Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation

Abstract

Background

Dexmedetomidine is a selective alpha‐2 agonist with minimal impact on the haemodynamic profile. It is thought to be safer than morphine or stronger opioids, which are drugs currently used for analgesia and sedation in newborn infants. Dexmedetomidine is increasingly being used in children and infants despite not being licenced for analgesia in this group.

Objectives

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.

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, and two trial registries in September 2023.

Selection criteria

We planned to include randomised controlled trials (RCTs) and quasi‐RCTs evaluating the effectiveness of dexmedetomidine compared with other non‐opioids, opioids, or placebo for sedation and analgesia in neonates (aged under four weeks) requiring mechanical ventilation.

Data collection and analysis

We used standard Cochrane methods. Our primary outcomes were level of sedation and level of analgesia. Our secondary outcomes included days on mechanical ventilation, number of infants requiring additional medication for sedation or analgesia (or both), hypotension, neonatal mortality, and neurodevelopmental outcomes. We planned to use GRADE to assess the certainty of evidence for each outcome.

Main results

We identified no eligible studies for inclusion.

We identified four ongoing studies, two of which appear to be eligible for inclusion; they will compare dexmedetomidine with fentanyl in newborn infants requiring surgery. We listed the other two studies as awaiting classification pending assessment of full reports. One study will compare dexmedetomidine with morphine in asphyxiated newborns undergoing hypothermia, and the other (mixed population, age up to three years) will evaluate dexmedetomidine versus ketamine plus dexmedetomidine for echocardiography. The planned sample size of the four studies ranges from 40 to 200 neonates. Data from these studies may provide some evidence for dexmedetomidine efficacy and safety.

Authors' conclusions

Despite the increasing use of dexmedetomidine, there is insufficient evidence supporting its routine use for analgesia and sedation in newborn infants on mechanical ventilation. Furthermore, data on dexmedetomidine safety are scarce, and there are no data available on its long‐term effects.

Future studies should address the efficacy, safety, and long‐term effects of dexmedetomidine as a single drug therapy for sedation and analgesia in newborn infants.

Plain language summary

Use of dexmedetomidine to reduce pain and induce sleep in newborn babies who need life support ventilation

Key messages

1. Dexmedetomidine is a medicine that is used to relieve pain and induce sleep. It is used in newborn babies who need mechanical ventilation (a machine to assist breathing). We found no evidence to support using or not using dexmedetomidine in newborn babies on mechanical ventilation.

2. Well‐designed studies are needed to determine the benefits and harms of dexmedetomidine in newborn babies, particularly in very preterm babies, as they are the sickest.

What is dexmedetomidine?

Dexmedetomidine is a sedative. Sedatives work by helping a person to relax and feel calm; often people fall asleep after taking a sedative. Dexmedetomidine also has pain relief properties. Dexmedetomidine is given to people of all ages to help them relax and feel less pain during intensive care, mechanical ventilation, and stressful diagnostic or surgical procedures.

Why is this important for newborn babies who are on mechanical ventilation?

About 9% of all newborns are admitted to a neonatal intensive care unit (NICU) directly after birth. Many of these infants require help breathing and are on mechanical ventilators. Mechanical ventilation and time in the NICU are stressful for babies. Pain and stress in newborns lead to long‐lasting complications (into adulthood). Medicines to relieve pain and reduce stress are therefore often needed during intensive care.

To reduce the pain and stress associated with ventilators, infants are usually given pain relief medicines like opioids (morphine, fentanyl) combined with midazolam. Midazolam is a benzodiazepine (sedative) and helps to relax the baby. Morphine and fentanyl both have serious side effects such as physical dependency, withdrawal problems, and slowed digestion and breathing.

Dexmedetomidine may be used in place of opioids and benzodiazepines, or in combination with smaller doses of opioids. Dexmedetomidine does not affect respiratory drive (the infant does not forget to breathe), simplifying assistance during kangaroo care (skin‐to‐skin contact).

What did we want to find out?

We wanted to find out if dexmedetomidine is an effective and safe medicine to use for pain and stress relief in sick newborn babies who need mechanical ventilation.

What did we do?

We searched for studies that looked at dexmedetomidine compared with opioids (such as morphine or fentanyl), non‐opioid relaxing medicines (such as ketamine, midazolam, phenobarbital, or propofol), or placebo (dummy treatment) in sick newborns in need of mechanical ventilation.

What did we find?

We did not find any studies comparing dexmedetomidine with relaxing medicines or placebo. We found four ongoing studies comparing dexmedetomidine with fentanyl, morphine, and ketamine plus dexmedetomidine. We are unsure if these studies will help answer the question about using dexmedetomidine for pain relief and sedation in babies on mechanical ventilation, because we do not yet know if the babies in the studies will need mechanical ventilation.

What are the limitations of the evidence?

We did not find evidence to support using or not using dexmedetomidine to reduce pain and discomfort in preterm infants on mechanical ventilation.

How up to date is this evidence?

The evidence is current to September 2023.

Background

Description of the condition

Mechanical ventilation is widely used to support newborn infants in neonatal intensive care units (NICUs). In the USA, 9% of newborns are admitted to the NICU (Kim 2021), and the World Health Organization (WHO) reports a range of 4% to 16% worldwide (WHO 2023). Between one‐fifth and one‐third of these preterm newborns require mechanical ventilation (Hatch 2021; Yue 2021). Research has shown that mechanical ventilation is a significant source of pain and discomfort for adults and children (Ashkenazy 2021; Dale 2020; Gelinas 2004). Newborn infants, including those born extremely preterm, have the capacity to perceive pain. Repeated and chronic exposure to pain is a major source of distress and is associated with deleterious consequences, including altered pain sensitivity (Morin 2014), permanent neuroanatomic abnormalities (Ranger 2014), emotional and behavioural abnormalities (Doesburg 2013), and learning disabilities (Vinall 2014). Recommendations are in place to aggressively prevent and treat pain in newborn infants. However, the routine use of continuous infusions of analgesics and sedatives such as morphine, fentanyl, midazolam, or ketamine in chronically ventilated preterm infants is not recommended because of concern about short‐term adverse effects and lack of long‐term outcome data (CFN 2016).

Description of the intervention

Dexmedetomidine is a selective alpha₂‐adrenergic agonist that is structurally similar to clonidine but has more than 800 times greater affinity for alpha₂‐receptors over alpha₁‐receptors. The sedative and anxiolytic effects of dexmedetomidine result primarily from stimulation of alpha₂‐adrenergic receptors in the locus coeruleus of the brainstem, leading to a reduction of central sympathetic output and thus greater firing of inhibitory neurons. The presence of dexmedetomidine at alpha₂‐adrenergic receptors in the dorsal horn of the spinal cord modulates the release of substance P and produces its analgesic effects (Buck 2010).

