Cochrane Database of Systematic Reviews

Dexmedetomidine for analgesia and sedation in newborn

infants receiving mechanical ventilation (Protocol)

Ibrahim M, Jones LJ, Lai NM, Tan K

Ibrahim M, Jones LJ, Lai NM, Tan K.

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation.
Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD012361.
DOI: 10.1002/14651858.CD012361.

www.cochranelibrary.com

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) i
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Dexmedetomidine for analgesia and sedation in newborn

infants receiving mechanical ventilation

Masitah Ibrahim1 , Lisa J Jones2 , Nai Ming Lai3 , Kenneth Tan4

1 Monash Newborn, Monash Medical Centre, Clayton, Melbourne, Australia. 2 Central Clinical School, Discipline of Obstetrics,
Gynaecology and Neonatology, University of Sydney, Sydney, Australia. 3 School of Medicine, Taylor’s University, Subang Jaya, Malaysia.
4
Department of Paediatrics, Monash University, Melbourne, Australia

Contact address: Kenneth Tan, Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, Victoria, VIC
3168, Australia. kenneth.tan@monash.edu. kenneth.tan@monashhealth.org.

Editorial group: Cochrane Neonatal Group.

Publication status and date: New, published in Issue 9, 2016.

Citation: Ibrahim M, Jones LJ, Lai NM, Tan K. Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical
ventilation. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD012361. DOI: 10.1002/14651858.CD012361.

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the overall effectiveness and safety of dexmedetomidine for sedation and analgesia in newborn infants receiving mechanical
ventilation compared with other non-opioids, opioids or placebo.

We will perform subgroup analyses according to method of dexmedetomidine administration; dose of dexmedetomidine; age of
initiation of dexmedetomidine; indication for mechanical ventilation; gestational age; and duration of treatment.

BACKGROUND 2014), permanent neuroanatomic abnormalities (Ranger 2014),

emotional and behavioural abnormalities (Doesburg 2013), and
learning disabilities (Vinall 2014). Recommendations are in place
Description of the condition to aggressively prevent and treat pain in newborn infants. How-
Mechanical ventilation is widely used to support newborn infants ever, the routine use of continuous infusions of analgesics and
in neonatal intensive care units (NICU). Approximately 18% of sedatives such as morphine, fentanyl, midazolam, or ketamine in
newborns admitted to NICU, and almost all preterm newborns chronically ventilated preterm infants is not recommended be-
delivered at less than 27 weeks of gestation who survive to hospital cause of concern about short-term adverse effects and lack of long-
discharge require mechanical ventilation (Wilson 2000). Among term outcome data (AAP 2006).
adults capable of self-reporting, mechanical ventilation has been
documented as a significant source of pain and discomfort (Gelinas
2004). Newborn infants, including those born extremely preterm, Description of the intervention
have the capacity to perceive pain. Repeated and chronic exposure
to pain is a major source of distress and is associated with delete- Dexmedetomidine is a selective alpha -adrenergic agonist which
rious consequences which include altered pain sensitivity (Morin is structurally similar to clonidine but has more than 800 times
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) 1
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

