scores may have been impacted by greater
cumulative dosing per body weight of dexmedetomidine in
Group C. Despite this nding, no dierence in two or more with-
drawal symptoms was found, potentially reecting the ecacy
of clonidine in circumventing additional withdrawal symptom
development.
Although there was no dierence in pain scores between
groups, there was a trend toward higher OME used during the
wean period by patients in Group D, which may also have impacted
level of sedation in the patients weaning o of dexmedetomidine
alone compared with patients receiving clonidine. Both dexme-
detomidine and clonidine have been described in the literature as
having opioid-sparing qualities (6–9, 35–38). Mariappan et al (38)
found intraoperative dexmedetomidine to have a greater opioid-
sparing eect than preoperative single-dose clonidine in spinal
surgery patients. It is possible that the dierence in analgesic eects
in our study was impacted by dierences in dexmedetomidine and
clonidine dosing. Our diverse patient sample also included surgi-
cal patients, who may require more analgesic medications than
nonsurgical patients. Given the small sample size, a small dier-
ence in surgical patients between groups may have contributed to
the dierence in OME requirements. Finally, patients in Group C
were assessed more frequently than patients in Group D, which
may have increased the chance of investigators detecting with-
drawal symptoms in Group C.
Based on the dierence in duration of dexmedetomidine aer
wean initiation, we calculated an average cost savings of $1,553.47
per patient that received clonidine. is only includes medication
cost and does not take into account the additional costs associated
with dexmedetomidine, such as a dedicated ICU bed with close
monitoring and titration. us, the decreased duration of dexme-
detomidine infusion upon initiation of clonidine may be econom-
ically signicant. Although a dierence in time to ICU discharge
with the use of clonidine was not
observed, this study may have been
underpowered to detect such a dif-
ference. e initiation of clonidine
at provider discretion may also have
impacted the ability to eectively
evaluate this measure. Larger, ran-
domized studies are needed to evalu-
ate the impact of clonidine on ICU
and hospital length of stay.
ere were several limitations to
this study. First, the study included
a small sample size at a single insti-
tution. Although this is the largest
prospective study to date, it may have
been underpowered to detect a sub-
tle change in withdrawal symptoms.
ere was also potential for selection
bias in this study, as providers decided
which patients were administered
TABLE 3. Total Daily Oral Morphine Equivalents
Time
Patients Administered
Clonidine Taper
(n = 15)
Patients Weaned Off
Dexmedetomidine Alone
(n = 27) p
2 d prior to wean, median (IQR) 105 (60–321.8) 435 (37.5–1,022) 0.17
1 d prior to wean, median (IQR) 105 (30–427.5) 390 (45–1,002) 0.14
Wean day 1, median (IQR) 120 (18.75–445) 390 (48.7–726.5) 0.36
Wean day 2a, median (IQR) 71 (26.5–371) 309 (52.5–891) 0.15
1 d after dexmedetomidine off, median (IQR) 37.5 (15–132) 30 (0–561.5) 0.29
2 d after dexmedetomidine off, median (IQR) 45 (11.25–96.5) 22.5 (0–276) 0.4
IQR = interquartile range.
aPatients who weaned off dexmedetomidine on day 1 were not included in wean day 2.
Figure 2. Individual dexmedetomidine withdrawal symptoms. CAM-ICU = Confusion Assessment Method for the
ICU, Group C = patients administered clonidine taper, Group D = patients weaned off dexmedetomidine alone,
HR = heart rate, RASS = Richmond Agitation-Sedation Scale, SBP = systolic blood pressure, WAT-1 = Withdrawal
Assessment Tool 1.
Observational Study
Critical Care Explorations www.ccejournal.org 7
clonidine based on their own risk assessment for withdrawal or
based on previous diculty with weaning dexmedetomidine.
Patients in Group C had higher median RASS scores at baseline
and had a higher average daily dose of dexmedetomidine over the
study period. For these reasons, the patients in Group C may have
had a higher predisposition for withdrawal symptoms. It is unclear
if earlier initiation of clonidine would result in fewer withdrawal
symptoms with the use of a clonidine taper. A larger, randomized
controlled trial may be benecial to evaluate the true incidence
of dexmedetomidine withdrawal symptoms with and without the
use of clonidine.
Strengths of this study include its prospective design focused
on an adult patient population, as most of the literature looking
at dexmedetomidine withdrawal is retrospective and includes
pediatric patients. Our study also evaluated concomitant medica-
tions to control for confounders and assessed a variety of potential
withdrawal symptoms. Despite our negative ndings, we believe
the lack of dierence in withdrawal symptoms clinically valuable
given the potential cost savings associated with the transition to
clonidine. In an era of high healthcare costs, the cost savings anal-
ysis was conservatively performed using medication costs alone to
provide an estimate of minimum potential savings.
CONCLUSIONS
is study found no dierence in the incidence of two or more
dexmedetomidine withdrawal symptoms in patients being
weaned o of prolonged dexmedetomidine infusions either alone
or with a clonidine taper. Patients receiving clonidine were able to
wean o dexmedetomidine more rapidly than those who did not
receive clonidine, which led to a considerable cost savings with no
dierence in adverse eects. Clonidine may be a safe and eec-
tive medication for more rapid weaning of dexmedetomidine in
patients on prolonged infusions. A larger randomized controlled
trial may be benecial to conrm these results.
ACKNOWLEDGMENTS
We would like to thank the following pharmacy students who
assisted with manual data collection: Kandys Kim, Monica Eng,
Cindy Nguyen, Alisha Soares, Julie Nguyen, and Shirley Ng.
This work was performed at University of California, San Francisco Medical
Center.
The authors have disclosed that they do not have any potential conflicts of
interest.
For information regarding this article, E-mail: Rima.Bouajram@ucsf.edu; phone:
415-353-3495
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