Current neonatal drug regimens used to achieve sedation and analgesia generally consist of combinations of benzodiazepines and opioids. Concerns over these drugs include side effects such as tolerance, withdrawal, paradoxical agitation, and respiratory depression (Hall 2007). Furthermore, studies have found that benzodiazepines, opioids, and N‐methyl‐D‐aspartic acid (NMDA) receptor agonists such as ketamine induce apoptotic neurodegeneration in neonatal animals (Young 2005).

Dexmedetomidine was approved by the U.S. Food and Drug Administration (FDA) in 1999 for sedation in people requiring intubation and mechanical ventilation in an intensive care setting, and prior to surgery and other procedures in people not requiring intubation (FDA Precedex 1999; Precedex Label 2023). Potentially serious adverse effects include bradycardia and sinus arrest, which have been observed in young, healthy adult volunteers with high vagal tone, and with rapid intravenous or bolus administration (Precedex Label 2023). There have also been reports of hypotension and transient hypertension in people using dexmedetomidine; transient hypertension is primarily observed during administration of the loading dose and is related to the stimulation of post‐synaptic α_2B‐adrenergic receptors leading to an initial peripheral vasoconstriction (Bloor 1992). The most common treatment‐emergent adverse effects include hypotension, bradycardia, and dry mouth, affecting more than 2% of adults receiving dexmedetomidine for sedation in an intensive care unit (Precedex Label 2023).

Dexmedetomidine provides both sedation and analgesia when used alone, and has benzodiazepine‐ and opioid‐sparing properties when used in combination with more conventional agents (Chrysostomou 2009). Randomised controlled trials (RCTs) evaluating the effectiveness of dexmedetomidine versus midazolam or propofol in adults demonstrated easy arousal without respiratory depression, shorter duration of mechanical ventilation, less delirium, and less frequent tachycardia and hypertension in the participants who received dexmedetomidine (Jakob 2012; Riker 2009). Preclinical 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 under 18 years of age (Precedex Label 2023), a phase II/III, open‐label, multicentre, safety, efficacy, and pharmacokinetic study demonstrated the efficacy of dexmedetomidine for sedating preterm and full‐term neonates (Chrysostomou 2014). The drug was well tolerated with few drug‐related adverse events, none of which were serious. There were also no adverse events or haemodynamic changes leading to the discontinuation of the drug. The study population consisted of 42 intubated and mechanically ventilated neonates with a gestational age of 28 to 44 weeks receiving dexmedetomidine by continuous infusion for six to 24 hours at doses ranging from 0.05 μg/kg/hr 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 (diastolic hypotension in the preterm group, and hypertension and significant agitation in the term and post‐term groups). 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 not yet known whether dexmedetomidine has any longer‐term harmful effects for newborn infants (Chrysostomou 2014).

In a retrospective chart review evaluating adverse effects 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 receive higher doses of dexmedetomidine and additional sedatives (Estkowski 2015). Extra caution should be exercised during commencement of therapy in children with congenital heart disease, as hypotension and bradycardia are more common during the initial 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. One pharmacokinetics study found that there is a longer half‐life in neonates, so it is possible that lower doses can achieve therapeutic plasma levels of the drug (Chrysostomou 2014). Dexmedetomidine is extensively metabolised through hepatic processes (i.e. through direct glucuronidation and the cytochrome P‐450 system). Immature hepatic function in preterm infants may contribute to prolonged elimination half‐life. Most of its metabolites are excreted in the urine (95%) and faeces (4%). It is unclear if these metabolites have any analgesic or sedative effects. As dexmedetomidine has a very high affinity for protein binding (94%), there is little displacement from other commonly used drugs in anaesthesia and intensive care, such as 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 NICUs is becoming increasingly common. However, there are no systematic reviews of its effectiveness and safety profile as a sedative and analgesic in newborn infants receiving mechanical ventilation.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

We planned to include RCTs and quasi‐RCTs. Trials with cluster allocation were eligible.

Types of participants

We planned to include all newborn infants (maximum postnatal age of 28 days after 40 weeks' gestation) receiving mechanical ventilation via an endotracheal tube who required sedation and analgesia.

We excluded studies in which newborn infants received dexmedetomidine exclusively for procedural sedation and analgesia.

We planned to include studies with mixed populations (e.g. newborn infants and children; mechanically ventilated and self‐ventilating) if:

1. most participants (at least 80%) met the inclusion criteria; or

2. we were able to obtain separate results (from study reports or study authors) for participants who met our eligibility criteria.

Types of interventions

We planned to include all trials comparing dexmedetomidine alone against:

1. other non‐opioids;

2. opioids (e.g. morphine, fentanyl, remifentanil); and

3. placebo.

Control arms with a combination of drugs were eligible.

We defined non‐opioids as drugs that have been used to achieve sedation and analgesia in newborn infants receiving mechanical ventilation. Eligible classes of non‐opioids were:

1. NMDA receptor antagonists (e.g. ketamine);

2. gamma‐aminobutyric acid (GABA) receptor agonists (benzodiazepines (e.g. midazolam, diazepam, lorazepam) and barbiturates (e.g. phenobarbitone, pentobarbitone)); and

3. combined GABA receptor agonists and NMDA receptor antagonists (e.g. propofol).

We applied no restrictions based on the method of administration, dose, frequency, or duration of dexmedetomidine.

We planned to group studies by class of drug in the control arm.

Types of outcome measures

Outcome measures did not form part of our eligibility criteria.

Primary outcomes

1. Level of sedation, assessed using tools or scales such as COMFORT (Ista 2005). Although COMFORT is a paediatric critical care tool, it was validated in a population that included infants.

2. Level of 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 Premature Infant Pain Profile‐Revised (PIPP‐R; Gibbins 2014). See Appendix 1 for a full list of eligible pain scales.

We planned to report the mean values of the sedation and analgesia scales. Typical time points of assessment range from 30 minutes to three hours after administration of the drug in question.

Secondary outcomes

1. Days on mechanical ventilation during the admission episode in the neonatal unit

2. Number of infants requiring additional drugs 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

6. Incidence of adverse effects associated with use of dexmedetomidine during the admission episode in the neonatal unit. These adverse effects included the following.

   1. Hypotension, defined as:

      1. mean blood pressure less than the gestational age in weeks for infants within 48 hours of age; or

      2. mean blood pressure less than 30 mmHg or below the 10th percentile for gestational and postnatal age (based on published data; Nuntnarumit 1999) for infants beyond 48 hours of age

   2. Transient hypertension, defined as blood pressure above the 95th percentile for postmenstrual age (based on published data; Dionne 2012) that resolves spontaneously or with dose reduction

   3. Bradycardia, defined as a decrease in heart rate by more than 30% below baseline, or a heart rate below 100 beats per minute, for 10 seconds or longer (Ballout 2017)

   4. Arrhythmia, defined as abnormalities in the rate or rhythm (or both) of the heart

   5. Any other unexpected adverse effects

7. Mortality before hospital discharge and mortality within 28 days of completion of therapy

8. Length of stay in NICU (days) at the end of hospitalisation

9. Neurodevelopmental outcomes in the short term (≤ 12 months), medium term (> 12 months to 36 months), and long term (> 36 months), measured with validated neurodevelopmental assessment tools (Bayley's mental and psychomotor development indices (MDI/PDI))

Search methods for identification of studies

An Information Specialist (MF) developed the search strategies. The strategies combined intervention terms with standard terms for the neonatal population developed by Cochrane Neonatal. We documented the search and selection process in sufficient detail to create a PRISMA flow diagram (Moher 2009). We performed searches for eligible trials without language or publication type limits. Searches for trials were run for all years; searches for systematic reviews were limited to 2022 and 2023.