greater affinity for alpha -receptors over alpha -receptors. The
sedative and anxiolytic effects of dexmedetomidine result primar-
ily from stimulation of alpha -adrenergic receptors in the locus
coeruleus of the brainstem, leading to a reduction of central sym-
pathetic output and thus greater firing of inhibitory neurons. The
presence of dexmedetomidine at alpha -adrenergic receptors in
the dorsal horn of the spinal cord modulates release of substance
P and produces its analgesic effects (Buck 2010).
Current neonatal drug regimens used to achieve sedation and anal-
gesia generally consist of combinations of benzodiazepines and
opioids. Concerns over these drugs include side effects such as
tolerance, withdrawal, paradoxical agitation, and respiratory de-
pression (Hall 2007). Furthermore, benzodiazepines, opioids, and
N-methyl-D-aspartic acid (NMDA) receptor agonists such as ke-
tamine, have been demonstrated to induce apoptotic neurodegen-
eration in neonatal animals (Young 2005).
Dexmedetomidine has been approved by the United States Food
and Drug Administration since 1999 for sedation in people re-
quiring intubation and mechanical ventilation in an intensive care
setting, and prior to surgery and other procedures in people not
requiring intubation (Hospira 2014). Potentially serious adverse
effects include bradycardia and sinus arrest which have been ob-
served in young, healthy adult volunteers with high vagal tone, and
with rapid intravenous or bolus administration (Hospira 2014).
Both hypotension and transient hypertension have been reported
with its use, the latter observed primarily during administration of
its loading dose, and is related to the stimulation of post-synaptic
α 2B -adrenergic receptors that leads to an initial peripheral vaso-
constriction (Bloor 1992). The most common treatment-emer-
gent adverse effects include hypotension, bradycardia, and dry
mouth, affecting greater than 2% of adults receiving dexmedeto-
midine for sedation in an intensive care unit (Hospira 2014).
Dexmedetomidine provides both sedation and analgesia when
used alone, and has benzodiazepine- and opioid-sparing proper-
ties when used in combination with more conventional agents
(Chrysostomou 2009). Randomized controlled trials evaluating
the effectiveness of dexmedetomidine use in adults have demon-
strated easy arousal without respiratory depression, shorter du-
ration of mechanical ventilation, less delirium, and less frequent
tachycardia and hypertension (Riker 2009; Jakob 2012). Preclini-
cal studies in developing animal brains have indicated a potentially
neuroprotective role for dexmedetomidine in preventing cortical
apoptosis induced by anaesthetic agents (Sanders 2008; Sanders
2010). Although not labelled for use in children less than 18
years of age (Hospira 2014), dexmedetomidine has recently been
demonstrated in a phase II/III, open-label, multi-centre safety,
efficacy, and pharmacokinetic study to be effective for sedating
preterm and full-term neonates, and is well tolerated without se-
rious adverse events related to the drug, and no adverse events
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
or haemodynamic changes occurred that led to discontinuation
of the drug (Chrysostomou 2014). The study population con-
sisted of 42 intubated and mechanically ventilated neonates with
a gestational age of 28 to 44 weeks receiving dexmedetomidine
by continuous infusion for 6 to 24 hours at doses ranging from
0.05 to 0.2 µg/kg/hr. Three participants (7%) had a total of four
adverse effects related to dexmedetomidine, three of which were
assessed as definite i.e. diastolic hypotension in the preterm group,
and hypertension as well as significant agitation in the term and
post-term group. As the study was powered to evaluate efficacy,
results on safety should be considered with caution. Only short-
term outcomes were evaluated, and it is yet unknown whether
dexmedetomidine has any longer-term harmful effects for new-
born infants. In a retrospective chart review evaluating adverse ef-
fects of dexmedetomidine in neonates and older infants managed
at a tertiary paediatric referral centre, 27% of the study population
