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©2021 American Association of Critical-Care Nurses doi:https://doi.org/10.4037/ccn2021462
Background Iatrogenic withdrawal syndrome is a well-known adverse effect of sedatives and analgesics
commonly used in patients receiving mechanical ventilation in the pediatric intensive care unit, with an
incidence of up to 64.6%. When standard sedative and analgesic treatment is inadequate, dexmedetomi-
dine may be added. The effect of supplemental dexmedetomidine on iatrogenic withdrawal syndrome is
unclear.
Objective To explore the potentially preventive effect of dexmedetomidine, used as a supplement to
standard morphine and midazolam regimens, on the development of iatrogenic withdrawal syndrome in
patients receiving mechanical ventilation in the pediatric intensive care unit.
Methods This retrospective observational study used data from patients on a 10-bed general pediatric
intensive care unit. Iatrogenic withdrawal syndrome was measured using the Sophia Observation with-
drawal Symptoms-scale.
Results In a sample of 102 patients, the cumulative dose of dexmedetomidine had no preventive effect on
the development of iatrogenic withdrawal syndrome (P = .19). After correction for the imbalance in the
baseline characteristics between patients who did and did not receive dexmedetomidine, the cumulative
dose of midazolam was found to be a significant risk factor for iatrogenic withdrawal syndrome (P < .03).
Conclusion In this study, supplemental dexmedetomidine had no preventive effect on iatrogenic with-
drawal syndrome in patients receiving sedative treatment in the pediatric intensive care unit. The cumu-
lative dose of midazolam was a significant risk factor for iatrogenic withdrawal syndrome. (Critical Care
Nurse. 2021;41[1]:e17-e23)
Barbara M. Geven, MSc, RN
Jolanda M. Maaskant, PhD, RN
Catherine S. Ward, MD
Job B.M. van Woensel, MD, PhD
Dexmedetomidine and
Iatrogenic Withdrawal
Syndrome in Critically Ill
Children
Sedative and analgesic treatment with benzodiazepines and opioids is often needed in critically
ill patients receiving mechanical ventilation in the pediatric intensive care unit (PICU).1,2 A poten-
tial complication of this sedative and analgesic treatment is iatrogenic withdrawal syndrome (IWS).
This syndrome is a serious condition that may occur when an analgesic or sedative drug is too abruptly
decreased or stopped.3,4 Symptoms include tachycardia, pyrexia, discomfort, anxiety, muscle tension,
disturbed sleeping pattern, diarrhea, and vomiting.5-7 The reported incidence of IWS in sedated PICU
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patients varies significantly but is as high as 64.6%,3,5,8 -11
with the cumulative doses and duration of sedative and
analgesic drug treatment, presence of cognitive impair-
ment, and young age being the most important risk
factors.3,5,12-15 Iatrogenic withdrawal syndrome can be
prevented and treated by more gradual weaning of seda-
tives and analgesics with oral equivalents.16-18 Although
this process can be safely carried out even outside a PICU
setting, the patient must remain in the hospital; therefore,
more gradual weaning regimens or treatment of IWS can
result in longer intensive care unit and hospital stays.19-21
Finding the optimal level of sedation can be challeng-
ing, and signs of patient discomfort may be present despite
appropriate use of the conventionally used sedatives and
analgesics such as midazolam and morphine. Dexmede-
tomidine has recently been introduced as a supplemental
agent with the aim of optimizing sedation levels without
increasing the doses of currently used sedatives and
analgesics.22,23
It has been the-
orized that dex-
medetomidine
use might pre-
vent the devel-
opment of IWS
associated with benzodiazepines and opioids.24 Dexme-
detomidine is an a2-agonist and has both sedative and
analgesic effects. It was approved by the US Food and
Drug Administration in 1999 for short-term sedation
in adults in an intensive care setting.25 The safety and
efficacy of dexmedetomidine in children remain
unclear26-32 and to date have been evaluated only in small
trials.22,25-30,32-36 When used in addition to morphine and
midazolam to achieve a more optimal level of sedation,
dexmedetomidine might reduce the incidence of IWS in
children, but the results of the trials evaluating the pre-
ventive effect of dexmedetomidine on IWS are contra-
dictory. Therefore, the aim of this study was to explore
the possible preventive effect of dexmedetomidine, when
used in addition to morphine and midazolam, on the
development of IWS in patients receiving mechanical
ventilation in the PICU.
