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Indian Pediatr 2021;58: 117-122 |
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Dexmedetomidine vs Midazolam for Sedation in
Mechanically Ventilated Children: A Randomized Controlled
Trial
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Krishna Mohan Gulla, Jhuma Sankar, Kana Ram Jat, Sushil
Kumar Kabra and Rakesh Lodha
From Division of Pediatric Pulmonology and Intensive
Care, Department of Pediatrics, All India Institute of
Medical Sciences, New Delhi, India
Correspondence to: Dr Rakesh Lodha, Professor, Division
of Pediatric Pulmonology and Intensive Care, Department of
Pediatrics, All India Institute of Medical Sciences, Ansari
Nagar, New Delhi 110 029, India.
Email:
[email protected]
Received: April 24, 2020;
Initial review: May 15, 2020;
Accepted: November 05, 2020.
Trial registration: CTRI/2016/10/007347
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Background: There is a paucity of
data on use of dexmedetomidine as a sedative agent in
mechanically ventilated children.
Objectives: To compare the efficacy
of dexmedetomidine and midazolam for sedation in
mechanically ventilated children aged 1 month - 15 years.
Secondary objectives were to compare the need for top-up
doses of fentanyl and paralytic agents, duration of
mechanical ventilation, ICU stay and hospital stay, and
adverse events.
Design: Open label, non-inferiority,
randomized controlled trial.
Setting: PICU of a tertiary care
teaching hospital in India.
Patients: Consecutive children aged 1
month to 15 years who were mechanically ventilated.
Intervention: Children were
randomized to either dexmedeto-midine or midazolam and the
doses were titrated to maintain target sedation score of 4
or 5 as measured by Penn State Children Hospital Sedation
algorithm.
Outcome: The percentage of time spent
in level 4 or 5 of Penn State Children Hospital sedation
algorithm for ventilated children.
Results: 49 children were randomized
(24 to ‘midazolam group’ and 25 to ‘dexmedetomidine group’).
There was no difference in the percentage of time spent in
the targeted sedation between the groups [midazolam 67.3%
(18.8) vs. dexmedetomidine 56.3 %. (28.6); P=0.12].
The absolute difference in the percentage of time spent was
-10.9% [SE (95% CI) 7.05: (-25.15 to 3.25)]. The lower end
of 95% CI for the difference breached the non-inferiority
limit of -20%. Number of fentanyl boluses, duration of
mechanical ventilation, ICU stay, and hospital stay were
similar. Four (17.4%) children in dexmedetomidine group
developed persistent bradycardia.
Conclusion: Non-inferiority of
dexmedetomidine compared to midazolam for sedation in
children on mechanical ventilation could not be established.
Keywords: Alpha-2 adrenoceptor agonist,
Benzodiazepines, Intubation, Pediatric intensive care unit.
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Sedatives are
required in mechanically ventilated children not only for
reducing pain and anxiety, but also to allow synchronized
respiratory support, and preventing accidental extubation.
Commonly used agents are benzodiazepines (midazolam) and
opiates (morphine/fentanyl) [1]. Dexmedetomidine, an alpha-2
adrenoceptor agonist acting on locus ceruleus and spinal
cord, with insignificant respiratory depression [2] has been
used as a sedative agent in children for day care
procedures, non-invasive and invasive ventilation [3-5]. In
adults, it has been shown that, compared to midazolam and
fentanyl, dexmedetomidine reduces the duration of mechanical
ventilation and length of ICU stay [6]. In children,
dexmedetomidine has been reported to be an effective
sedative agent without much side effects compared to
benzodiazepines or opioids with the additional advantage of
reducing the dose of conventio-nal sedative agents [4,7-9].
Though use of dexme-detomidine in mechanically ventilated
children has increased over last few years, there is wide
variation in practice regarding the dose and duration of the
drug [10]. A recent meta-analysis has shown the superiority
of dexmedetomidine over midazolam for sedation in children
undergoing day care procedures [11]. However, few trials
that exist, evaluating the efficacy of dexmedetomidine as a
sedative agent in mechanically ventilated children, have
several limitations [12-14]. Hence, we conducted this
non-inferiority trial with an objective to compare
dexmede-tomidine with midazolam for adequacy of sedation in
mechanically ventilated children.