Electronic searches

We searched the following databases in September 2023.

1. Ovid MEDLINE(R) All (1946 to 14 September 2023)

2. Cochrane Central Register of Controlled Trials (CENTRAL 2023, Issue 9) via CRS (searched 14 September 2023)

3. Ovid Embase 1974 (1974 to 14 September 2023)

4. CINAHL Complete, EBSCOhost (1982 to 14 September 2023)

We searched the following two trial registries on 14 September 2023.

1. World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; who.int/ictrp)

2. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov)

Appendix 2 presents our search strategies.

Searching other resources

We searched the following conference abstracts.

1. PAS (Pediatric Academic Societies)

2. PSANZ (Perinatal Society of Australia and New Zealand)

3. EAPS (European Academy of Paediatric Societies)

4. Frontiers Event Abstracts (www.frontiersin.org/Community/Abstracts.asp).

Appendix 2 provides further details.

We planned to search the reference lists of trials included in this review and of systematic reviews related to the topic of this review. However, we identified no eligible trials. We planned to search Retraction watch for retractions of trials included in this review. We also planned to consult experts in the field.

Data collection and analysis

For each included study, we planned to collect information regarding the method of randomisation, blinding, interventions, stratification, and whether the trial was conducted in a single centre or multiple centres. We planned to use the standard systematic review methods of Cochrane, as documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

Selection of studies

Two pairs of review authors (JL and CK; OR and NML) independently conducted the title/abstract and full‐text review. We resolved disagreements between review authors by discussion or by consulting a third review author (KT). We accepted published and unpublished studies, both in full article and abstract forms, as long as the study fulfilled our selection criteria in terms of population, intervention, and study design. If the published data were insufficient, we planned to contact the study authors to obtain further information on study design, participant characteristics, co‐interventions, and follow‐up data. We documented the reasons for excluding studies during the full‐text review in the Characteristics of excluded studies table. We also provided any information we could obtain about ongoing studies in the Characteristics of ongoing studies table.

Data extraction and management

Two review authors (JL and CK) planned to independently extract and code all data for each included study, using a pro forma designed specifically for this review. We planned to pilot the form within the review team using a sample of included studies.

We planned to extract the following data from each included study.

1. Identifying information: first author, year of publication, dates of the study, conflicts of interest

2. Study design and setting: trial design, duration, country and setting of trial

3. Population: sex, birth weight, gestational age, age and weight at recruitment, eligibility criteria, number of participants, cluster (if applicable), unit of allocation (e.g. individuals or NICUs), number randomised to each group

4. Intervention and comparison: details on dexmedetomidine (constituents, concentration, dose, frequency, route of delivery), comparator, co‐interventions

5. Outcomes, as described in Types of outcome measures

We planned to screen for duplicate entry of participants by matching the initial number of participants recruited against the total number at each step in the conduct of the study. Were we to find a discrepancy, we planned to look for an explanation in the article (e.g. multiple enrolment of the same participant in different hospital admissions). We planned to contact the study authors if we had any queries or required additional information. We planned to resolve any disagreement among the review authors by discussion, with the input of another review author (KT) as required.

Assessment of risk of bias in included studies

Had we identified any eligible studies, two review authors (CK, JL) would have independently assessed the risk of bias (low, high, or unclear) of all included trials using the original Cochrane risk of bias tool (RoB 1), which covers the following domains (Higgins 2011).

1. Sequence generation (selection bias)

2. Allocation concealment (selection bias)

3. Blinding of participants and personnel (performance bias)

4. Blinding of outcome assessment (detection bias)

5. Incomplete outcome data (attrition bias)

6. Selective reporting (reporting bias)

7. Any other bias

We planned to resolve any disagreements by discussion or by consulting a third review author (NML). Appendix 3 provides a more detailed description of the risk of bias assessment for each domain.

Measures of treatment effect

Where possible, we planned to express the treatment effect for each dichotomous outcome using risk ratios (RRs), risk differences (RDs), and the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) if there was a statistically significant difference between the groups. Each estimate would be accompanied by 95% confidence intervals (CIs).

For continuous outcomes, we planned to express the effect using mean differences (MDs) with 95% CIs if all studies measured the outcome using the same scale, and standardised mean differences (SMDs) with 95% CIs if the studies measured the same outcome using different scales.

Unit of analysis issues

The expected unit of analysis in this review is the individual infant, with one treatment episode per infant. We planned to deal with multiple observations based on the same outcome (e.g. neurodevelopmental outcomes at 12 months, > 12 months to 36 months, and > 36 months) by conducting separate analyses for each follow‐up period.

We planned to use the outcome measures reported by the study authors. Where the outcomes reported were to be derived from multiple measurements at different time points (e.g. sedation, analgesia, blood pressure), we planned to analyse the derived measurements as reported by the study authors, as long as the data matched our prespecified outcomes. If relevant data were not published in sufficient detail, we planned to request them from the study authors.

Had we identified any cluster‐randomised trials (e.g. trials that assigned whole NICUs to the intervention and control groups), we would have followed the recommended methods in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). First, we would have assessed whether trials had adjusted for the effects of clustering using appropriate analysis methods, such as generalised estimating equation (GEE) modelling. If the results were unadjusted, we would have adjusted them by calculating the design effect based on a fairly large assumed intracluster correlation coefficient (ICC) of 0.10, which studies on implementation research have shown is a generally realistic estimate (Campbell 2001). If the study did not state the unit of analysis, we planned to inspect the width of the standard error (SE) or 95% CI of the estimated treatment effects. If we found an inappropriately small SE or a narrow 95% CI, we planned to ask the authors of the study to provide information on the unit of analysis.

Dealing with missing data

We planned to determine the dropout rates from each study and assess the number of infants that were initially randomised against the total number analysed. We would have considered a dropout rate greater than 20% as significant (Guyatt 1993). Had we found a significant dropout rate with no reasonable explanation, or markedly different dropout rates between the assigned groups, we would have judged the study at high risk of attrition bias. Where critical data were missing, we would have approached the analysis of missing data as follows.

