Dexmedetomidine Sedation in Mechanically

Ventilated Critically Ill Children: A Pilot Randomized

Controlled Trial
Simon J. Erickson, MBBS, FRACP, FCICM1; Johnny Millar, MB ChB, PhD, MRCP, FRACP, FCICM2,3;
Brian J. Anderson, MB ChB, PhD, FANZCA, FCICM4,5; Marino S. Festa, MD, FCICM6;
Lahn Straney, PhD7; Yahya Shehabi, MBBS, PhD, FCICM8,9; Debbie A. Long, RN, PhD10,11; for the
Baby SPICE Investigators and the Australian and New Zealand Intensive Care Society Paediatric
Downloaded from http://journals.lww.com/pccmjournal by BhDMf5ePHKbH4TTImqenVIiuKVF7qTxs1W+oIWQuQ7XxwtmptojNIu7z81y9c1iI on 09/04/2020

Study Group (ANZICS-PSG)

Objectives: To assess the feasibility, safety, and efficacy of a se-
dation protocol using dexmedetomidine as the primary sedative in
mechanically ventilated critically ill children.
Design: Open-label, pilot, prospective, multicenter, randomized,
controlled trial. The primary outcome was the proportion of se-
dation scores in the target sedation range in the first 48 hours.
Safety outcomes included device removal, adverse events, and
vasopressor use. Feasibility outcomes included time to randomi-
zation and protocol fidelity.
Setting: Six tertiary PICUs in Australia and New Zealand.
Patients: Critically ill children, younger than 16 years old, requiring
intubation and mechanical ventilation and expected to be mechan-
ically ventilated for at least 24 hours.
1
Paediatric Critical Care, Perth Children’s Hospital, Perth, WA, Australia.
2
Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne,
VIC, Australia.
3
Murdoch Children’s Research Institute, University of Melbourne, Melbourne,
VIC, Australia.
4
Paediatric Intensive Care Unit, Starship Children’s Hospital, Auckland,
New Zealand.
5
Department of Anaesthesiology, University of Auckland, Auckland, New
Zealand.
6
Kids Critical Care Research, The Children’s Hospital at Westmead,
Westmead, NSW, Australia.
7
Department of Epidemiology and Preventive Medicine, Monash University,
Melbourne, VIC, Australia.
8
School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
9
Clinical School of Medicine, University of New South Wales, Sydney,
Interventions: Children randomized to dexmedetomidine received
a dexmedetomidine-based algorithm targeted to light sedation
(State Behavioral Scale –1 to +1). Children randomized to usual
care received sedation as determined by the treating clinician (but
not dexmedetomidine), also targeted to light sedation.
Measurements and Main Results: Sedation with dexmedetomi-
dine as the primary sedative resulted in a greater proportion of
sedation measurements in the light sedation range (State Behav-
ioral Scale –1 to +1) over the first 48 hours (229/325 [71%] vs
181/331 [58%]; p = 0.04) and the first 24 hours (66/103 [64%]
vs 48/116 [41%]; p < 0.001) compared with usual care. Cumu-
lative midazolam dosage was significantly reduced in the dexme-
detomidine arm compared with usual care (p = 0.002).There were
more episodes of hypotension and bradycardia with dexmedeto-
midine (including one serious adverse event) but no difference in
vasopressor requirements. Median time to randomization after in-
tubation was 6.0 hours (interquartile range, 2.0–9.0 hr) in the dex-
medetomidine arm compared with 3.0 hours (interquartile range,
1.0–7.0 hr) in the usual care arm (p = 0.24).
Conclusions: A sedation protocol using dexmedetomidine as the
primary sedative was feasible, appeared safe, achieved early, light
sedation, and reduced midazolam requirements. The findings of
this pilot study justify further studies of sedative agents in critically
ill children. (Pediatr Crit Care Med 2020; 21:e731–e739)
Key Words: child; critical illness; dexmedetomidine; hypnotics and
sedatives; mechanical ventilation; midazolam

O
NSW, Australia. ptimal sedation is an integral component of the com-
10
Paediatric Intensive Care Unit, Queensland Children’s Hospital, Bris- prehensive medical care of the critically ill child and
bane, QLD, Australia.
provides anxiolysis, amnesia, and facilitates mechan-
11
Children’s Health Research Centre, The University of Queensland, Bris-
bane, QLD, Australia. ical ventilation. There is no universally accepted approach to
Copyright © 2020 by the Society of Critical Care Medicine and the World the sedation of mechanically ventilated children due to lack of
Federation of Pediatric Intensive and Critical Care Societies high quality evidence to guide sedation practice in critically ill
DOI: 10.1097/PCC.0000000000002483 children (1–5). Sedative and analgesic medications used and