METHODS
Mechanically ventilated children, 1 month
to 15 years old, admitted in a pediatric intensive care unit
of a tertiary care referral center between August, 2016 to
April, 2018 were eligible. Children with
catecholamine resistant shock (shock persisting despite the
use of the epinephrine at the rate of >0.3 mcg/kg/min or
norepinephrine at the rate of >0.3mcg/kg/min), children
already on sedative drug infusion, bradycardia,
atrioventricular conduction block, primary central nervous
system involvement at the time of admission, hepatic
impairment, infusion of muscle relaxants, or previous
participation in this study, were excluded. Since these
stringent criteria resulted in the slow recruitment of
subjects, the exclusion criteria were modified after
institutional ethics committee approval from December, 2017
onwards, with catecholamine-resistant shock at the time of
randomization and children already receiving sedation prior
to randomization, being removed from exclusion criteria
list. The study was approved by institute’s ethics
committee and was registered pros-pectively in Clinical
Trial Registry of India.
Based on a study in adults [15], we
assumed 5% difference between the two groups with SD of
43.5% for the percentage time spent in the desired sedation
level, the estimated sample size was 39 per group to be 80%
sure that lower limit of one-sided 95% confidence interval
would be above the non-inferiority margin of -20%.
Computer generated, block random sequence
was created by a person, not a part of the study. Block size
of 4 with the investigator being ignorant of the block size.
Random codes were printed on a pieces of paper placed in a
serially numbered, opaque sealed envelopes. Envelopes were
opened by the investigator after taking informed consent
from the parent/legally authorized representative of the
child, who was found to be eligible for the study.
Two mL of dexmedetomidine (1 mL=100 mcg)
was diluted with 48 mL of 0.9% saline to get a concentration
of 4 mcg/mL. Midazolam was diluted to a concentration of 0.1
mg per mL. After randomization, midazolam bolus of 0.1mg/kg
and fentanyl bolus of 1 mcg/kg were given to both the groups
prior to initiation of infusion of the drugs. Bolus dose of
dexmedetomidine was not given in order to avoid bradycardia
and hypotension. Starting doses of midazolam and
dexmedetomidine were 1 mcg/kg/min and 0.25 mcg/kg/h,
respectively. Sedation level was assessed using Penn State
Children Hospital (PSCH) sedation algorithm for ventilated
children [16]. The sedation targeted for primary outcome was
Level 4 or 5. Level of sedation was assessed every 2 hours
by the investigator or treating residents who were trained
optimally regarding the appropriate application of sedation
scale on mechanically ventilated children. Doses were
titrated, based on the sedation score. While midazolam
infusion was increased by 1 mcg/kg/min till maximum dose of
4 mcg/kg/min, dexmedetomidine infusion was increased by 0.25
mcg/kg/hr till a maximum dose of 0.75 mcg/kg/hr. The maximum
infusion dose of dexmedetomidine was chosen as 0.75
mcg/kg/min to avoid side effects such as bradycardia.
Fentanyl boluses (2 mcg/kg/bolus) were administered in case
of agitation and asynchronous ventilation. Infusion of drugs
was continued till seven days or weaning from mechanical
ventilation, whichever occurred earlier.
The number of fentanyl or vecuronium
boluses received by children was recorded. Number of
episodes of bradycardia (<60 bpm), hypotension (systolic
blood pressure <5th centile for age) [17], duration of
mechanical ventilation, ICU stay and hospital stay were
recorded. The sum of the time periods of receiving
continuous infusion of the sedative drug, the time periods
for which the patient was monitored for sedation, the time
periods in which the patient was at level of sedation 4 or
5, were calculated. Percentage of the total monitored
duration of sedation, which was spent in level 4 or 5
sedation was calculated. Treatment failure was defined as
self-extubation or inability to maintain desired sedation
level score even after maximum doses of
midazolam/dexme-detomidine infusion as decided by the
treating team.
Our primary outcome was percentage of
time spent in level 4 or 5 of PSCH sedation algorithm for
ventilated children out of total duration of sedation
monitored. Secondary outcomes were: top up doses of fentanyl
and vecuronium, episodes of bradycardia/hypotension, length
of mechanical ventilation, ICU stay and hospital stay.