Methods
Setting and Study Population
We conducted this study in a tertiary PICU in a sin-
gle university hospital. This general PICU has 10 beds and
provides care for approximately 550 intensive care patients
annually, ranging in age from newborn to 18 years.
The study included all patients admitted to the PICU
between January 1, 2016, and December 6, 2018, who
underwent mechanical ventilation and received sedative
treatment with morphine and midazolam for at least 48
hours continuously. Midazolam and morphine were admin-
istered and dose adjustments were made according to a
sedation and analgesic protocol, which was part of stan-
dard patient care. Midazolam and morphine were started
on a low continuous dosage and, when necessary, increased
to a maximum continuous dosage of 0.3 mg/kg/h mid-
azolam and 30 μg/kg/h morphine. If sedation levels
remained unsatisfactory, dexmedetomidine was started
as an adjuvant treatment. The continuous dosage of dex-
medetomidine was adjusted to reach the optimal level
of sedation, to a maximum dosage of 1.5 μg/kg/h. No
loading dose was administered when dexmedetomidine
was started. Sedation levels were assessed using the
COMFORT behavioral scale. When the patient was deemed
ready for extubation, analgesic and sedative treatment was
gradually weaned and stopped following a protocol that
specifies a decrease in continuous dosage of midazolam of
0.05 mg/kg/h every 8 hours and a decrease of morphine
of 5 μg/kg/h every 8 hours. The dexmedetomidine dose
was decreased by 0.2 μg/kg/h every 8 hours.
Patients transferred to another PICU during sedative
treatment, those who died during sedative treatment, and
those who received clonidine were excluded from the
study. Patients who received clonidine were excluded to
avoid bias. Both clonidine and dexmedetomidine are
Authors
Barbara M. Geven is a pediatric intensive care nurse and clinical
epidemiologist, Amsterdam UMC/Emma Children’s Hospital,
University of Amsterdam, Amsterdam, the Netherlands.
Jolanda M. Maaskant is a senior nurse researcher and clinical
epidemiologist, Department of Clinical Epidemiology, Biostatistics,
and Bioinformatics, Amsterdam UMC/University of Amsterdam.
Catherine S. Ward is a general and pediatric anesthesiologist,
Amsterdam UMC/Emma Children’s Hospital.
Job B.M. van Woensel is medical director of the pediatric intensive
care unit, Amsterdam UMC/Emma Children’s Hospital.
Corresponding author: Barbara M. Geven, MSc, RN, Pediatric Intensive Care Unit,
Amsterdam UMC/Emma Children’s Hospital, University of Amsterdam, PO Box
22660, 1100 DD, Amsterdam, the Netherlands (email: b.m.geven@amsterdamumc.nl).
To purchase electronic or print reprints, contact the American Association of Critical-
Care Nurses, 27071 Aliso Creek Rd, Aliso Viejo, CA 92656. Phone, (800) 899-1712
or (949) 362-2050 (ext 532); fax, (949) 362-2049; email, reprints@aacn.org.
Finding the optimal level of sedation
can be challenging, and signs of
patient discomfort may be present
despite appropriate use of conven-
tionally used sedatives.