Pediatric Critical Care Medicine www.pccmjournal.org e731

Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Erickson et al
sedation goals may vary widely between and even within hospi-
tals and optimal levels of sedation are often not achieved (6, 7).
Over-sedation may result in prolonged mechanical venti-
lation, delirium, and drug tolerance and withdrawal, while
under-sedation may lead to loss or displacement of IV access
and drains, unplanned extubation, and emotional distress. A
systematic review of sedation practices protocols and algo-
rithms demonstrated that sedation guidelines can reduce drug
exposure and PICU length of stay (8), and nurse-driven
sedation and analgesia protocols have demonstrated reduc-
tions in drug exposure. However, the impact of sedation
protocols on patient-centered outcomes such as duration of
ventilation and neurocognitive outcome is still unclear (9–11).
Midazolam is still widely used as a primary sedative in chil-
dren (7, 12–14). Midazolam has been linked to neurotoxicity
in animal studies (15, 16) and may be associated with delirium
and drug withdrawal, in addition to long-term neurocognitive
sequelae in children (17–21).
Dexmedetomidine, a selective α2-adrenoreceptor agonist,
exerts its therapeutic effects via reduction of norepinephrine
in the sympathetic nerve endings in the central and peripheral
nervous systems, resulting in sedation, anxiolysis, and anal-
gesia, and has not been linked to neurotoxicity (22).
We conducted a randomized controlled pilot feasibility trial
to compare the use of dexmedetomidine as a primary sedative,
compared with usual sedation practice in mechanically venti-
lated, critically ill children.
MATERIALS AND METHODS
Study Design
The trial was an open-label, randomized, controlled pilot trial
conducted in six tertiary PICUs in Australia and New Zealand.
Study Participants
Inclusion Criteria. Children, younger than 16 years old, who
were mechanically ventilated via an endotracheal tube and had
been intubated (excluding time spent intubated within an op-
erating or procedural theater), for less than 12 hours, and the
treating clinician anticipated that: 1) the patient required im-
mediate and ongoing sedative medication for comfort, safety,
and to facilitate the delivery of life support measures and 2) the
patient was expected to remain intubated for at least 24 hours
after enrollment.
Main Exclusion Criteria.
1) Primary diagnosis of proven or suspected acute brain in-
jury resulting in impaired conscious level or cognition
2) Primary diagnosis of proven or suspected neurologic injury
or pathology resulting in permanent or prolonged weakness
3) Requirement or anticipated requirement for continuous
neuromuscular blockade
4) Cardiovascular instability manifested by either of the following:
a) Mean arterial blood pressure less than 2 sds below
normal mean for age despite fluid and vasopressor re-
suscitation (23)
e732 www.pccmjournal.org September 2020 • Volume 21 • Number 9
Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
b)  Heart rate less than 2 sds below normal mean for age (23)
A complete list of the exclusion criteria is shown in Supple-
mentary Table 1 (Supplemental Digital Content 1, http://links.
lww.com/PCC/B437).
The trial protocol was registered with Australian and New
Zealand Clinical Trials Registry (number 12614000225617).
Ethical approval was obtained at each participating site, and
consent was obtained from the parent/guardian for all study
participants. Subjects were randomly assigned, in permuted
blocks of 2–6 via concealed envelopes, in a 1:1 ratio to dex-
medetomidine as the primary sedative or to usual sedation
practice.
Background Treatments
Pain relief for all children was provided by an infusion or bolus
of an opioid (e.g., morphine or fentanyl) or other drugs (e.g.,
ketamine) at the discretion of the treating clinician. The de-
fault sedation target was light sedation, as defined by State
Behavioral Scale (SBS) (24) range of –1 to +1 (responsive to
gentle touch to restless) unless otherwise clinically indicated
(e.g., painful procedures or neuromuscular blockade). Patients
who required neuromuscular blockade after randomization
received additional sedatives (if required) to ensure SBS –2
to –3 to prevent awareness during neuromuscular blockade.
Concurrent dexmedetomidine infusion was continued during
this period. Once there was no need for further neuromuscular
blockade, sedative management continued as per protocol.
Agitation (SBS > +1) was managed by increasing the pri-
mary sedative agent. Persistent agitation was then managed by
the addition of second-line agents (such as propofol, ketamine,
chloral hydrate, phenobarbital, and antihistamines) at the dis-
cretion of the treating physician. In refractory agitation, ben-
zodiazepines or dexmedetomidine use was permitted in both
groups. All other routine care, including ventilation manage-
ment and weaning, cardiovascular support and monitoring,
was performed using local unit protocols.
Pain and sedation (using SBS) were assessed by the
bedside nurse every four hours or more frequently if re-
quired. Withdrawal was assessed daily using the Withdrawal
Assessment Tool-1 (WAT-1) (25, 26) after 72 hours following
randomization or when sedation was being weaned. Patients
were assessed daily for delirium if SBS greater than or equal
to –1, using Preschool Confusion Assessment Method for the
ICU if 6 months to 5 years old (27) or Pediatric Confusion
Assessment Method for ICU if greater than 5 years old (28).
Intervention Arm—(Dexmedetomidine)
Following randomization, dexmedetomidine was commenced
as the primary sedative agent at 1.0 µg/kg/hr without a load-
ing dose and titrated to achieve target sedation up to an age-
dependent maximum dose (29, 30) (Supplemental Fig. 1,
Supplemental Digital Content 2, http://links.lww.com/PCC/
B438; legend, Supplemental Digital Content 4, http://links.
lww.com/PCC/B440).
Dexmedetomidine infusion was continued until sedation was
no longer required or to a maximum of 14 days after enrollment.