had at least one episode of hypotension. Bradycardia occurred less
frequently in neonates, but older infants were more likely to re-
ceive higher doses of dexmedetomidine and additional sedatives
(Estkowski 2015). Extra caution should be exercised during com-
mencement of therapy in children with congenital heart disease,
as hypotension and bradycardia are more common during the ini-
tial loading dose. This includes children with cardiomyopathy or
single-ventricle physiology, in whom negative chronotropic stress
response will have a significant effect on cardiac output (Tobias
2011).
How the intervention might work
Newborn infants appear to handle dexmedetomidine differently
from older children and adults. A pharmacokinetics study has
shown that there is a longer half-life in neonates, therefore it is pos-
sible that lower doses may be needed in order to achieve therapeu-
tic plasma levels of the drug (Chrysostomou 2014). Dexmedeto-
midine is extensively metabolized through hepatic processes, i.e.
through direct glucuronidation and the cytochrome P-450 sys-
tem. Immature hepatic function in preterm infants may con-
tribute to prolonged elimination half-life. Most of its metabolites
are excreted in the urine (95%) and faeces (4%). It is as yet un-
clear if these metabolites have any analgesic or sedative effects.
As dexmedetomidine has a very high affinity for protein bind-
ing (94%), there is little displacement from other commonly used
drugs in anaesthesia and intensive care like fentanyl, lignocaine,
theophylline and ketorolac (Gertler 2001).
Why it is important to do this review
Dexmedetomidine is not labelled for use in children and infants.
The off-label use of dexmedetomidine in neonatal intensive care
units is becoming increasingly common. However, its effective-
ness and safety profile as a sedative and analgesic in newborn in-
2
fants receiving mechanical ventilation has not been systematically
reviewed.
OBJECTIVES
To determine the overall effectiveness and safety of dexmedeto-
midine for sedation and analgesia in newborn infants receiving
mechanical ventilation compared with other non-opioids, opioids
or placebo.
We will perform subgroup analyses according to method of
dexmedetomidine administration; dose of dexmedetomidine; age
of initiation of dexmedetomidine; indication for mechanical ven-
tilation; gestational age; and duration of treatment.
METHODS
Criteria for considering studies for this review
Types of studies
Randomized and quasi-randomized controlled trials.
Types of participants
We will include all newborn infants (maximum postnatal age of
28 days after reaching postmenstrual age of 40 weeks’ gestation)
receiving mechanical ventilation via an endotracheal tube who re-
quire sedation and analgesia. We will exclude trials whose popula-
tions receive dexmedetomidine exclusively for procedural sedation
and analgesia. Trials including mixed populations (e.g. newborn
infants and children; mechanically ventilated and self-ventilating)
will be included if:
• the majority (at least 80%) of the study population meet
the systematic review inclusion criteria; or
• the trials report separate results for those participants
meeting the inclusion criteria.
Types of interventions
We will include all trials comparing dexmedetomidine alone
against other non-opioids, or opioids (e.g. morphine, fentanyl,
remifentanil), administered separately or in combination, and
placebo.
Non-opioids are defined as drugs that fall under the following
classes of medications which have been used to achieve sedation
and analgesia in newborn infants receiving mechanical ventilation.
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. N-methyl-D-aspartic acid (NMDA) receptor antagonists
e.g. ketamine.
2. γ -aminobutyric acid (GABA) receptor agonists:
benzodiazepines (e.g. midazolam, diazepam, lorazepam);
barbiturates (e.g. phenobarbitone, pentobarbitone).
3. Combined GABA receptor agonists and NMDA receptor
antagonists e.g. propofol.
There will be no restrictions based on method of administration,
dose, frequency, or duration of dexmedetomidine.
Primary comparisons will lump together all studies that have a
drug in the class.