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We found that only the cumulative
dose of midazolam was a signicant
risk factor for development of iatro-
genic withdrawal syndrome.
a2-agonists and have similar mechanisms of action. In
addition, clonidine is used to treat acute withdrawal syn-
drome in adults.25
Design and End Points
The primary outcome of this retrospective observa-
tional study was the incidence of IWS, measured using
the Sophia Observation withdrawal Symptoms-scale
(SOS), after administration of continuous sedative and
analgesic treatment for a minimum of 48 hours.10,11,36,37
The SOS assesses 15 clinical items, each of which is
given a score of 0 or 1 point, resulting in a maximum
score of 15.11 The validity of the SOS was evaluated in
a prospective study in which it was compared with the
Numeric Rating Scale Withdrawal tool, another with-
drawal scoring instrument.11 The results of that study
showed acceptable sensitivity and specificity of 83% and
93%, respectively.11,37 The patient’s level of sedation and
distress was measured with the COMFORT behavioral
scale.38 This scale assesses 6 behavioral items, each of
which has 5 response alternatives rated from 1 to 5,
resulting in a total score of between 6 and 30.39 A score
between 11 and 17 was considered to indicate an optimal
level of sedation. In a systematic review, the clinimetric
properties of this scale were assessed.38 Most studies
showed internal consistency and interrater reliability val-
ues of greater than 0.70, indicating adequate reliability.38
Data Collection
To evaluate the preventive effect of supplemental
dexmedetomidine on the development of IWS, we
recorded the following data: exposure to dexmedetomi-
dine, median dosage (μg/kg/h), cumulative dose (μg/
kg), and total duration of dexmedetomidine administra-
tion (hours), including the duration of weaning (hours).
In addition, the following risk factors were assessed:
age, risk of death, presence of cognitive impairment,
duration of mechanical ventilation, length of PICU stay,
total duration of morphine treatment, cumulative and
average doses of morphine (μg/kg), total duration of
midazolam treatment, cumulative and average doses
of midazolam (mg/kg), and total duration of sedative
administration.5,6,13,37,40 All available data were collected
from the electronic health record (EHR) system and
entered directly into a research database.
The SOS and the COMFORT scale are used in stan-
dard nursing care, and the resulting scores are recorded
in the EHR for all patients who are sedated for at least 72
hours. Both scores are assessed at least 3 times a day, with
more frequent assessment when the patient shows signs
of IWS or discomfort. The cumulative dose of medication
was calculated by multiplying the dosage by the duration
of treatment. The dosage and duration of medication are
ordered by a physician and then recorded in the EHR by
a nurse. Duration of mechanical ventilation, length of
PICU stay, primary diagnosis, and Pediatric Risk of Mor-
tality (PRISM III) score were collected in a separate data-
base. The research database programs used were Microsoft
Excel and Microsoft Access, and the data were combined
into a single Excel database upon completion of data col-
lection. Data collection was performed by 2 of the authors
(B.M.G. and C.S.W.).
Statistical Analysis
For continuous variables with a normal distribution,
the mean and SD are presented; otherwise, the median
and interquartile range (IQR) are presented. For dichot-
omous variables, frequencies and percentages were cal-
culated. Univariate analysis was used to compare patients
with and without dexmedetomidine exposure. Statistical
uncertainty
was expressed
using the 95%
CI, and P ≤ .05
was considered
statistically sig-
nificant. Variables for which a statistically significant
difference was found between patients who did and did
not receive dexmedetomidine were included in a multi-
variate model.
To correct for any significant differences between the
groups with and without dexmedetomidine exposure that
could result in confounding by indication, we calculated
a propensity score for baseline characteristics and included
the propensity score in the multivariate analysis. All data
were analyzed using the software package R Statistics
version 1.0.153 for Mac.
Results
Characteristics of the Sample
A total of 167 patients were eligible for inclusion in the
study. Of these, 25 patients were transferred to another
PICU during treatment, 24 patients died, and 16 received
clonidine, resulting in a sample of 102 patients included
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in the final analysis. The median age was 6.5 (IQR, 2-35)
months, 57 patients (55.9%) were male, and the median
duration of mechanical ventilation was 6 (IQR, 4-8) days
(Table 1). In total, 63 (61.2%) patients developed IWS.