Supplemental sedative agents such as propofol (maximum
dose 4 mg/kg/hr, maximum duration 24 hr), ketamine, chloral
hydrate, sedating antihistamines, and phenobarbital according
to physician preference were used if dexmedetomidine at the
maximum allowable and tolerable dose did not provide suffi-
cient sedation.
Benzodiazepine use was permitted only for salvage treat-
ment of refractory agitation. Clonidine was prohibited as a
sedative agent with use reserved for management of suspected
dexmedetomidine withdrawal (after cessation for 96 hr).
Usual Care Arm
The primary sedative agent was at the discretion of the treat-
ing clinician, given by bolus dose or infusion (excluding dex-
medetomidine or any other alpha-2 agonist) titrated to target
sedation range. Sedative agents could include propofol (max-
imum dose 4 mg/kg/hr, maximum duration 24 hr), benzodiaz-
epines, chloral hydrate, ketamine, and barbiturates, guided by
individual unit practice. Clonidine was used only as a supple-
mental (rather than primary) sedative in this group.
Dexmedetomidine could be used at the discretion of
the treating intensivist if the target sedation range was not
achieved despite maximum titration of conventional sedative
agents (except when clonidine had been used).
Outcome Measures
The primary outcome measure was the percentage of sedation
scores in the target light sedation range (SBS –1 to +1) over the
first 48 hours of sedation in intensive care.
Safety outcomes were drug withdrawal (defined as WAT-1
score > 3) (25, 26), unplanned extubation and reintubation,
loss of vascular cannulae, and adverse events including hypo-
tension and bradycardia (defined as heart rate or blood pres-
sure more than two sds below mean for age) (23).
Feasibility outcomes were the proportion of screened and
eligible patients who were recruited, time from eligibility to
randomization, compliance with study protocol, and propor-
tion of patients who were intubated for longer than 24 hours
and loss to follow-up at 90 days.
Additional clinical outcome measures included the per-
centage of sedation scores in the target light sedation range in
the first 24 hours, the proportion of daily sedation score assess-
ments in SBS categories –2 to –3 (deep sedation), –1 to +1
(light sedation) and agitation (+2), daily cumulative weight-
adjusted doses of IV sedative agents and opioids given, occur-
rence rate of delirium, the duration of mechanical ventilation,
intensive care and hospital length of stay, and vital status at
hospital discharge and after 90 days of follow-up.
Statistical Analysis
The primary outcome was the difference in proportion of mea-
surements in the target light sedation range in the first 48 hours
in each arm. The main efficacy outcomes included the difference
in the number of patients receiving the primary sedative agents,
number of days, and cumulative doses of each agent. Feasibility
outcomes included time to randomization and time to achieve
Pediatric Critical Care Medicine www.pccmjournal.org e733
Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
Online Clinical Investigations
light sedation. A sample size of 60 patients was estimated to pro-
vide over 700 SBS assessments in the first 48 hours and 3,600
sedation hours to allow meaningful assessment of efficacy and
safety. All analyses were performed on an intention to treat prin-
ciple. Data were collected for 14 days or until ICU discharge.
Data were presented as percentages and numbers, medians with
interquartile ranges (IQRs), or means with sd. Two-sample Wil-
coxon rank-sum (Mann-Whitney U) tests were used to compare
subgroups. Two-sample t tests were used to compare normally
distributed variables, and chi-square tests were used to compare
categorical variables between the intervention and standard
treatment arms. A two-sample test of proportions was used to
compare the proportion of children achieving target sedation
between treatment arms. The difference in proportions was cal-
culated with odds ratios and 95% CIs. A p value of less than 0.05
were considered statistically significant. To account for within-
patient correlation for repeated assessments, comparisons have
been made with generalized linear modeling for repeated meas-
ures using a binomial distribution.
Time to randomization was the time between eligibility (in-
tubation) and randomization. All drug dosages were adjusted
for weight. All statistical analyses were conducted using Stata
(Version 15.0; StataCorp, College Station, TX).
RESULTS
Study Participants
The study was conducted over an 18-month period from Jan-
uary 2015 to July 2016. There were 60 children included; 29
were randomized to the dexmedetomidine arm and 31 to the
usual care arm.
(Supplemental Fig. 2, Supplemental Digital Content 3,
http://links.lww.com/PCC/B439; legend, Supplemental Digital
Content 4, http://links.lww.com/PCC/B440)
Baseline demographic characteristics are shown in Table 1.
The median age was higher in the dexmedetomidine arm (16 mo
[IQR, 4–30 mo]) compared with the usual care arm (3 mo [IQR,
1–13 mo) (p = 0.02). There were no other baseline imbalances.
Primary Outcome. During the first 48 hours of sedation
after randomization, 229 of 325 (71%) of SBS measurements
were in the light sedation range in the dexmedetomidine arm
compared with 181 of 311 (58%) in the usual care arm (odds
ratio, 2.20; 95% CI, 1.03–4.72; p = 0.04). During the first 24
hours, 66 of 103 (64%) of SBS measurements were in the light
sedation range in the dexmedetomidine arm compared with 48
of 116 (41%) in the usual care arm (odds ratio, 2.5; 95% CI, 9.8–
50.3%; p < 0.001). Time to achieve light sedation was shorter
with dexmedetomidine (median, 5.0  hr; IQR, 2.6–8.5  hr)
compared with usual care (9.0; 6.6–13.8; p = 0.02).
The distribution of SBS scores for each study arm over the
first 24 and 48 hours are shown in Figure 1.
Clinical and Safety Outcomes. Feasibility, safety, and clin-
ical outcomes including median duration of ventilation, length
of ICU stay, and hospital stay are shown in Table 2.
There were eight episodes of bradycardia (in seven patients)
in the dexmedetomidine arm, six were classified as mild with no
 Erickson et al