Treatment failure, hemodynamic status using vaso-active
inotropic score (VIS), mortality were also compared between
the groups
Statistical analyses: Data was
entered into MS Excel spreadsheets, and analysis was
performed using STATA ver. 13 (Stata Corp). Variables were
compared by using Chi square test and Fisher exact test, as
applicable. Normally distributed continuous variables were
compared by applying unpaired t test. The mean
difference in the percentage of time spent by mechanically
ventilated children in level 4 or 5 of the Penn State
Children Hospital sedation algorithm was compared between
the two groups by Mann-Whitney test.
RESULTS
Of the 151 eligible children screened, 49
were randomized (24 in midazolam group and 25 in
dexmedetomidine group) (Fig.1). Protocol was
modified to relax strict exclusion criteria so as to improve
recruitment rate. Fifteen children were enrolled after
protocol modification (4 children were receiving sedative
infusion, 3 had catecholamine refractory shock and 3 were
receiving sedation as well as were in catecholamine
refractory shock). Data were analyzed for 47 children (24 in
midazolam group and 23 in dexmedetomidine group). Trial was
stopped prior to completion of sample size due to higher
rates of side effects in dexmedetomidine group and due to
the time bound nature of study of 18 months.
 |
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Fig. 1 Study flow chart.
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Baseline characteristics of both the
groups are shown in Table I. Ten (42%) children in
the midazolam group and 2 (9%) in the dexmedetomidine group
had congenital heart disease. In the midazolam group, 2 had
underlying bronchiectasis, 2 had gastroesophageal reflux
disease and one had airway malacia. In the dexmedetomidine
group, 1 child each had underlying hepatic
hemangio-endo-thelioma, congenital diaphragmatic hernia,
Budd-Chiari syndrome, acute lymphoblastic leukemia, juvenile
dermatomyositis, idiopathic pulmonary hemorrhage and primary
immunodeficiency. Twenty-four children in midazolam group
and 22 children in dexmedetomidine group received pressure
controlled synchronized intermittent mandatory ventilation
with pressure support (PC-SIMV-PS). One child in
dexmedetomidine group received high frequency oscillation
ventilation (HFOV).
Table I Baseline Characteristics of Mechanically Ventilated Children Enrolled in the Study
| Characteristics |
Dexmedetomidine |
Midazolam |
|
group (n=23) |
group (n=24) |
| Age (mo) |
8 (3, 24) |
5.5 (2.5, 11.7) |
| Boys, n (%) |
12 (52) |
12 (50) |
|
%Predicted mortalitya |
13.5 (13.3, 27) |
13.5 (13, 21) |
| Weight (z scores) |
-2.52 (-3.61,-1.59) |
-3.64 (-4.76,-2.65) |
| Length (z scores) |
-1.84 (-2.48,-0.62) |
-1.74 (-3.31,-0.87) |
| Admission diagnoses, n (%) |
|
|
| Pneumonia |
9 (39) |
12 (50) |
| Gastrointestinal sepsis |
3 (13) |
1 (4) |
| Sepsis without focus |
4 (17.5) |
1 (4) |
| Postoperative ventilation 3 (13) |
4 (17) |
|
| Others |
4 (17.5) |
6 (25) |
| Values in median
(IQR) or as stated. PIM: Pediatric Index of
Mortality; ausing PIM-2. |
The dose range for midazolam was 1- 4
mcg/kg/min and for dexmedetomidine was 0.25-0.75 mcg/kg/hr.
Median (IQR) duration of drug received in midazolam group
was 64 (38, 135) hours and in dexmedetomidine group was 30
(14, 64) hours (P=0.02). Four (16.6%) children in
midazolam group (16.6%) and 13 (56.5%) children in
dexmedetomidine group (56.5%) had treatment failure (P=0.005).