Univariate Analysis
Of the 102 patients, 56 (54.9%) received supplemen-
tary dexmedetomidine. Statistically significant differences
were found in patient age, weight, length, and median
COMFORT scale score between the group that received
dexmedetomidine and the group that did not (Table 1).
Propensity Score
The significant differences found in univariate analy-
sis indicated confounding by indication. Therefore, base-
line characteristics (age, sex, weight, length, PRISM III
score, primary diagnosis, presence of comorbidity,
presence of cognitive impairment, minimum COMFORT
scale score, maximum COMFORT scale score, and median
COMFORT scale score) were summarized into a propen-
sity score. The median propensity score for patients who
were treated with dexmedetomidine was higher (0.82)
than that for patients who were not treated with dexme-
detomidine (0.37). This finding indicates that, on the
basis of baseline characteristics, patients exposed to dex-
medetomidine had a higher chance of being exposed to
dexmedetomidine than patients who were not exposed
to dexmedetomidine.
Multivariate Analysis
When the cumulative doses of dexmedetomidine,
morphine, and midazolam and the propensity score
were combined in a multivariate model, the cumulative
dose of dexmedetomidine had no preventive effect on
Table 1 Characteristics of patients
Characteristic Total (N = 102)
Patients given
dexmedetomidine (n = 56)
Patients not given
dexmedetomidine (n = 46) P
Age, median (IQR), mo 6.5 (2-35) 14 (3-65) 2 (1-7) <.001
Sex, No. (%)
Male
Female
57 (55.9)
45 (44.1)
33 (58.9)
23 (41.1)
24 (52.2)
22 (47.8)
.55
Weight, median (IQR), kg 7.3 (3.9-13.0) 10.3 (6.0-18.3) 4.7 (3.4-7.5) <.001
Length, median (IQR), cm 77.6 (54.0-88.0) 80.0 (62.0-102.0) 57 (52.0-62.0) <.001
PRISM III score, median (IQR) 4 (2-8) 3 (2-8) 5 (3-7) .058
Primary diagnosis, No. (%)
Respiratory
Circulatory
Trauma
Postoperative
Other
83 (81.4)
2 (2.0)
3 (2.9)
9 (8.8)
5 (4.9)
44 (78.6)
1 (1.8)
2 (3.6)
7 (12.5)
2 (3.6)
39 (84.8)
1 (2.2)
1 (2.2)
2 (4.3)
3 (6.5)
.64
Cognitive impairment, No. (%)
Yes
No
13 (12.7)
89 (87.3)
7 (12.5)
49 (87.5)
6 (13.0)
40 (87.0)
> .99
Comorbidity, No. (%)
Yes
No
47 (46.1)
55 (53.9)
28 (50.0)
28 (50.0)
19 (41.3)
27 (58.7)
.43
Duration of mechanical ventilation,
median (IQR), d 6.0 (4.0-8.0) 5.0 (4.0-8.0) 6.0 (4.8-9.0) .25
Length of stay in PICU, median (IQR), d 8.0 (6.0-11.0) 7.0 (6.0-11.5) 8.0 (6.0-10.8) .85
COMFORT scale score, median (IQR)
Median
Minimum
Maximum
13 (12-14)
8 (7-9)
20 (16-24)
13 (12-15)
9 (7-9)
21 (17-24)
12 (11-13)
8 (7-9)
20 (16-23)
.02
.46
.22
SOS score, median (IQR)
Median
Minimum
Maximum
2 (1-3)
0 (0-1)
6 (3-8)
2 (1-3)
0 (0-0)
5 (3-7)
3 (1-4)
0 (0-1)
7 (3-8)
.51
.57
.34
Abbreviations: IQR, interquartile range; PICU, pediatric intensive care unit; PRISM III, Pediatric Risk of Mortality; SOS, Sophia Observation withdrawal Symptoms-scale.