TABLE 1.Baseline Characteristics and arm compared with a median (IQR) of 3.0 (1.0–7.0) in the
Patients Demographics usual care arm (p = 0.24).
There was very high compliance with the protocol with only
Dexmedetomidine Usual Care four protocol violations reported (one patient given dexme-
Patient Characteristics (n = 29) (n = 28)
detomidine prior to other sedatives in the usual care arm and
Age, mo, median (IQR) 16 (4–30) 3 (1–13) three subjects given midazolam prior to other sedatives in the
16 (55) 16 (57)
dexmedetomidine arm).
Gender, male, n (%)
There were 56 of 60 children (93%) ventilated and sedated
Weight, kg, median (IQR) 9.15 (5–14) 5.65 (3.7–9.4) for more than 24 hours. One patient lost to follow-up.
Nonoperative, n (%) 22 (76) 23 (82)
Sedative Medications
Pre admission cardiac 7 (24) 5 (18)
surgery, n (%) The sedation protocol was successfully adhered to with 28 of 29
children (96.5%) in the dexmedetomidine arm receiving dexme-
ICU admission source, n (%) detomidine compared with two of 28 children (7.1%) in usual
  Operating theater/recovery 11 (38) 8 (29) care (p < 0.0001). Midazolam was used more frequently in usual
  Emergency department 2 (7) 6 (21) care (26/28 [92.8%]) compared with the dexmedetomidine arm
(11/29 [37.9%]) (p < 0.0001). There were no significant differ-
 Ward 4 (14) 4 (14)
ences between the groups in the proportion of children receiving
  Other ICU/neonatal ICU 1 (3) 0 (0) propofol, ketamine, morphine, or fentanyl (Table 3).
same hospital Apart from dexmedetomidine and midazolam, there were
  Direct ICU admission 11 (38) 10 (36) no significant differences in the cumulative doses of other IV
  Elective admission 8 (28) 5 (18)
sedatives or opioids over the study period (Table 3) or the first
48 hours (Fig. 2A).
Diagnostic group, n (%) Children in the dexmedetomidine arm received propofol
  Cardiovascular (incl 7 (24) 6 (21) on more sedation days (48/165 [29%]) compared with usual
postoperative) care (22/144 [15%] sedation days; p = 0.004) and ketamine on
 Respiratory 11 (38) 13 (46) more sedation days (28/165 [17%]) compared with usual care
(1/144 [0.6%]) sedation days; p < 0.001).
 Postoperative 6 (21) 3 (11)
Daily exposure (number of subjects) to IV sedatives and
 Neurologic 1 (3) 0 (0) opioids over the first 7 days are shown in Figure 2B.
 Trauma 0 (0) 1 (4)
 Miscellaneous 4 (14) 5 (18) DISCUSSION
Children sedated with dexmedetomidine as the primary sed-
Pediatric Index of Mortality 0.032 (0.034) 0.035 (0.065)
3 risk of death, mean (sd) ative achieved target sedation levels more often in the first 48
hours following initiation of mechanical ventilation when com-
IQR = interquartile range, n = number of children (percentages).
All p were > 0.05 except for age (p = 0. 02). pared with usual care. Children treated with dexmedetomidine
were also more likely to achieve target sedation levels in the first
intervention needed, one was classified as moderate requiring 24 hours, and time from randomization to achieve target seda-
cessation of dexmedetomidine. There were five episodes of mild tion levels was shorter. Children in the dexmedetomidine arm
hypotension (in three patients) in the dexmedetomidine arm, were less likely to receive midazolam, although almost a third
none requiring intervention. These events occurred across all age of these children required the addition of a second-line seda-
ranges (mean age, 27 mo). There was one severe adverse event: a tive during the first 48 hours to achieve target sedation levels
2.5-year-old patient in the dexmedetomidine arm required a brief despite the administration of maximum age-specific doses of
period of cardiopulmonary resuscitation for bradycardia during dexmedetomidine. Dexmedetomidine is known to have both
an airway intervention. This was classified as possibly related to sedative and analgesic properties (31) but not amnestic proper-
the study drug (independent data monitoring and safety commit- ties as described for midazolam. Despite the use of higher age-
tee review). There was no difference in vasopressor use between appropriate maximum doses than previously suggested (based
the groups (p = 0.4). There was no difference in the occurrence on pharmacokinetic/pharmacodynamic [PKPD] analysis)
rate of drug withdrawal or delirium between the groups. in this study (28, 29), it is unclear whether the need for addi-
Feasibility Outcomes. The number of children eligible for tional sedatives (fentanyl, propofol, and ketamine) in a third of
randomization was 254, of which 60 patients (23.6%) were children was due to inadequate sedative, analgesic or amnestic
randomized. The consent rate was 58% (103 families were properties, or inadequate dosing of dexmedetomidine. It is also
approached for consent). unclear whether use of higher dexmedetomidine doses would
Randomization occurred within a median (IQR) of 6.0 be limited by adverse effects, as shown in a minority of patients
hours (2.0–9.0 hr) after intubation in the dexmedetomidine receiving dexmedetomidine in this study.

e734 www.pccmjournal.org September 2020 • Volume 21 • Number 9

Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Online Clinical Investigations

other adverse events such as

accidental removal of airway
or vascular invasive devices
were seen. Data from other
studies suggest that seda-
tive choice may impact on
a pediatric delirium (32).
No differences between the
groups with respect to drug
withdrawal or delirium were
observed in our study, al-
though delirium data were
limited by more than 50% of
children excluded from de-
lirium assessment as they were
less than 6 months old. Hence,
our study cannot make any
Figure 1. Distribution of State Behavioral Scale (SBS) scores over the first 24 and 48 hr in the confident conclusions about
dexmedetomidine arm versus usual care. Values are expressed as percentage (%) of total daily assessments.
the relative occurrence rate of
At the doses used in this study, all but one episode of hy- delirium with dexmedetomidine and other sedatives.
potension or bradycardia in the dexmedetomidine arm were Three previous randomized controlled trials in children
self-limiting and required no specific intervention and overall have compared dexmedetomidine sedation to other agents.
vasopressor requirements were similar between study arms. Tobias and Berkenbosch (33) demonstrated a reduction in
One patient in the dexmedetomidine arm required a brief pe- rescue morphine requirements in children receiving dexme-
riod of cardiac massage for bradycardia during an airway in- detomidine compared with midazolam. Aydogan et al (34)
tervention, and it is possible that dexmedetomidine may have showed that lighter sedation, reduced pain scores, and reduced
contributed to the severity of bradycardia in this case. No fentanyl consumption was achieved with dexmedetomidine