1. Contact the original study investigators to request the missing data.

2. Where possible, impute the missing standard deviations (SDs) using the coefficient of variation (CV) or calculate from other available statistics, including SEs, CIs, t values, and P values.

3. Where data are assumed to be missing at random, analyse the data without imputing any missing values.

4. If this cannot be assumed, impute the missing outcomes with replacement values, assuming all missing to have a poor outcome.

5. Assess the effect of missing data by conducting sensitivity analyses, evaluating whether the pooled estimates change substantially without studies at high risk of attrition bias and without the incorporation of imputed data.

Assessment of heterogeneity

Had there been more than one eligible study that contributed suitable data for meta‐analysis, two review authors (JL, CK) would have assessed clinical heterogeneity, proceeding with meta‐analysis only when both authors agreed that study participants, interventions, and outcomes were sufficiently similar.

We planned to assess statistical heterogeneity by visual inspection of forest plots, the Chi² test, and the I² statistic. We would have interpreted I² values using the following cut‐offs, as recommended by Cochrane Neonatal.

1. Less than 25%: no heterogeneity

2. 25% to 49%: low heterogeneity

3. 50% to 74%: moderate heterogeneity

4. 75% or higher: high heterogeneity

In cases of moderate or high heterogeneity, we would have explored possible causes through subgroup and sensitivity analyses based on the following factors.

1. Baseline characteristics of the participants (gestational age, birth weight)

2. Clinical settings of the studies (e.g. tertiary or secondary neonatal unit)

3. Co‐interventions

4. Risk of bias (in particular, selection and attrition bias, as detailed in the Assessment of risk of bias in included studies section)

The aim of this exploration would be to determine whether it was better to report an overall pooled estimate or to conduct the analysis in subgroups.

Assessment of reporting biases

Had we included more than 10 studies in any outcome, we would have assessed publication bias by visual inspection of funnel plot asymmetry. If we found significant asymmetry in the funnel plot, we would have included a statement in our results with a corresponding note of caution in our discussion (Higgins 2022).

Data synthesis

Had there been sufficient data (either published or supplied by the trial investigators), we would have performed data synthesis using RevMan (RevMan Web 2023), using a fixed‐effect model as per the standard methodological recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We would have used the inverse variance method for continuous outcomes and the Mantel‐Haenzel method for dichotomous outcomes. We planned to report the effect estimates using typical statistical expressions such as RR, RD, MD, and SMD, all with 95% CIs. For any outcomes where the included studies were not sufficiently homogeneous, or where insufficient data were available for meta‐analysis, we planned to present a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

We planned to conduct the following a priori subgroup analyses.

1. Method of dexmedetomidine administration (intranasal or intravenous; bolus or continuous infusion)

2. Dose of dexmedetomidine (low: < 0.2 μg/kg/hr; standard: 0.2 to < 0.4 μg/kg/hr; or high: ≥ 0.4 μg/kg/hr)

3. Age of initiation of dexmedetomidine (within first week of life, eight to 28 days of age, or beyond 28 days of age)

4. Indication for mechanical ventilation (e.g. respiratory disease, airway protection, or elective surgery)

5. Gestational age (term, moderate to late preterm (32 to < 37 weeks), very preterm (28 to < 32 weeks), and extremely preterm (< 28 weeks))

6. Duration of treatment (< 24 hours, 1 to 5 days, or > 5 days)

We planned to investigate whether the results of subgroups were significantly different by inspecting the overlap of CIs and conducting the test for subgroup differences available in RevMan (RevMan Web 2023).

Sensitivity analysis

Had we identified sufficient studies for inclusion, and where we identified substantial heterogeneity, we planned to perform sensitivity analyses for all outcomes, to assess the impact of excluding the following studies.

1. Studies at high risk of selection and attrition bias

2. Studies with imputed data (see Dealing with missing data)

Summary of findings and assessment of the certainty of the evidence

If we had identified any eligible studies, we would have used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence of the following prespecified and clinically relevant outcomes.

1. Level of sedation

2. Level of analgesia

3. Days on mechanical ventilation

4. Number of infants requiring additional drugs for sedation or analgesia (or both)

5. Hypotension

6. Mortality before hospital discharge and mortality within 28 days of completion of therapy

7. Neurodevelopmental outcomes in the short term (≤ 12 months), medium term (> 12 months to 36 months), and long term (> 36 months)

Two review authors (NML, JL) would have independently assessed the certainty of the evidence for each of the outcomes above. We would have considered evidence from RCTs and quasi‐RCTs as high certainty to begin with, downgrading by one level for serious (or two levels for very serious) limitations based on the following considerations.

1. Design (risk of bias)

2. Consistency across studies

3. Directness of the evidence

4. Precision of estimates

5. Presence of publication bias

We would have interpreted the GRADE ratings as follows.

1. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

2. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

4. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

We intended to use RevMan web to create a summary of findings table (RevMan 2023).

Results

Description of studies

Results of the search

The searches identified 882 references (567 without duplicates). We excluded 538 records based on their title/abstract and reviewed 29 full‐text articles or trial registry records. At this stage, we excluded 22 studies (25 references), and identified four ongoing studies, two of which we listed as awaiting classification. We found no eligible studies for inclusion in the review (Figure 1).

1.

PRISMA flow diagram.

Included studies

We identified no eligible studies for inclusion.

Excluded studies

We excluded 22 studies (25 reports) during the full‐text review for one or more of the following reasons.

1. Study design (two studies): non‐randomised comparative studies (Chrysostomou 2014; ISRCTN11031435)

2. Population (17 studies): infants older than one month (Cai 2013; ChiCTR‐IPR‐15006112; CTRI/2016/05/006925; CTRI/2016/10/007347; CTRI/2020/02/023636; CTRI/2021/03/031988; EUCTR2006‐004836‐61‐GB; EUCTR2015‐002114‐80‐IT; Grant 2016; Li 2016; Long 2018; NCT02996058; Prasad 2012; Saleh 2016; Tobias 2004; Tong 2017; Xie 2018)

3. Intervention (five studies): dexmedetomidine not evaluated as a stand‐alone medication (Chernyshuk 2016); dexmedetomidine used as a premedication for intubation and not during mechanical ventilation (IRCT20190114042358N2), comparison of different administration methods or doses of dexmedetomidine (Li 2016; Li 2018; Xie 2018).

The Characteristics of excluded studies table provides further details.

Studies awaiting classification

Two ongoing studies are awaiting classification because we are unsure if they meet our eligibility criteria. The information made available in the trial registry records is insufficient to determine whether recruited infants will be ventilated (ChiCTR‐IOR‐16009780; NCT04772222).

A description of each study is available in the Characteristics of studies awaiting classification table.