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the subsequent development of IWS (P = .19). Further-
more, we found that only the cumulative dose of midaz-
olam was a significant risk factor for development of IWS
(odds ratio, 1.09 [95% CI, 1.04-1.17]; P < .03), whereas
the cumulative dose of morphine was not (odds ratio,
1.00 [95% CI, 1.00-1.00]; P = .09). Further details are
shown in Table 2.
Discussion
In this study, we aimed to explore the possible pre-
ventive effect of supplementary dexmedetomidine on
the development of IWS in critically ill children under-
going mechanical ventilation who received continuous
intravenous midazolam and morphine. We found that
dexmedetomidine had no preventive effect on the devel-
opment of IWS in our cohort.
Although the cumulative dose of dexmedetomidine
had no preventive effect, it did not appear to be a risk
factor for the development of IWS. These findings are
similar to the results of previous studies.25,26 However,
some controversy remains, as Haenecour et al30 found
that the cumulative dose of dexmedetomidine was a sig-
nificant risk factor for IWS. More recently, in a study in
which dexmedetomidine was used as a single continuous
sedative agent during noninvasive ventilation, Shutes et
al41 found that patients with a higher cumulative dose of
dexmedetomidine had an increased risk of IWS. How-
ever, taking into account both our results and the find-
ings from previous research, it is difficult to draw firm
conclusions regarding the potential risk or benefit posed
by dexmedetomidine in the development of IWS. Also,
the fact that we used dexmedetomidine as a supplement
to standard sedative and analgesic treatment with ben-
zodiazepines and opioids, which are themselves indepen-
dent risk factors for IWS development,22,28-30,32,42,43
influences the conclusions that are drawn. Perhaps the
greatest challenge is to distinguish the individual agent
responsible for causing IWS in each patient.
Before beginning our study, we assumed that the
addition of supplementary dexmedetomidine in cases
of unsatisfactory sedation levels would allow achieve-
ment of an optimal level of sedation without the need
for increased doses of other sedatives, which might
prevent or decrease the risk of IWS. Contrary to our
hypothesis, however, we found that median continuous
dosages of morphine and midazolam were even higher
in patients receiving dexmedetomidine, although this
difference was not significant. Dexmedetomidine is
used as an adjuvant more frequently in patients in whom
optimal levels of sedation have not been reached, and
the patients in
this study
who were
treated with
dexmedeto-
midine had significantly higher median COMFORT scale
scores, as shown in Table 1. This situation could account
for the higher median continuous dosages of midazolam
and morphine recorded for this patient group. The cumu-
lative dose of midazolam is an independent risk factor for
the development of IWS, which might explain the lack
of a preventive effect of dexmedetomidine on the devel-
opment of IWS in our cohort. The results might be dif-
ferent when dexmedetomidine is prescribed as a primary
sedative agent.
In accordance with previous research, we found
that the cumulative dose of midazolam was a signifi-
cant risk factor for development of IWS.3,5,8,9,11,12-14,43
In previous research with larger cohorts, multivariate
analysis revealed more statistically significant predic-
tors: duration of midazolam administration, duration
of morphine administration, the number of additional
sedatives/opioids, the length of analgesic therapy,
commencement of gradual tapering, a younger age,
mean daily opioid dose, and preexisting cognitive
impairment.3,5,11,12-14 In research with a similar cohort
Table 2 Logistic regression analysis
Regression coefficient (SE) Odds ratio (95% CI) P
Intercept -1.38 (0.68) 0.25 (0.06-0.91) .04
Morphine cumulative dose, µg/kg 0.0004 (0.00027) 1.00 (1.00-1.00) .09
Midazolam cumulative dose, mg/kg 0.089 (0.03) 1.09 (1.04-1.17) .003
Dexmedetomidine cumulative dose, µg/kg 0.0059 (0.004) 1.01 (1.00-1.02) .19
Propensity score -0.511 (0.9) 0.60 (0.10-3.42) .57
A nurse-driven pediatric sedation
protocol can reduce withdrawal symp-
toms in patients admitted to the PICU.