Clinical Outcome Differences Between Those Children Given Dexmedetomidine

TABLE 2.
and Those Managed With Usual Care
Dexmedetomidine, Usual Care,
Clinical Outcomes n = 29 n = 28 p

Time to randomization, hr, median (IQR) 6 (2–9) 3 (1–7) 0.2

Neuromuscular blockade, n (%) 20 (69.0) 17 (60.7) 0.4
Physical restraints, n (%) 10 (34.5) 7 (25.0) 0.4
Vasopressor, n (%) 9 (31.0) 12 (42.9) 0.4
Accidental device removal, n (%) 0 0 Not applicable
Renal replacement therapy, n (%) 0 (0.0) 4 (2.8) 0.2
Bradycardia, n (%) 9 (31.0) 0 (0.0) 0.002
Hypotension, n (%) 5 (17.2) 0 (0.0) 0.05
Withdrawal Assessment Tool-1 > 3, n (%) 5 (17.2) 3 (10.7) 0.5
Preschool Confusion Assessment Method for the ICU/Pediatric 3/18 (16.7) 1/10 (10.0) 0.2
Confusion Assessment Method for ICU positivea, n (%)
Intubation duration, hr, median (IQR) 69.5 (31.2–111.5) 57.3 (43.4–82.5) 0.6
ICU LOS, hr, median (IQR) 115.0 (71.0–219.8) 90.5 (69.1–185.9) 0.5
Hospital LOS, hr, median (IQR) 332.2 (222.4–416.9) 286.5 (163.4–436.9) 0.4
Mortality in ICU, n (%) 0 (0.0) 1 (3.6) 0.5
IQR = interquartile range, LOS = length of stay, n = number of children (percentages).
Twenty-nine points excluded from having assessments as under 6 mo old (11 from dexmedetomidine and 18 from usual care).
a

Although bradycardia was more common in those managed with dexmedetomidine, there was weak evidence for an increased occurrence rate of hypotension.

Pediatric Critical Care Medicine www.pccmjournal.org e735

Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Erickson et al

TABLE 3. Cumulative IV Sedative and Opioid per/kg Body Weight and Duration of
Treatment
Dexmedetomidine, Usual Care,
Drugs Given Dexmedetomidine Usual Care p n = 29, n (%) n = 28, n (%) p

Dexmedetomidine (μg) 47.8 (35.87–70.97) 3.51 (2.96–4.05) 0.005 28 (96.6) 2 (7.1) < 0.0001
  Days on dexmedetomidine 3 (2–5) 0 (0–0) < 0.0001
Midazolam (mg) 0.17 (0.09–0.56) 2.72 (1.16–5.10) 0.002 11 (37.9) 26 (92.9) < 0.0001
  Days on midazolam 0 (0–1) 3 (2–4) < 0.0001
Propofol (mg) 58 (15.65–67.53) 15.42 (8.50–49.25) 0.3 18 (62.1) 11 (39.3) 0.1
  Days on propofol 1 (0–2) 0 (0–1.25) 0.06
Ketamine (mg) 0.84 (0.36–6.21) 0.12 (0.12–0.12) 0.4 8 (27.6) 1 (3.6) 0.03
  Days on ketamine 0 (0–1) 0 (0–0) 0.01
Morphine (mg) 1.90 (1.12–3.96) 1.55 (1.11–2.34) 0.3 26 (89.7) 27 (96.4) 0.6
  Days on morphine 3 (2–5) 3 (2–4.25) 0.7
Fentanyl (μg) 42.2 (25.73–83.54) 21.49 (6.55–53.42) 0.4 16 (55.2) 8 (28.6) 0.06
  Days on fentanyl 1 (0–2) 0 (0–1) 0.03
Cumulative doses shown as median (interquartile range).

compared with midazolam following scoliosis surgery. Prasad
et al (35) showed a shorter time to extubation after cessation
of dexmedetomidine compared with fentanyl postcardiac sur-
gery. Other data concerning pediatric sedation comprises case
series, case control studies, and surveys (36–40). Our study is
notable for inclusion of a wide range infants and children in
multiple centers across a region. Our findings are consistent
with the study by Aydogan et al (34) in that lighter sedation
was achieved with dexmedetomidine, In contrast to the study
by Tobias and Berkenbosch (33), there was no opioid-sparing
effect and no difference in time to extubation as shown in the
study by Prasad et al (35).
This pilot study was designed to test the feasibility of a
sedation strategy using dexmedetomidine as the primary
sedative when compared with usual care. Our results demon-
strated that a strategy using dexmedetomidine was feasible,
practical, and safe. Our study was not blinded as it was felt
that blinding in a process of care sedation study would be
difficult and a potential safety risk, and we acknowledge the
increased potential for bias in our results. Although the use
of sedative agents in the usual care arm was not protocolized
as such, other conduct including management of sedation,
withdrawal and delirium scores in both arms was identical,
as was the protocolized use of sedation targets. The dosing of
dexmedetomidine was necessarily prescriptive as it was a rel-
atively new drug, it was being used off-label (not approved
by the regulatory body, the Australian Therapeutic Goods
Administration for use in children). We were using higher
doses in some age groups, based on PKPD analysis (28, 29),
and for longer periods than previously described. Curley et
al (11), in the Randomized Evaluation of Sedation Titration
for Respiratory Failure (RESTORE) trial, showed no benefit
on the duration of ventilation in a protocolized nursing se-
dation regimen. Nevertheless, protocolized care improved
achievement of sedation targets. Our study protocol com-
pared dexmedetomidine as the primary sedative to the usual
care group in which the primary sedative was at the discretion
of the treating physician. Although the approach to analgesia,
neuromuscular blockade, and sedation monitoring and tar-
geted sedation levels were identical between the groups, it is
possible that the protocolized dosing regimen used for dex-
medetomidine may have improved achievement of sedation
targets compared with the usual care group. Alternatively and
more likely, the choice of primary sedative or combination of
sedative agents were more important factors in achieving the
lighter sedation levels observed in our study. This is supported
by a post hoc analysis of the RESTORE trial by Grant et al
(41), which showed efficacy of dexmedetomidine as a single
sedative agent in noninvasively ventilated children.
Our trial was a centrally coordinated, collaborative study
with good protocol adherence and successful implementa-
tion of and the randomization and recruitment processes
by the study team. An important strength of our trial is the
early enrollment and commencement of dexmedetomidine
within hours of initiation of mechanical ventilation. Patients
were correctly predicted to require prolonged ventilation,
with 93% of patients randomized were ventilated for more
than 24 hours. Consent rate was high and study participants
were quickly randomized. However, almost 40% of eligible
children were missed, primarily due to the lack of availability
of a research coordinator, competing studies, or ineligibility
due to unit protocols (e.g., individual unit sedation pro-
tocol mandating clonidine infusion as primary sedative for
infants).