Ongoing studies

We identified two ongoing studies that appear to be eligible; both are parallel RCTs (CTRI/2022/01/039656; NCT05324891). CTRI/2022/01/039656 is set in India and is recruiting neonates of over 35 weeks' gestation undergoing surgery. NCT05324891 is set in Egypt and is recruiting postoperative neonates of unspecified gestation who are receiving mechanical ventilation. Both studies will evaluate the use of dexmedetomidine versus fentanyl for sedation during mechanical ventilation. The primary outcome for both studies is pain, assessed using the Neonatal Pain, Agitation and Sedation Scale (N‐PASS; Morgan 2020).

A more detailed description of each study is available in the Characteristics of ongoing studies table.

Risk of bias in included studies

No studies met the eligibility criteria of this review.

Effects of interventions

No studies met the eligibility criteria of this review.

Discussion

Summary of main results

We found no published RCTs or quasi‐RCTs addressing the harms and benefits of dexmedetomidine as a single therapy for sedation and analgesia in newborn infants on mechanical ventilation.

We identified two ongoing studies that appear to be eligible. One includes newborns in need of postsurgical mechanical ventilation and has a planned sample size of 40 neonates (NCT05324891). The second study includes neonates undergoing surgery and has a planned sample size of 76 newborn infants (CTRI/2022/01/039656). The comparison in both studies is intravenous dexmedetomidine versus intravenous fentanyl.

We identified two further studies in progress that may be relevant. We listed them as awaiting classification pending assessment of full reports. The first study will evaluate intravenous dexmedetomidine versus intravenous morphine in neonates with hypoxic‐ischaemic encephalopathy undergoing hypothermia; the planned sample size is 50 newborns (NCT04772222). The second study evaluates intranasal dexmedetomidine versus intranasal dexmedetomidine plus ketamine during echocardiography in a mixed paediatric population (aged up to three years) with congenital heart disease; the planned sample size is 200 children (ChiCTR‐IOR‐16009780). In both studies, it is unclear whether the newborn infants will be on mechanical ventilation.

Overall completeness and applicability of evidence

We found no studies to answer our review question. In view of the increasing use of dexmedetomidine worldwide, there is an urgent need for well‐designed studies with unbiased reporting on the efficacy and safety of the drug in newborn infants (McDonald 2022).

Quality of the evidence

We identified no studies for inclusion.

Potential biases in the review process

We applied the standard methods of the Cochrane Neonatal Group when conducting this systematic review. The literature search was as comprehensive as possible, and we applied no language restrictions. Nevertheless, it is possible that we missed some clinical trials published in the grey literature. To minimise bias in the review process, two review authors independently performed study selection and data extraction.

The Differences between protocol and review section describes some minor changes that were made between the original protocol and the current review, such as updating the references in the Background, rewording some outcomes, and updating the risk of bias assessment to a current standard. We are confident that these changes did not interfere with study selection, and will not interfere with data extraction, data analysis, or outcome reporting in future updates of this review.

We planned to follow Cochrane standards to assess the risk of bias. We also planned to apply the GRADE method to rate the certainty of evidence and interpret the data appropriately.

Agreements and disagreements with other studies or reviews

We have identified no other systematic review on this topic.

We did find one protocol for a systematic review on "Opioids and alpha‐2‐agonists for analgesia and sedation in newborn infants" (Kinoshita 2020). The objective is to summarise the evidence on opioids and alpha‐2‐agonists for pain and stress management in critically ill neonates. Opioids and alpha‐2‐agonists, or a combination of both, will be compared with a non‐pharmacological intervention, oral sugar solution, the same drug with a different dose or route, or a different drug or combinations of such drugs. The primary outcomes will be all‐cause mortality during hospitalisation and hypotension. Level of sedation and analgesia (the primary outcomes of our review) are listed as secondary outcomes (Kinoshita 2020).

Two narrative reviews that reported data from several retrospective and prospective observational studies on dexmedetomidine in neonates suggest that dexmedetomidine is efficacious for sedation in combination with other sedative drugs, such as opioids (McDonald 2022; Ojha 2022).

Authors' conclusions

Implications for practice.

Despite the increasing use of dexmedetomidine, there is insufficient evidence supporting its routine use for analgesia and sedation in newborn infants on mechanical ventilation. Furthermore, data on dexmedetomidine safety are scarce, and there are no data available on its long‐term effects.

We identified four ongoing studies, two of which are awaiting classification pending assessment of full reports. Two ongoing studies that appear eligible will evaluate dexmedetomidine versus fentanyl in newborn infants requiring surgery. One study awaiting classification will assess dexmedetomidine versus morphine in asphyxiated newborns undergoing hypothermia, and the other study (mixed population, age up to three years) will evaluate dexmedetomidine versus ketamine plus dexmedetomidine for echocardiography. The planned sample size of these four studies ranges from 40 to 200 neonates.

Implications for research.

Future studies should address the efficacy and safety of dexmedetomidine as a single drug therapy for sedation and analgesia in newborn infants. This will provide better knowledge of dexmedetomidine pharmacodynamic properties in the neonatal population. Studies should provide rigorous reporting of short‐term adverse effects and investigate the possible long‐term neurodevelopmental outcome of dexmedetomidine. Researchers should perform subgroup analysis based on postnatal age because of the rapidly changing pharmacokinetic properties of dexmedetomidine depending on the age of the neonate.

History

Protocol first published: Issue 9, 2016

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)

Appendix 2. Search strategies

Summary

Date	Database	Results
Sept‐14‐2023	Ovid MEDLINE(R) All	204
Sept‐14‐2023	Central via CRA	234
Sept‐14‐2023	Embase 1974 to 2023 September 13	217
Sept‐14‐2023	CINAHL Complete	110
Sept‐14‐2023	trial registries	111
Sept‐14‐2023	Conference abstracts	6
	Gross	882
	Duplicates	315
	Net	567

CENTRAL via CRS Web

	Search date: 14 Sept 2023
1	MESH DESCRIPTOR Dexmedetomidine AND CENTRAL:TARGET	2611
2	(dexmedetomidin* or "bxcl 501" or "bxcl501" or cepedex or "da 9501" or "da9501" or dexdor or "mpv 1440" or "mpv1440" or precedex or primadex or sedadex or sileo or "tpu 006" or "tpu006"):ti,ab,kw AND CENTRAL:TARGET	8362
3	#1 OR #2	8434
4	MESH DESCRIPTOR Infant, Newborn EXPLODE ALL AND CENTRAL:TARGET	20589
5	MESH DESCRIPTOR Intensive Care, Neonatal AND CENTRAL:TARGET	383
6	MESH DESCRIPTOR Intensive Care Units, Neonatal AND CENTRAL:TARGET	1044
7	MESH DESCRIPTOR Gestational Age AND CENTRAL:TARGET	4056
8	("babe" or "babes" or baby* or "babies" or "gestational age" or "gestational ages" or infant? or "infantile" or infancy or "low birth weight" OR "low birth weights" or "low birthweight" or "low birthweights" or neonat* or "neo‐nat*" or newborn* or "new born?" or "newly born" or "premature" or "pre‐mature" or "pre‐matures" or prematures or prematurity or "pre‐maturity" or "preterm" or "preterms" or "pre term?" or "preemie" or "preemies" or "premies" or "premie" or "VLBW" or "VLBWI" or "VLBW‐I" or "VLBWs" or "LBW" or "LBWI" or "LBWs" or "ELBW" or "ELBWI" or "ELBWs" or "NICU" or "NICUs"):ti,ab,kw AND CENTRAL:TARGET	84883
9	#4 OR #5 OR #6 OR #7 OR #8	89000
10	#9 AND #3	234