Specific interventions and comparisons include:
1. dexmedetomidine vs. opioids;
2. dexmedetomidine vs. other non-opioids;
3. dexmedetomidine vs. opioid and/or non-opioid
combination; and
4. dexmedetomidine vs. placebo.
Types of outcome measures
Primary outcomes
1. Sedation assessed utilising tools or scales such as
COMFORT (Ista 2005) - which although is a paediatric critical
care tool, was validated in a population that included infants.
2. Analgesia assessed using validated pain scales with age-
appropriate behavioural measures and physiological parameters
such as the Neonatal Infant Pain Scale (NIPS) (Lawrence 1993),
Pain Assessment Tool (PAT) (Hodgkinson 1994), Premature
Infant Pain Profile (PIPP) (Stevens 1996), and the Premature
Infant Pain Profile-Revised (PIPP-R) (Gibbins 2014). See
Appendix 1 for a more detailed list.
We will report the mean values of the sedation and analgesia scales
assessed at 30 minutes and 3 hours post-administration of the drug
in question.
Secondary outcomes
1. Days on mechanical ventilation during the admission
episode to the neonatal unit.
2. Number of infants requiring additional medications for
sedation or analgesia or both during the administration of
selected drugs.
3. Number of infants with pneumothorax at the end of
hospitalisation.
4. Number of infants with intraventricular haemorrhage
(Grades III and IV), defined according to Papile’s classification
(Papile 1978), at the end of hospitalisation.
5. Number of infants with periventricular leukomalacia,
defined as periventricular cysts on brain imaging, excluding
subependymal or choroid plexus cysts, at the end of
hospitalisation.
3
 6. Incidence of adverse effects associated with use of
dexmedetomidine during the admission episode to the neonatal
unit, such as:
◦ hypotension: defined as mean blood pressure less than
the gestational age in weeks for infants within 48 hours of age, or
mean blood pressure less than 30 mmHg or less than 10th
percentile for gestational and postnatal age based on published
data (Nuntnarumit 1999) for infants beyond 48 hours of age, or
both;
◦ transient hypertension: defined as blood pressure
greater than 95th percentile for postmenstrual age, based on
published data (Dionne 2012), which resolves spontaneously, or
with dose reduction;
◦ bradycardia: defined as heart rate less than 100 beats
per minute;
◦ arrhythmia: defined as abnormalities in the rate or
rhythm (or both) of the heart; and
◦ any other unexpected adverse effects.
7. Neonatal mortality (death within 28 days of birth) and all-
cause mortality (death within 28 days of completion of therapy).
8. Length of stay in neonatal intensive care unit (days) at the
end of hospitalisation.
9. Neurodevelopmental outcomes at short (≤ 12 months),
medium (> 12 months to 36 months), and long term (> 36
months), using validated neurodevelopmental assessment tools
(Bayley’s mental and psychomotor development indices (MDI/
PDI)).
Search methods for identification of studies
See: Cochrane Neonatal Review Group search strategy (
neonatal.cochrane.org/).
Electronic searches
We will search the Cochrane Central Register of Controlled Trials
(CENTRAL, the Cochrane Library, current issue), MEDLINE
(1950 to present), and Embase (1980 to present). We will search
the World Health Organization (WHO) International Clinical
Trials Registry Platform (who.int/ictrp), Current Controlled Trials
(controlled-trials.com), and ClinicalTrials.gov for ongoing trials
and the Cochrane Neonatal Review Group Specialised Register,
using the search terms: infant, newborn (MeSH); infant; newborn;
child; dexmedetomidine; mpv 1440; randomized trial.pt.
No language or other restrictions will be applied.
Search strategies for the Cochrane Library, MEDLINE, EMBASE
and CINAHL are shown in Appendix 2; Appendix 3; Appendix
4; Appendix 5.
Searching other resources
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We will search reference lists of previous reviews and trials in-
cluded in this review for citations and cross-references. We will
search abstracts from conference proceedings including Pediatric
Academic Societies (PAS) (1998 to present) and the Perinatal So-