e736 www.pccmjournal.org September 2020 • Volume 21 • Number 9

Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Online Clinical Investigations

investigators commented that

the disappointing recruitment
rate reflected a reluctance of
families to provide consent
once sedation had been es-
tablished and a reluctance of
clinicians to recruit unstable
patients. We estimated that a
phase III trial comparing dex-
medetomidine to standard
sedation with a primary out-
come of reduction in duration
of ventilation would require
approximately 600 patients.
Based on our recruitment rate
for this pilot study, recruit-
ment would take many years;
however, we anticipate recruit-
ment would be improved by
better research infrastructure
and resources and by minimiz-
ing exclusion criteria, in par-
ticular those with acute and
chronic brain injury, given the
increased use of dexmedeto-
midine in this patient group in
clinical practice.
This pilot study showed
that randomization of venti-
lated children in intensive care
to alternative sedation arms is
feasible and that a treatment
algorithm with dexmedeto-
midine as the primary seda-
tive agent may be superior to
achieve more rapid safe seda-
tion levels. Although a collab-
orative, binational, multicenter
approach was achievable in this
pilot study, adequate recruit-
ment to a definitive randomized
controlled trial comparing the
efficacy and safety of dexme-
detomidine as the primary sed-
ative, particularly its effect on
Figure 2. Comparison of IV sedative and opioid use between dexmedetomidine and usual care groups.
A, Cumulative total IV sedative and opioid given over the first 48 hr comparing dexmedetomidine to usual care.
patient-centered outcomes, will
All cumulative doses expressed per kg body weight. Median cumulative dose expressed by black bars. likely require a multinational
B, Exposure to IV sedative and opioid drugs over the first 7 d comparing dexmedetomidine to usual care. approach. Notwithstanding
Values are expressed as the total number of children given each drug on each day.
the varied and ever-changing
approaches to sedation in
Randomized trials in pediatric critical care sedation have PICU, and difficulties in gaining consensus on study design,
proven difficult, mainly due to recruitment issues. The mul- a large randomized trial to confirm the main findings of this
ticenter European clonidine study (42) recruited 200 patients pilot study is essential to support evidence-based sedation pro-
in over 5 years, and the U.K. clonidine trial (43) recruited 129 tocols which are safe and effective. Such a study would provide a
patients of a planned 1,000. Both trials were unable to show unique opportunity to understand optimal sedation practice in
positive outcomes due to inadequate sample size. The trial improving long-term outcomes for critically ill children.