Table II Sedation Duration and Time Spent in PSCH Level 4 or 5 in Children
Receiving Dexmedetomidine or Midazolam
Characteristics
|
Dexmedetomidine group
(n=23)
|
Midazolam group
(n=24)
|
P
value |
| Sedation duration (h) |
26 (14, 48) |
53 (31, 83.5) |
0.014 |
| Time spent in level 4 or 5 of PSCH sedation algorithm (h)
|
20 (6, 28) |
38 (20.5, 66) |
0.006 |
|
Time spent in Level 4 or 5 of PSCH sedation algorithm (%)ab
|
56.5 (28.6) |
67.3 (18.8) |
- |
| PSCH: Penn State Children Hospital. Values in median (IQR) or amean (SD); bMean difference (95% CI)= -10.9 (-25.15 to 3.25)%. |
The mean difference in the percentage of
time spent by mechanically ventilated children in level 4 or
5 of the PSCH sedation algorithm between dexmedetomidine and
midazolam groups was -10.94%. The lower end of 95% CI
(confidence interval) for this difference breached the
non-inferiority limit of -20% [difference= -10.94% (SE=
7.05); 95% CI: -25.15 to 3.25]. Hence, non-inferiority of
dexme-detomidine as compared to midazolam could not be
established (Table II). The secondary outcome
para-meters were comparable between the groups (Table
III) While none of the children in midazolam group
had bradycardia, 4 (17.4%) children in the dexmedetomidine
group, developed persistent bradycardia (<60 bpm)
necessitating withdrawal of the drug (P=0.05).
Hemo-dynamic stability, assessed by vasoactive inotropic
score, was not different between the groups [10 (IQR 0, 20)
in midazolam group or 17.5 (IQR 0, 46) in dexmedetomi-dine
group, P=0.40].
Table III Comparison of Secondary Outcomes Between Dexmedetomidine and Midazolam Groups
| Characteristics |
Dexmedeto- |
Midazolam |
P |
|
midine group |
group |
value |
|
(n=23) |
(n=24) |
|
| Fentanyl boluses |
4(2.2,5.7) |
4(2,6) |
0.79 |
|
Adjusted bolusesa
|
1(1,3.4) |
4(1.5,6) |
0.06 |
| Vecuronium boluses |
0(0,1) |
0(0,1) |
0.90 |
| Mechanical ventilation (h) |
162(58,432) |
132(36,312) |
0.90 |
| ICU stay (d) |
10.5(4.8,20.8) |
9.2(5,15.2) |
0.95 |
| Hospital stay (d) |
21(11,33) |
17.5(13.5,37.5) |
0.87 |
| All values are in median (IQR); aadjusted for period of 24 hours per person sedation monitored. |
DISCUSSION
In our study, non-inferiority of
dexmedetomidine compared to midazolam for desired sedation
in mechani-cally ventilated children could not be
established. Though the intended sample (36 in each group)
size could not be attained due to the time bound nature of
study of 18 months, wide margin of treatment failure rate in
dexmedetomidine (56.5%) compared to midazolam (16.6%) group,
and the adverse events such as bradycardia in
dexmedetomidine group (14.4%) may not have changed even if
the sample size was completed.
A study in ventilated adults [15] showed
that, though the percentage time spent in the target
sedation range was similar between dexmedetomidine (77.3%)
and midazolam (75.1%) groups, the absolute duration of
sedation was lower in dexmedetomidine group [3.5 days vs 4.1
days, P=0.01] like ours. Another recent trial in
adults confirmed non-inferiority of dexmedetomidine when
compared with midazolam with respect to the time spent in
desired sedation range [18]. However, in contrast to our
study, the duration of drug infusion was similar in both the
groups. In our study, the median (IQR) number of fentanyl
boluses received were similar in both groups, while the
first reported pediatric trial that compared infusion of
dexmedetomidine with midazolam in mechanically ventilated
children found the number of rescue morphine boluses
received in midazolam group was significantly higher [12].
The difference is perhaps due to the fact that the total
duration of sedation in both the groups was less than 24
hours in their study. In another trial in children
undergoing open heart surgery, there was no difference in
the need for rescue sedation between dexmedetomidine and
fentanyl groups and sedation scores were comparable [13].
However, the mean duration of sedation infusion was only 13
hours, making it difficult to confirm effectiveness of
dexmedetomidine infusion in providing adequate sedation in
mechanically ventilated patients.
While studies in adults and pediatric
population showed that sedation attained by dexmedetomidine
is comparable to midazolam for mechanically ventilated
population [10,12,15,18,19], our study could not establish
the non-inferiority of dexmedetomidine compared to midazolam.