ciety of Australia and New Zealand (PSANZ) (1998 to present);
and we will consult expert informants.
Data collection and analysis
We will collect and analyse data in accordance with the standard
methods of the Cochrane Neonatal Review Group.
Selection of studies
At least two review authors will independently assess the eligibility
of retrieved studies based on the full text version. Disagreement
between review authors will be settled in consultation with a third
party.
Data extraction and management
The data will be independently extracted by at least two review
authors using a data extraction form. The data will be checked
and any differences resolved by consensus. All analyses will be
performed using Review Manager software (RevMan 2014).
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias of
each included study using the guidelines provided in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011).
Any disagreements will be resolved by discussion or by a third
assessor.
The ’Risk of bias’ table will be completed to address six specific
domains for each included study. Each domain will be assigned
a judgement of ’Low risk’ of bias, ’High risk’ of bias, or ’Unclear
risk’ of bias. The six domains are as follows:
• selection bias
• performance bias
• detection bias
• attrition bias
• reporting bias
• or any other bias
See Appendix 6 for a more detailed description of risk of bias for
each domain.
Measures of treatment effect
Where possible, the treatment effect for each dichotomous out-
come will be expressed using risk ratio (RR), risk difference (RD),
and number needed to treat for an additional beneficial outcome
(NNTB) or number needed to treat for an additional harmful
4
outcome (NNTH) if RD is significant, each with 95% confidence
intervals (CI). The treatment effect for each continuous outcome
will be expressed using mean difference (MD) with 95% CI.
Unit of analysis issues
The unit of analysis will be at the individual infant level with
one treatment episode per infant. Where there are multiple ob-
servations based on the same outcome (e.g. neurodevelopmental
outcomes at 12 months, > 12 months to 36 months, and > 36
months), separate analyses will be conducted for each outcome at
each follow-up period.
We will utilize the outcome measures reported by the authors of
included studies. Where the outcomes reported are derived from
multiple measurements at different time points (e.g. sedation,
analgesia, blood pressure), we will analyse the derived measure-
ment as reported by the authors. If the individual original data
points are relevant to prespecified outcomes and published, we will
include them for analysis. If these data are not published, we will
request the relevant data from the authors for detailed analysis.
We will include cluster randomized trials if they are eligible based
on the systematic review inclusion criteria. They will be analysed
based on the methods specified in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). For example,
we will utilize the methods outlined in Chapter 16, Section 3,
that incorporates the intra-cluster coefficient (ICC) to calculate
the effective sample size of both the intervention and control arms
in order to avoid unit of analysis errors.
Dealing with missing data
Where data are missing, and cannot be derived as described, we
will approach the analysis of missing data as follows.
1. Contact the original study investigators to request the
missing data.
2. Where possible, missing standard deviations will be
imputed using the coefficient of variation (CV) or calculated
from other available statistics including standard errors,
confidence intervals, t values, and P values.
3. If the data are assumed to be missing at random, the data
will be analysed without imputing any missing values.
4. If this cannot be assumed then the missing outcomes will
be imputed with replacement values, assuming all to have a poor
outcome. Sensitivity analyses will be conducted to assess any
changes in direction or magnitude of effect resulting from data
imputation.
Assessment of heterogeneity
Two authors will assess clinical heterogeneity, and they will con-