Pediatric Critical Care Medicine www.pccmjournal.org e737

Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Erickson et al
The Baby SPICE Investigators and the Australian and New Zealand In-
tensive Care Society Paediatric Study Group (ANZICS PSG) are listed
in Appendix 1.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http:/journals.lww.com/
pccmjournal).
The study was aided by Perth Children’s Hospital Foundation Grant and
Hospira (Pfizer; unrestricted study grant).
Drs. Millar’s and Long’s institution received funding from Princess Mar-
garet Hospital Foundation. Drs. Millar’s, Festa’s, Shehabi’s, and Long’s
institutions received funding from Pfizer (Hospira). Dr. Festa disclosed
off-label product use of dexmedetomidine infusion. Dr. Shehabi received
competitive grant funding from the National Health and Medical Research
Council of Australia. The remaining authors have disclosed that they do
not have any potential conflicts of interest.
For information regarding this article, E-mail: simon.erickson@health.
wa.gov.au
REFERENCES
1. Playfor S, Jenkins I, Boyles C, et al; United Kingdom Paediatric
Intensive Care Society Sedation; Analgesia and Neuromuscular
Blockade Working Group: Consensus guidelines on sedation
and analgesia in critically ill children. Intensive Care Med 2006;
32:1125–1136
2. Playfor SD, Thomas DA, Choonara I: Sedation and neuromuscular
blockade in paediatric intensive care: A review of current practice in
the UK. Paediatr Anaesth 2003; 13:147–151
3. Rhoney DH, Murry KR: National survey on the use of sedatives and
neuromuscular blocking agents in the pediatric intensive care unit.
Pediatr Crit Care Med 2002; 3:129–133
4. Marx CM, Rosenberg DI, Ambuel B, et al: Pediatric intensive care
sedation: Survey of fellowship training programs. Pediatrics 1993;
91:369–378
5. Twite MD, Rashid A, Zuk J, et al: Sedation, analgesia, and neuromus-
cular blockade in the pediatric intensive care unit: Survey of fellow-
ship training programs. Pediatr Crit Care Med 2004; 5:521–532
6. Vet NJ, Ista E, de Wildt SN, et al: Optimal sedation in pediatric inten-
sive care patients: A systematic review. Intensive Care Med 2013;
39:1524–1534
7. Long D, Erickson S; for the ANZICS Paediatric Study Group: Baby
Spice: Sedation practice in paediatric intensive care evaluation in
Australia and New Zealand. Pediatr Crit Care Med 2014; 15:19
(abstract)
8. Poh YN, Poh PF, Buang SN, et al: Sedation guidelines, protocols,
and algorithms in PICUs: A systematic review. Pediatr Crit Care Med
2014; 15:885–892
9. Keogh SJ, Long DA, Horn DV: Practice guidelines for sedation and
analgesia management of critically ill children: A pilot study evaluat-
ing guideline impact and feasibility in the PICU. BMJ Open 2015;
5:e006428
10. Gaillard-Le Roux B, Liet J-M, Bourgoin P, et al: Implementation of a
nurse-driven sedation protocol in a PICU decreases daily doses of
midazolam. Pediatr Critical Care Med 2017; 18:e9–e17
11. Curley MA, Wypij D, Watson RS, et al; RESTORE Study Investigators
and the Pediatric Acute Lung Injury and Sepsis Investigators Network:
Protocolized sedation vs usual care in pediatric patients mechanically
ventilated for acute respiratory failure: A randomized clinical trial.
JAMA 2015; 313:379–389
12. Kudchadkar SR, Yaster M, Punjabi NM: Sedation, sleep promotion,
and delirium screening practices in the care of mechanically venti-
lated children: A wake-up call for the pediatric critical care commu-
nity*. Crit Care Med 2014; 42:1592–1600
13. Garcia Guerra G, Joffe AR, Cave D, et al; Sedation Withdrawal and
Analgesia Team, and the Canadian Critical Care Trials Group: Survey
of sedation and analgesia practice among Canadian pediatric critical
care physicians. Pediatr Crit Care Med 2016; 17:823–830
e738 www.pccmjournal.org September 2020 • Volume 21 • Number 9
Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
14. Taffarel P, Bonetto G, Jorro Barón F, et al: Sedation and analgesia in
patients on mechanical ventilation in pediatric intensive care units in
Argentina. Arch Argent Pediatr 2018; 116:e196–e203
15. Young C, Jevtovic-Todorovic V, Qin YQ, et al: Potential of ketamine
and midazolam, individually or in combination, to induce apoptotic
neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;
146:189–197
16. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al: Early exposure to
common anesthetic agents causes widespread neurodegeneration in
the developing rat brain and persistent learning deficits. J Neurosci
2003; 23:876–882
17. Colville G, Kerry S, Pierce C: Children’s factual and delusional memo-
ries of intensive care. Am J Respir Crit Care Med 2008; 177:976–982
18. Mody K, Kaur S, Mauer EA, et al: Benzodiazepines and development
of delirium in critically ill children: Estimating the causal effect. Crit
Care Med 2018; 46:1486–1491
19. Amigoni A, Vettore E, Brugnolaro V, et al: High doses of benzodiaze-
pine predict analgesic and sedative drug withdrawal syndrome in pae-
diatric intensive care patients. Acta Paediatr 2014; 103:e538–e543
20. Best KM, Boullata JI, Curley MA: Risk factors associated with iatro-
genic opioid and benzodiazepine withdrawal in critically ill pediatric
patients: A systematic review and conceptual model. Pediatr Crit
Care Med 2015; 16:175–183
21. Traube C, Silver G, Reeder RW, et al: Pediatric delirium in critically-
ill children: An international point prevalence study. Crit Care Med
2017; 45:584–590
22. Hayden JC, Breatnach C, Doherty DR, et al: Efficacy of α2-agonists
for sedation in pediatric critical care: A systematic review. Pediatr Crit
Care Med 2016; 17:e66–e75
23. Shann F: Drug Doses. 17th Edition. Melbourne, VIC, Australia,
Collective, 2017
24. Curley MA, Harris SK, Fraser KA, et al: State Behavioral Scale (SBS)
a sedation assessment instrument for infants and young children sup-
ported on mechanical ventilation. Pediatr Critical Care Med 2006;
7:107–114
25. Franck LS, Harris SK, Soetenga DJ, et al: The Withdrawal Assessment
Tool-1 (WAT-1): An assessment instrument for monitoring opioid and
benzodiazepine withdrawal symptoms in pediatric patients. Pediatr
Crit Care Med 2008; 9:573–580
26. Franck LS, Scoppettuolo LA, Wypij D, et al: Validity and generalizability
of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic
withdrawal syndrome in pediatric patients. Pain 2012; 153:142–148
27. Smith HA, Gangopadhyay M, Goben CM, et al: The Preschool
Confusion Assessment Method for the ICU (psCAM-ICU): Valid and
reliable delirium monitoring for critically ill infants and children. Crit
Care Med 2016; 44:592–600
28. Smith HA, Boyd J, Fuchs DC, et al: Diagnosing delirium in critically ill
children: Validity and reliability of the pediatric confusion assessment
method for the intensive care unit. Crit Care Med 2011; 39:150–157
29. Potts AL, Anderson BJ, Warman GR, et al: Dexmedetomidine phar-
macokinetics in pediatric intensive care–a pooled analysis. Paediatric
Anaesth 2009; 19:1119–1129
30. Potts AL, Warman GR, Anderson BJ: Dexmedetomidine disposition in
children: A population analysis. Paediatr Anaesth 2008; 18:722–730
31. Gertler R, Brown HC, Mitchell DH, et al: Dexmedetomidine: A
novel sedative-analgesic agent. Proc (Bayl Univ Med Cent) 2001;
14:13–21
32. Smith HAB, Gangopadhyay M, Goben CM, et al: Delirium and benzo-
diazepines associated with prolonged ICU stay in critically ill infants
and young children. Crit Care Med 2017; 45:1427–1435
33. Tobias JD, Berkenbosch JW: Sedation during mechanical ventilation
in infants and children: Dexmedetomidine versus midazolam. South
Med J 2004; 97:451–455
34. Aydogan MS, Korkmaz MF, Ozgül U, et al: Pain, fentanyl consumption,
and delirium in adolescents after scoliosis surgery: Dexmedetomidine
vs midazolam. Paediatr Anaesth 2013; 23:446–452
35. Prasad SR, Simha PP, Jagadeesh AM: Comparative study between
dexmedetomidine and fentanyl for sedation during mechanical venti-
lation in post-operative paediatric cardiac surgical patients. Indian J
Anaesth 2012; 56:547–552