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size, only the peak and cumulative doses of midaz-
olam remained statistically significant.8,9,14
Incidence of IWS
We found a high incidence of IWS in our cohort
(61.2%), although this finding was similar to the rate
reported in previous studies (up to 64.6%).5,8-11 A pos-
sible explanation for the high incidence in our study is
that in our study population the diagnosis of IWS was
made when a single score of the SOS was 4 or higher.
It could be argued that using only 1 score without
confirmation might result in false classification and
an overestimation of the incidence of IWS. However,
on the basis of the clinimetric performance of the SOS
in a prospective study evaluating its validity,11 we
believe that the relatively high incidence found in our
cohort is likely correct.
Recommendations for Nursing Practice
Assessment of patients’ level of comfort and sedation
and, when necessary, making adjustments to sedative and
analgesic treatment are part of specialist nursing care in
the intensive care unit. A nurse-driven pediatric sedation
protocol can reduce withdrawal symptoms in patients
admitted to the PICU,44,45 and a sedative and analgesic
drug rotation protocol can also help to reduce the risk of
IWS.46 Therefore, nurses must fully understand the clini-
cal consequences and potential side effects of sedative
and analgesic therapy and the potential risk factors for
development of IWS. A better understanding of sedation
weaning protocols and risk stratification for IWS can be
helpful to nurses in assessing and reducing the risk of
IWS in patients admitted to the PICU.44
Future Research
Dexmedetomidine is currently approved only for
use in adults in an intensive care setting.25 All pediat-
ric use at this time remains off-label. To ensure that
children are treated with medications that are fully
tested in their population, more prospective research
is needed to determine the most appropriate treatment
and dosing regimen of dexmedetomidine in critically
ill children. In particular, a randomized controlled trial
targeting dose finding and efficacy of dexmedetomi-
dine in children is urgently needed. Finally, given the
increased risk of IWS posed by midazolam use, more
prospective studies are needed to determine the
suitability of dexmedetomidine as an effective primary
sedative drug and an alternative to midazolam.
Limitations
Our study has some limitations. Importantly, all data
were gathered retrospectively after reviews of the patient
records. Data collected in this way must always be inter-
preted with caution. The results of this type of retro-
spective research are dependent on the accuracy of the
information documented by physicians and nurses. This
type of study carries a risk of incomplete data, although
we found no obviously missing data in the medication
records. Second, we used the SOS to diagnose IWS in
children who were treated for a minimum of 48 hours,
whereas the SOS has been validated only for treatment
of at least 72 hours.7,11,37
Third, owing to overlap in symptoms, distinguishing
a patient with IWS from one with delirium is difficult in
daily practice.47 Recent research has combined the assess-
ment of IWS with that of delirium in the SOS-Pediatric
Delirium, suitable for use in children older than 3 months.48
However, this screening tool was not in use at the time of
this study, and therefore it is uncertain whether the chil-
dren diagnosed with IWS actually had IWS or delirium.
Finally, this research was performed at a single-center
PICU, and generalizability of the results to a wider popu-
lation may be limited.
Conclusion
The results of this study indicate that use of dexme-
detomidine as a supplement to the conventionally used
sedative drug regimen in the PICU has no preventive
effect on the development of IWS. These results should
be confirmed in future prospective studies. Dexmedeto-
midine may have a prominent place in the sedative regi-
mens of critically ill children, but it should be used with
caution. Although our results do not allow us to draw firm
conclusions about the preventive effect of dexmedetomi-
dine on the development of IWS, they do indicate that
the cumulative dose of midazolam is a significant inde-
pendent risk factor for the development of IWS. CCN
Financial Disclosures
None reported.
See alsoSee also
To learn more about pediatric critical care, read “Priority Outcomes
in Critically Ill Children: A Patient and Parent Perspective” by Fayed
et al in the American Journal of Critical Care, 2020;29(5):e94-e103.
Available at www.ajcconline.org.
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