duct meta-analysis only when both agree that study participants,
interventions, and outcomes are sufficiently similar.
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We will assess statistical heterogeneity by visual inspection of forest
plots, the I² statistic, and Chi² test. We will use the following cut-
offs as recommended by the Cochrane Neonatal Review Group for
the reporting of heterogeneity: less than 25%, no heterogeneity;
25% to 49%, low heterogeneity; 50% to 74%, moderate hetero-
geneity; and 75% or higher, high heterogeneity. In cases of mod-
erate or high heterogeneity, we will explore the possible causes in
terms of the population, intervention, comparison and outcome
assessment, and determine whether a meta-analysis is appropriate.
Assessment of reporting biases
We will assess publication bias by visual inspection of funnel plot
asymmetry in meta-analyses consisting of at least 10 studies. If we
find significant asymmetry in the funnel plot, we will report this
in the corresponding results.
Data synthesis
We plan to perform meta-analysis of primary and secondary out-
comes, as well as of predefined subgroups, subject to the avail-
ability of data (either published or supplied by the trial investi-
gators). We will utilize standard methodologies for meta-analysis
as described in the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011). Meta-analysis will be conducted us-
ing the inverse variance method for continuous outcomes, and the
Mantel-Haenzel method for dichotomous outcomes. We will use
the fixed-effect model and present all our results with 95% CI. We
will calculate the RR, RD, and NNTB or NNTH if RD is signif-
icant, each with 95% CI, for categorical outcomes; and MD with
95% CI for continuous outcomes. Where continuous outcomes
are measured using different scales, the treatment effect will be
expressed as standardized mean difference (SMD) with 95% CI.
For any outcomes where the included studies are not sufficiently
homogeneous, or where insufficient data are available for meta-
analysis, we will present a narrative synthesis.
Quality of evidence
We will use the Grading of Recommendations Assessment, De-
velopment and Evaluation (GRADE) approach, as outlined in the
GRADE Handbook (Schünemann 2013), to assess the quality of
evidence for the following (clinically relevant) outcomes: 1) Level
of sedation; 2) Adequacy of analgesia; 3) Days on mechanical ven-
tilation; 4) Number of infants requiring additional medications for
sedation, analgesia or both; 5) Number of infants with hypoten-
sion; 6) All-cause mortality; 7) Neurodevelopmental outcomes at
medium term (> 12 months to 36 months) and long term (> 36
months).
Two authors will independently assess the quality of the evidence
for each of the outcomes above. We will consider evidence from
randomized controlled trials as high quality but downgrade the
5
evidence one level for serious (or two levels for very serious) limi-
tations based upon the following: design (risk of bias), consistency
across studies, directness of the evidence, precision of estimates
and presence of publication bias. We will use the GRADEpro 2008
Guideline Development Tool to create a ‘Summary of findings’
table to report the quality of the evidence.
The GRADE approach results in an assessment of the quality of
a body of evidence in one of four grades:
1. High: We are very confident that the true effect lies close to
that of the estimate of the effect.
2. Moderate: We are moderately confident in the effect
estimate: the true effect is likely to be close to the estimate of the
effect, but there is a possibility that it is substantially different.
3. Low: Our confidence in the effect estimate is limited: the
true effect may be substantially different from the estimate of the
effect.
4. Very low: We have very little confidence in the effect
estimate: the true effect is likely to be substantially different from
the estimate of effect.
Subgroup analysis and investigation of heterogeneity
Where there are sufficient studies, the following a priori subgroup
analyses will be conducted.
REFERENCES
Additional references