36. Czaja AS, Zimmerman JJ: The use of dexmedetomidine in critically ill
children. Pediatr Crit Care Med 2009; 10:381–386
37. Chrysostomou C, Di Filippo S, Manrique AM, et al: Use of dexme-
detomidine in children after cardiac and thoracic surgery. Pediatr Crit
Care Med 2006; 7:126–131
38. Hosokawa K, Shime N, Kato Y, et al: Dexmedetomidine sedation in
children after cardiac surgery. Pediatr Crit Care Med 2010; 11:39–43
39. Bejian S, Valasek C, Nigro JJ, et al: Prolonged use of dexmedeto-
midine in the paediatric cardiothoracic intensive care unit. Cardiol
Young 2009; 19:98–104
40. Kleiber N, de Wildt SN, Cortina G, et al: A comparative analysis of
preemptive versus targeted sedation on cardiovascular stability after
high-risk cardiac surgery in infants. Pediatr Crit Care Med 2016;
17:321–331
APPENDIX 1. BABY SPICE INVESTIGATORS
AND THE AUSTRALIAN AND NEW ZEALAND
INTENSIVE CARE SOCIETY PAEDIATRIC
STUDY GROUP (ANZICS PSG)
The Baby SPICE Investigators are as follows: Brian Anderson,
Claire Sherring (Starship Hospital, Auckland, New Zealand),
Debbie Long, Anthony Slater (Queensland Children’s Hospital,
Brisbane, QLD, Australia), Johnny Millar, Carmel Delzoppo
(Royal Children’s Hospital, Melbourne, VIC, Australia), Marino
Festa (Children’s Hospital at Westmead, Westmead, NSW, Aus-
tralia), Mary Lou Morritt, Janelle Young, John Awad (Sydney
Children’s Hospital, Sydney, NSW, Australia), Simon Erickson,
Sara Shea, Samantha Barr (Perth Children’s Hospital, Perth,
WA, Australia), Belinda Howe (Australian New Zealand Inten-
siveCare Research Centre, School of Public Health and Preven-
tive Medicine, Monash University, Melbourne, VIC, Australia),
and Elizabeth MacKinnon (Statistics-Telethon Kids Institute:
Child and Adolescent Health Service, Perth, WA, Australia).
Pediatric Critical Care Medicine www.pccmjournal.org e739
Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
Online Clinical Investigations
41. Grant MJ, Schneider JB, Asaro LA, et al; Randomized Evaluation
of Sedation Titration for Respiratory Failure Study Investigators:
Dexmedetomidine use in critically ill children with acute respiratory
failure. Pediatr Crit Care Med 2016; 17:1131–1141
42. Hünseler C, Balling G, Röhlig C, et al; Clonidine Study Group:
Continuous infusion of clonidine in ventilated newborns and
infants: A randomized controlled trial. Pediatr Crit Care Med 2014;
15:511–522
43. Wolf A, McKay A, Spowart C, et al: Prospective multicentre ran-
domised, double-blind, equivalence study comparing clonidine and
midazolam as intravenous sedative agents in critically ill children: The
SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric inten-
sive care Sedation) study. Health Technol Assess 2014; 18:1–212
The Australian and New Zealand Intensive Care So-
ciety Paediatric Study Group (ANZICS PSG) are as fol-
lows: Anusha Ganeshalingam, Claire Sherring, Starship
Children’s Hospital, Auckland, New Zealand; Simon Erick-
son, Samantha Barr, Perth Children`s Hospital, Perth, Aus-
tralia; Andreas Schibler, Debbie Long, Luregn Schlapbach
(Chair), Jan Alexander (ANZPIC registry), Queensland
Children’s Hospital, Brisbane, Australia; Shane George,
Gold Coast University Hospital; Gary Williams, Vicky
Smith, Sydney Children’s Hospital, Randwick, Australia;
Warwick Butt, Carmel Delzoppo, Johnny Millar (ANZPIC
registry lead), Ben Gelbart (Vice Chair), Royal Children’s
Hospital, Melbourne, Australia; Felix Oberender, Monash
Children`s Hospital, Melbourne, Australia; Subodh Ganu,
Georgia Letton, Women’s and Children’s Hospital, Ad-
elaide, Australia; Jonathan Egan, Gail Harper, Marino
Festa (Past Chair), Westmead Children’s Hospital, Sydney,
Australia.