This is likely to be due to individual patient traits,
genetic polymorphisms in pharmacokinetics and
pharmacodynamics [20] and a relatively conservative
dexmedetomidine dose used in the study. Studies had shown
that other factors like disease severity at admi-ssion was
also associated with efficacy of dexme-detomidine [21,22].
Patients with lower baseline Simplified Acute Physiology
Score (SAPS II) had higher clearance of dexmedetomidine
[23] and those with lower Modified
Acute Physiology and Chronic Health Evaluation (APACHE II)
score had successful sedation with dexme-detomidine [24].
Since pharmacokinetic studies on dexmedetomidine have shown
wide inter-patient variability of plasma levels [20], it is
questionable whether adequate plasma levels are achieved in
critically ill patients. Recent study from Japan in children
less than 2 years old, on dexmedetomidine infusion (012-1.4
mcg/kg/hr) found that there was no correlation between
plasma drug concentration and administered drug dose [25].
In our study, since majority of children were infants,
possibly adequate plasma concentration of dexme-detomidine
for sedation could not be attained. The trials in adults
which established non-inferiority of dexme-detomidine
compared to midazolam, used higher doses (>0.7 mcg/kg/h) to
obtain desired sedation levels, thereby suggesting that
adequate plasma levels may be attained with high doses
[15,18,26]. It is possible that if a higher dose of
dexmedetomidine i.e, more than 0.75 mcg/kg/hr was
used in our study, our results could have been different.
Genetic polymorphisms in alpha-2 receptor may reduce
affinity towards dexmedetomidine with resultant variation of
its pharmacodymanic properties. Two important polymorphisms
have been identified i.e., ADRA2A"1291C/G SNP (single
nucleotide polymor-phism) and ADRA2AC753G. Study of ADRA2A
C1291G polymorphism in 110 adult patients, who underwent
coronary artery bypass graft, showed that patients carrying
the G allele compared to those carrying C allele had better
sedation [27]. Though we did not look at the genetic
polymorphism of alpha-2 receptor in our study, this could be
another reason for non-establishment of non- inferiority of
dexmedetomidine compared to midazolam. Studies on the
receptor polymorphism is lacking in Indian children.
Dexmedetomidine is known to cause
hemodynamic adverse effects such as bradycardia,
hypotension, and even transient hypertension in few patients
[2]. Authors [15, 18] have reported between 14 and 42% of
mechani-cally ventilated adult patients to have bradycardia
in dexmedetomidine group with some requiring intervention
for bradycardia. In pediatric population, incidence of
bradycardia with dexmedetomidine infusion varied from 3% to
27% and majority not requiring intervention [4,8]. In our
study, 4 children (17.4%) in dexmedetomidine group had
persistent bradycardia (<60 bpm) which necessitated
discontinuation of drug.
Strength of our study is that it is one
of the few randomized controlled trials in mechanically
ventilated children for sedation, especially in the Indian
scenario. The limitations of the study include lack of
assessment of withdrawal symptoms in either groups, targeted
sample size not covered, observer bias due to the study
being open label, exclusion criteria being relaxed for some
children. Future studies on dexmedetomidine, with adequate
sample size, for sedation in ventilated children are
desirable.
Our study could not establish the
non-inferiority of dexmedetomidine compared to midazolam for
sedation in children on mechanical ventilation. Further
studies are required to ascertain the utility of
dexmedetomidine as a sedative for mechanically ventilated
children.
Ethics clearance: The study
was approved by Institute Ethics Committee, AIIMS, New
Delhi; IECPG/403, dated June 29, 2016.
Contributors: KMG: design of the
study, patient management, data collection, data analysis,
and preparation of manuscript; JS,KRG,SKK: design of the
study, patient management, reviewed manuscript; RL: design
of the study, patient management and reviewed manuscript.
Funding: None; Competing
interest: None stated.
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WHAT IS ALREADY KNOWN
•
Dexmedetomidine is shown to decrease the
duration of mechanical ventilation, intensive care
unit stay and sedation withdrawal, compared to
midazolam in mechanically ventilated adults.
WHAT THIS STUDY ADDS
•
For sedation in mechanically ventilated
children, dexmedetomidine as continuous infusion,
compared to midazolam, may not be as effective as
seen in adults.
•
Dexmedetomidine is associated with higher
episodes of bradycardia compared to midazolam.
|
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