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Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• Method of dexmedetomidine administration (intranasal,
intravenous; bolus or continuous infusion).
• Dose of dexmedetomidine (low: < 0.2 mcg/kg/hr; standard:
0.2 to < 0.4 mcg/kg/hr; or high: ≥ 0.4 mcg/kg/hr).
• Age of initiation of dexmedetomidine (within first week of
life; 8 to 28 days of age; or beyond 28 days of age).
• Indication for mechanical ventilation e.g. respiratory
disease, airway protection, or elective surgery.
• Gestational age (term; moderate to late preterm (32 to < 37
weeks); very preterm (28 to < 32 weeks); and extremely preterm
(< 28 weeks)).
• Duration of treatment (< 24 hours, 1 to 5 days, > 5 days).
We will investigate whether the results of subgroups are signif-
icantly different by inspecting the overlap of confidence inter-
vals and conducting the test for subgroup differences available in
RevMan 2014.
Sensitivity analysis
Where possible, sensitivity analyses will be conducted to assess any
change in the direction of effect from including only those studies
with:
1. low risk of selection and attrition bias;
2. imputation of missing data using the approaches detailed in
’Dealing with missing data’.
Carbajal 1997
Carbajal R, Paupe A, Hoenn E, Lenclen R, Olivier-Martin
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Estkowski LM, Morris JL, Sinclair EA. Characterization
of dexmedetomidine dosing and safety in neonates and
infants. Journal of Pediatric Pharmacology and Therapeutics
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Gelinas 2004
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assessment and management in critically ill intubated
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Gertler 2001
Gertler R, Brown HC, Mitchell DH, Silvius EN.
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APPENDICES
Appendix 1. Neonatal Pain Scores
1. Neonatal Infant Pain Scale (NIPS) (Lawrence 1993)
2. Pain Assessment Tool (PAT) (Hodgkinson 1994)
3. Premature Infant Pain Profile (PIPP) (Stevens 1996)
4. APN: evaluation behavioral scale of acute pain in newborn infants (Carbajal 1997)
5. Neonatal Facial Coding System (NFCS) (Grunau 1986; Peters 2003)
6. DAN (Douleur Aiguë du Nouveau-né) (Carbajal 2005)
7. ABC Pain Scale (Bellieni 2005)
8. Neonatal Pain, Agitation, and Sedation Scale (N-PASS) (Hummel 2009)
9. ’Faceless’ Acute Neonatal pain Scale (FANS) (Milesi 2010)
10. Premature Infant Pain Profile-Revised (PIPP-R) (Gibbins 2014)
Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
from www.guidelinedevelopment.org/handbook updated
October 2013.
Stevens 1996
Stevens B, Johnston C, Petryshen P, Taddio A. Premature
Infant Pain Profile: development and initial validation.
Clinical Journal of Pain 1996;12(1):13–22. [PUBMED:
8722730]
Tobias 2011
Tobias JD, Gupta P, Naguib A, Yates AR. Dexmedetomidine:
applications for the pediatric patient with congenital heart
disease. Pediatric Cardiology 2011;32(8):1075–87.
Vinall 2014
Vinall J, Grunau RE. Impact of repeated procedural pain-
related stress in infants born very preterm. Pediatric Research
2014;75(5):584–7. [PUBMED: 24500615]
Wilson 2000
Wilson A, Gardner MN, Armstrong MA, Folck BF, Escobar
GJ. Neonatal assisted ventilation: predictors, frequency, and
duration in a mature managed care organization. Pediatrics
2000;105(4 Pt 1):822–30. [PUBMED: 10742327]
Young 2005
Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang
H, Labruyere J, et al. Potential of ketamine and midazolam,
individually or in combination, to induce apoptotic
neurodegeneration in the infant mouse brain. British
Journal of Pharmacology 2005;146(2):189–97. [PUBMED:
15997239]
∗
Indicates the major publication for the study
8
Appendix 2. CENTRAL Search Strategy
1. MeSH descriptor: [Dexmedetomidine] explode all trees
2. “dexmedetomidine”:ti,ab,kw (Word variations have been searched)
3. MeSH descriptor: [Infant] explode all trees
4. infant
5. infant near newborn
6. infant near preterm
7. infant near premature
8. neonat*
9. child
10. child near preschool
11. child near school
12. MeSH descriptor: [Child] explode all trees
13. child, preschool
14. #1 or #2
15. #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13
16. #14 and #15