MEDLINE

	Ovid MEDLINE(R) All
	Search date: 14 Sept 2023
#	Searches	Results
1	dexmedetomidine/	5435
2	(dexmedetomidin* or bxcl 501 or bxcl501 or cepedex or da 9501 or da9501 or dexdor or mpv 1440 or mpv1440 or precedex or primadex or sedadex or sileo or "tpu 006" or tpu006).ti,ab,kw,kf.	8720
3	or/1‐2 [Intervention: dexmedetomidine]	8957
4	exp Infant, Newborn/ or Intensive Care, Neonatal/ or Intensive Care Units, Neonatal/ or Gestational Age/	725983
5	(babe or babes or baby* or babies or gestational age? or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity or pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs).ti,ab,kw,kf.	1052350
6	or/4‐5 [Filter: Neonatal Population 04‐2022‐MEDLINE]	1364002
7	randomized controlled trial.pt.	599805
8	controlled clinical trial.pt.	95420
9	randomized.ti,ab.	670664
10	placebo.ti,ab.	247961
11	drug therapy.fs.	2622326
12	randomly.ti,ab.	417397
13	trial.ti,ab.	768928
14	groups.ti,ab.	2596413
15	or/7‐14 [Cochrane HSSS‐SM Filter; Box 6.4.a Cochrane Handbook]	5821031
16	(quasirandom* or quasi‐random* or random*).ti,ab,kw,kf.	1452035
17	(control* adj2 (group? or trial? or study)).ti,ab,kw,kf.	1106113
18	or/16‐17 [Additional terms to increase sensitivity]	2055364
19	exp animals/ not humans/	5154669
20	(or/15,18) not 19 [RCT Filter: Medline]	5577188
21	meta‐analysis/ or "systematic review"/ or network meta‐analysis/ [/ finds same as.pt. syntax]	322454
22	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kf,kw.	330227
23	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kf,kw.	39695
24	(data synthes* or data extraction* or data abstraction*).ti,ab,kf,kw.	41495
25	(hand search* or handsearch*).ti,ab,kf,kw.	11231
26	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kf,kw.	36287
27	meta‐analysis as topic/ or network meta‐analysis/	28290
28	(meta analy* or metanaly* or meta regression* or metaregression*).ti,ab,kf,kw.	282654
29	(medline or cochrane or pubmed or medlars or embase or cinahl).ab.	344497
30	(cochrane or systematic review?).jw.	20513
31	or/21‐30 [SR filter‐Medline; based on CADTH https://searchfilters.cadth.ca]	642022
32	3 and 6 and 20 [Dexmedetomidine AND Neonate AND RCT]	200
33	3 and 6 and 31 and ("2022" or "2023").yr. [Dexmedetomidine AND Neonate AND SR]	9
34	or/32‐33 [All results Medline]	204

Embase

	Embase Ovid 1974 to 2023 September 13
	Search date: 14 Sept 2023
#	Searches	Results
1	dexmedetomidine/	18792
2	(dexmedetomidin* or bxcl 501 or bxcl501 or cepedex or da 9501 or da9501 or dexdor or mpv 1440 or mpv1440 or precedex or primadex or sedadex or sileo or "tpu 006" or tpu006).ti,ab,kw,kf.	12527
3	or/1‐2 [Intervention: dexmedetomidine]	19298
4	newborn/ or prematurity/ or newborn intensive care/ or newborn care/ or gestational age/	796482
5	(babe or babes or baby* or babies or gestational age? or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity or pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs).ti,ab,kw,kf.	1258127
6	or/4‐5 [Filter: Neonatal Population 03‐2022‐OVID EMBASE]	1529377
7	Randomized controlled trial/ or Controlled clinical study/	976434
8	random$.ti,ab,kw.	1980348
9	Randomization/	98387
10	placebo.ti,ab,kw.	365481
11	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab,kw.	273769
12	double blind procedure/	210520
13	(controlled adj7 (study or design or trial)).ti,ab,kw.	450422
14	parallel group$1.ti,ab.	32117
15	(crossover or cross over).ti,ab.	124558
16	((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.	415098
17	(open adj label).ti,ab.	108615
18	(quasirandom* or quasi‐random* or random*).ti,ab,kw,kf.	1981546
19	(control* adj2 (group? or trial? or study)).ti,ab,kw,kf.	1542897
20	or/7‐19 [ Terms based on Cochrane Central strategy‐ How Central is Created]	3493295
21	(exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/) and (human/ or normal human/ or human cell/)	25564301
22	exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/	32812391
23	22 not 21 [Animal Exclusion‐https://community‐cochrane‐org.ezproxy.uvm.edu/sites/default/files/uploads/inline‐files/Embase%20animal%20filter.pdf]	7248090
24	20 not 23 [Filter: RCT‐EMBASE]	3021998
25	meta‐analysis/ or "systematic review"/ or "meta analysis (topic)"/ [EMTREE]	600740
26	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kw.	398493
27	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kw.	55685
28	(data synthes* or data extraction* or data abstraction*).ti,ab,kw.	50561
29	(hand search* or handsearch*).ti,ab,kw.	13699
30	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kw.	47961
31	(meta analy* or metanaly* or meta regression* or metaregression*).ti,ab,kw.	358427
32	(medline or cochrane or pubmed or medlars or embase or cinahl).ab.	433642
33	(cochrane or systematic review?).jn,jx.	32088
34	(overview adj2 reviews).ti.	149
35	or/25‐34 [SR Filter: EMBASE based on CADTH filter: https://searchfilters.cadth.ca]	911390
36	3 and 6 and 24 [Dex AND Neonate AND RCT]	202
37	3 and 6 and 35 and ("2022" or "2023").yr. [Dex AND Neonate AND SR]	28
38	or/36‐37 [Embase all results]	217