Appendix 3. MEDLINE Search Strategy

1. exp Infant/ or exp infant, newborn/ or exp infant, low birth weight/ or exp infant, small for gestational age/ or exp infant, very
low birth weight/ or exp infant, extremely low birth weight/ or exp infant, postmature/ or exp infant, premature/ or exp infant,
extremely premature/ or infant.mp. or newborn.mp. or neonatal.mp. or neonate.mp. or preterm.mp. or premature infant.mp. or exp
very low birth weight/ or exp low birth weight/ or extremely low birth weight.mp. or VLBW.mp. or LBW.mp. or ELBW.mp. [mp=
title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept
word, rare disease supplementary concept word, unique identifier]
2. ((exp Dexmedetomidine/ or exp Imidazoles/ or precedex.mp. or exp hypnotics/) and sedatives/) or mpv-1440.mp. or
mpv1440.mp. or dexmedetomidine.mp. or dexmedetomidine hydrochloride.mp. [mp=title, abstract, original title, name of substance
word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept
word, unique identifier]
3. (randomised controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab.
or trial.ab. or groups.ab.
4. 1 and 2 and 3
5. (animals not humans).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading
word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
6. 4 not 5

Appendix 4. Embase Search Strategy

’dexmedetomidine’/exp OR ’dexmedetomidine’ OR ’dexmedetomidine hydrochloride’/exp OR ’dexmedetomidine hydrochloride’ OR
’precedex’ OR ’mpv 1440’
AND (’child’ OR ’newborn’ OR ’neonate’ OR neonatal OR ’premature’ OR ’very low birth weight’ OR ’low birth weight’ OR ’vlbw’
OR lbw OR infan* OR neonat* OR child*)
AND ’human’ NOT animal
AND (’randomised controlled trial’ OR ’controlled clinical trial’ OR randomised OR placebo OR ’clinical trials as topic’ OR randomly
OR trial OR ’clinical trial’ OR ’cross over procedure’ or ’single blind procedure’ OR ’double blind procedure’ OR ’triple blind procedure’)

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) 9
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 5. CINAHL Search Strategy
- Search Terms:
1. dexmedetomidine
2. precedex
(note: 1 and 2 searched as keywords)
3. 1 AND 2
Search Options: Limiters - Publication Type: Clinical Trial; Age Groups: Infant, Newborn: birth-1 month, Infant: 1-23 months, Child,
Preschool: 2-5 years

Appendix 6. Risk of bias tool

Table 8.5.a (Higgins 2011): Cochrane’s tool for assessing risk of bias

Domain Support for judgement Review authors’ judgement

Selection bias

Random sequence generation Describe the method used to generate the Selection bias (biased allocation to inter-
allocation sequence in sufficient detail to ventions) due to inadequate generation of
allow an assessment of whether it should a randomized sequence
produce comparable groups

Allocation concealment Describe the method used to conceal the Selection bias (biased allocation to inter-
allocation sequence in sufficient detail to ventions) due to inadequate concealment
determine whether intervention allocations of allocations prior to assignment
could have been foreseen in advance of, or
during, enrolment

Performance bias

Blinding of participants and personnel Describe all measures used, if any, to blind Performance bias due to knowledge of the
Assessments should be made for each main study participants and personnel from allocated interventions by participants and
outcome (or class of outcomes). knowledge of which intervention a partici- personnel during the study
pant received. Provide any information re-
lating to whether the intended blinding was
effective

Detection bias

Blinding of outcome assessment Assess- Describe all measures used, if any, to Detection bias due to knowledge of the al-
ments should be made for each main outcome blind outcome assessors from knowledge located interventions by outcome assessors
(or class of outcomes). of which intervention a participant re-
ceived. Provide any information relating to
whether the intended blinding was effec-
tive

Attrition bias

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) 10
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Incomplete outcome data Describe the completeness of outcome data Attrition bias due to amount, nature or
Assessments should be made for each main for each main outcome, including attri- handling of incomplete outcome data
outcome (or class of outcomes). tion and exclusions from the analysis. State
whether attrition and exclusions were re-
ported, the numbers in each intervention
group (compared with total randomized
participants), reasons for attrition/exclu-
sions where reported, and any re-inclusions
in analyses performed by the review authors

Reporting bias

Selective reporting State how the possibility of selective out- Reporting bias due to selective outcome re-
come reporting was examined by the review porting.
authors, and what was found

Other bias

Other sources of bias State any important concerns about bias Bias due to problems not covered elsewhere
not addressed in the other domains in the in the table.
tool
If particular questions/entries were pre-
specified in the review’s protocol, responses
should be provided for each question/entry

CONTRIBUTIONS OF AUTHORS
Ibrahim M: development and writing of protocol; providing a clinical perspective; reviewed and edited protocol.
Jones LJ: providing a methodological perspective; providing a clinical perspective; designing search strategies; reviewed protocol.
Lai NM: reviewed and edited protocol; providing a clinical perspective.
Tan K: registered review topic; development of protocol; providing a clinical perspective; supervising the work of co-authors.

DECLARATIONS OF INTEREST
None known.

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) 11
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health,
Department of Health and Human Services, USA.
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver
National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human
Services, USA, under Contract No. HHSN275201100016C

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation (Protocol) 12
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.