CINAHL

	CINAHL Complete
	Ebscohost
	Search date: 14 September 2023
	Search modes ‐ Boolean/Phrase
1	bxcl 501 or bxcl501 or cepedex or da 9501 or da9501 or dexdor or mpv 1440 or mpv1440 or precedex or primadex or sedadex or sileo or "tpu 006" or tpu006	136
2	dexmedetomidine	2582
3	S1 OR S2	2,697
4	(MH "Infant, Newborn+")	159,233
5	TI ( (infant or infants or infant? or infantile or infancy or newborn* or new born or new borns or newly born or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or pre term or preemie or preemies or premies or low birth weight or low birthweight or VLBW or LBW or ELBW or NICU) ) OR AB ( (infant or infants or infant? or infantile or infancy or newborn* or new born or new borns or newly born or neonat* or baby* or babies or premature or prematures or pre ...	583,062)
6	S4 OR S5	583,062)
7	(randomized controlled trial OR controlled clinical trial OR randomized OR randomised OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)	693,305)
8	S3 AND S6 AND S7	110

Trial registries

Date	Site	Terms	Results
Sept‐14‐2023	ICTRP	Main search screen: dexmedetomidine AND (infant or neonate); limited to trials in children; synonyms automatically searched: syMPV 1440; MPV1440; Precedex	45
Sept‐14‐2023	clinicaltrials.gov	Classic interface. Other terms: infant or neonate AND Intervention/Treatment: Dexmedetomidine	66
			111

Conferences

Conference
Search date: 14 Sept 2023
		Searched dexmedetomidine
PAS 2023	5	https://2023.pas‐meeting.org and abstract book
PAS 2022	0	https://2022.pas‐meeting.org [searched abstracts of oral and poster sessions
PAS 2021		No conference
PAS 2019	0	Conference book
PAS 2018	0	https://onlinelibrary.wiley.com/toc/14401754/2018/54/S1
PSANZ‐2023	0	https://onlinelibrary.wiley.com/toc/14401754/2023/59/S1
PSANZ‐2022	0	https://onlinelibrary.wiley.com/toc/14401754/2022/58/S2
PSANZ‐2021	0	Virtual conference held; unable to find abstracts
PSANZ‐2020	0	https://onlinelibrary.wiley.com/toc/14401754/2020/56/S1
PSANZ‐2019	0	https://onlinelibrary.wiley.com/toc/14401754/2019/55/S1
PSANZ 2018	0	https://onlinelibrary.wiley.com/toc/14401754/2017/53/S2
PSANZ 2017	0	https://onlinelibrary.wiley.com/toc/14401754/2017/53/S3
PSANZ 2016	0	https://onlinelibrary.wiley.com/toc/14401754/2016/52/S2
PSANZ 2015	0	https://onlinelibrary.wiley.com/toc/14401754/2015/51/S1
PSANZ 2014	0	https://onlinelibrary.wiley.com/toc/14401754/2014/50/S1
Multiple	0	Frontiers Event Abstracts; Neonatalogy. Keyword searched https://www.frontiersin.org/Community/Abstracts.aspx
EAPS 2022	0	Frontiers Event Abstracts: 10.3389/978‐2‐88971‐024‐9
EAPS 2021	0	Frontiers Event Abstracts
EAPS 2020	1	Frontiers Event Abstracts
Total	6
Key: PAS (Pedatric Academic Societies); PSANZ (Perinatal Society of Australia and New Zealand) ; EAPS (European Academy of Paediatric Societies_

Appendix 3. Cochrane risk of bias tool (RoB 1)

Sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.
Criteria for a judgement of 'Low risk' of bias.	The investigators describe a random component in the sequence generation process, such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; or minimisation*. *Minimisation may be implemented without a random element, and this is considered to be equivalent to being random.
Criteria for the judgement of 'High risk' of bias.	The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; or sequence generated by some rule based on hospital or clinic record number. Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorisation of participants, for example: allocation by judgement of the clinician; allocation by preference of the participant; allocation based on the results of a laboratory test or a series of tests; or allocation by availability of the intervention.
Criteria for the judgement of 'Unclear' risk of bias.	Insufficient information about the sequence generation process to permit Low risk' or 'High risk' judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
Criteria for a judgement of 'Low risk' of bias.	Participants and investigators enroling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based and pharmacy‐controlled randomisation); sequentially numbered drug containers of identical appearance; or sequentially numbered, opaque, sealed envelopes.
Criteria for the judgement of 'High risk' of bias.	Participants or investigators enroling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; or any other explicitly unconcealed procedure.
Criteria for the judgement of 'Unclear' risk of bias.	Insufficient information to permit 'Low risk' or 'High risk' judgement. This is usually the case if the method of concealment is not described or not described in sufficient detail (e.g. if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed).
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
Criteria for a judgement of 'Low risk' of bias.	Any one of the following: no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; or blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
Criteria for the judgement of 'High risk' of bias.	Any one of the following: no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Criteria for the judgement of 'Unclear' risk of bias.	Any one of the following: insufficient information to permit 'Low risk' or 'High risk' judgement; or the study did not address this outcome.
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.
Criteria for a judgement of 'Low risk' of bias.	Any one of the following: no blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; or blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
Criteria for the judgement of 'High risk' of bias.	Any one of the following: no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Criteria for the judgement of 'Unclear' risk of bias.	Any one of the following: insufficient information to permit 'Low risk' or 'High risk' judgement; or the study did not address this outcome.
Incomplete outcome data Attrition bias due to amount, nature, or handling of incomplete outcome data.
Criteria for a judgement of 'Low risk' of bias.	Any one of the following: no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is insufficient to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes is insufficient to have a clinically relevant impact on the observed effect size; or missing data have been imputed using appropriate methods.
Criteria for the judgement of 'High risk' of bias.	Any one of the following: reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is sufficient to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (mean difference or standardised mean difference) among missing outcomes is sufficient to induce clinically relevant bias in the observed effect size; 'as‐treated' analysis done with substantial departure of the intervention received from that assigned at randomisation; or potentially inappropriate application of simple imputation.
Criteria for the judgement of 'Unclear' risk of bias.	Any one of the following: insufficient reporting of attrition/exclusions to permit 'Low risk' or 'High risk' judgement (e.g. number randomised not stated, no reasons for missing data provided); the study did not address this outcome.
Selective reporting Reporting bias due to selective outcome reporting.
Criteria for a judgement of 'Low risk' of bias.	Any of the following: the study protocol is available and all the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way; or the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon).
Criteria for the judgement of 'High risk' of bias.	Any one of the following: not all of the study's prespecified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; or the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Criteria for the judgement of 'Unclear' risk of bias.	Insufficient information to permit 'Low risk' or 'High risk' judgement. It is likely that most studies will fall into this category.
Other bias Bias due to problems not covered elsewhere in the table.
Criteria for a judgement of 'Low risk' of bias.	The study appears to be free of other sources of bias.
Criteria for the judgement of 'High risk' of bias.	There is at least one important risk of bias. For example, the study: had a potential source of bias related to the specific study design used; has been claimed to have been fraudulent; or had some other problem.
Criteria for the judgement of 'Unclear' risk of bias.	There may be a risk of bias, but there is either: insufficient information to assess whether an important risk of bias exists; or insufficient rationale or evidence that an identified problem will introduce bias.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Cai 2013	This study evaluated the use of dexmedetomidine for rigid bronchoscopic airway foreign body removal in children aged over 28 days. Excluded on the basis of population.
Chernyshuk 2016	An abstract that reported an RCT comparing the infusion of dexmedetomidine with morphine boluses (study group, n = 30) with the standard regimen of morphine infusion with diazepam boluses (control group, n = 30). The study did not evaluate the use of dexmedetomidine alone, as prespecified in our protocol, so was excluded on the basis of intervention.
ChiCTR‐IPR‐15006112	This study evaluated the use of different doses of anaesthetic drugs including dexmedetomidine in cataract surgery in infants. The infants were not under mechanical ventilation. Excluded on the basis of population.
Chrysostomou 2014	A non‐randomised trial that investigated the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full‐term neonates of 28 to 44 weeks' gestational age. Excluded on the basis of study design.
CTRI/2016/05/006925	Registered record of an RCT evaluating dexmedetomidine versus midazolam for sedation in mechanically ventilated children with neuromuscular problems in PICU. The trial is still not yet recruiting as of November 2023. Excluded on the basis of population and trial status.
CTRI/2016/10/007347	RCT that evaluated dexmedetomidine versus midazolam for sedation in mechanically ventilated children. The enroled participants were beyond the neonatal age range. Excluded on the basis of population.
CTRI/2020/02/023636	RCT that evaluated dexmedetomidine versus midazolam for sedation in mechanically ventilated children in PICU, which accommodated children older than the neonatal age group. Excluded on the basis of population.
CTRI/2021/03/031988	RCT that evaluated dexmedetomidine versus midazolam in mechanically ventilated children beyond neonatal age. Excluded on the basis of population.
EUCTR2006‐004836‐61‐GB	Study that evaluated dexmedetomidine as a sedative in PICU with children beyond the neonatal age. The registry record states (quote:) "not recruiting". Excluded on the basis of population. The registry also stated that the trial prematurely ended on 30 September 2006.
EUCTR2015‐002114‐80‐IT	RCT that evaluated dexmedetomidine during weaning from analgesia and sedation in PICU on children beyond the neonatal age group. Excluded on the basis of population.
Grant 2016	Study that evaluated dexmedetomidine in critically ill children beyond neonatal age with acute respiratory failure. Excluded on the basis of population.
IRCT20190114042358N2	RCT that evaluated the use of dexmedetomidine versus fentanyl for neonates that required surgery. The study examined the use of dexmedetomidine only for intubation, and not for analgesia and sedation during mechanical ventilation. Excluded on the basis of intervention.
ISRCTN11031435	Non‐randomised, pilot comparative study that assessed the feasibility of using dexmedetomidine as an alternative to sevoflurane together with high dose fentanyl for neonatal anaesthesia. Excluded on the basis of study design.
Li 2016	Study that compared 2 means of administering intranasal dexmedetomidine for sedation in children. Dexmedetomidine was used in both groups. Excluded on the basis of population and intervention.
Li 2018	Study that evaluated pharmacokinetic and pharmacodynamic of 2 modes of administration of dexmedetomidine: intranasal and intravenous administration. Excluded on the basis of intervention.
Long 2018	RCT assessing dexmedetomidine for sedation on mechanically ventilated children beyond neonatal age. Excluded on the basis of population.
NCT02996058	Study assessing dexmedetomidine for sedation in intubated mechanically ventilated infants beyond neonatal age. Excluded on the basis of population.
Prasad 2012	Study that compared dexmedetomidine and fentanyl for sedation during mechanical ventilation in postoperative paediatric cardiac surgical patients beyond neonatal age. Excluded on the basis of population.
Saleh 2016	RCT that compared dexmedetomidine and fentanyl in children beyond neonatal age after surgical procedures. Excluded on the basis of population.
Tobias 2004	RCT that compared dexmedetomidine and midazolam for sedation during mechanical ventilation in infants and children in PICU (beyond neonatal age). Excluded on the basis of population.
Tong 2017	RCT that evaluated dexmedetomidine and midazolam for sedation in critically ill children beyond neonatal age with multiple trauma. Excluded on the basis of population.
Xie 2018	RCT that evaluated different doses of dexmedetomidine in children beyond neonatal age with non‐tracheal intubation intravenous general anaesthesia. Excluded on the basis of population (age and status of not requiring ventilation) and intervention (dexmedetomidine was used in both groups).

PICU: paediatric intensive care unit; RCT: randomised controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

ChiCTR‐IOR‐16009780.

Methods	Design: parallel‐group RCT Single/multicentre: single centre Country: China
Participants	Inclusion criteria Congenital heart disease (ASA I or II) Age ≤ 3 years Scheduled echocardiography under sedation Exclusion criteria History of allergy to EMLA cream or ketamine dexmedetomidine Presence of dysfunction (clinical or investigative derangements) of cardiovascular, central nervous, or hepatic system Use of chronic hepatic enzyme‐inducing drugs Developmental disabilities Sample size: 200
Interventions	Intranasal dexmedetomidine versus intranasal dexmedetomidine combined with ketamine
Outcomes	MOAAS score Ramsay score
Notes	Status of study: recruiting as of 20 November 2023 Reason awaiting classification: unclear what proportion of the population will be neonates on mechanical ventilation, and this information can only be assessed upon study completion.

NCT04772222.

Methods	Design: parallel‐group RCT Single/multicentre: multicentre (2) Country: USA
Participants	Inclusion criteria ≥ 36 weeks' gestational age Diagnosis of moderate‐to‐severe neonatal encephalopathy Treatment with TH (target temperature 33.5 °C) for a planned duration of 72 hours Need for sedation or treatment, or both, to prevent shivering during TH as assessed by N‐PASS scores and a modified BSAS Informed consent document approved by the IRB obtained prior to randomisation Exclusion criteria Known chromosomal anomalies Cyanotic congenital heart defects Redirection of care being considered because of a moribund condition, or a decision made to withhold full support Sample size: 50
Interventions	Open‐label dexmedetomidine versus morphine for pain and sedation
Outcomes	Primary outcome Adverse events such as hypotension, hypertension, bradycardia, cardiac arrhythmias, hypothermia, acute renal failure, liver failure, and seizures Secondary outcomes Number of participants who experience shivering Number of participants who require respiratory support Days to full oral feedings by bottle or breast GMA scores 7 days after weaning off of study drug or discharge, whichever happens first GMA scores at 3–4 months of age HINE scores at 3–4 months of age HINE scores at 6–9 months of age TIMP scores at 3–4 months of corrected age PDMS‐2 at 6–9 months of age AQS at 6–9 months of age
Notes	Status of study: recruiting as of 21 November 2023 Reason awaiting classification: this study is enroling newborn infants with hypoxic ischaemic encephalopathy for therapeutic hypothermia. Mechanical ventilation was not stated as an inclusion or exclusion criterion. We placed this study under awaiting classification pending a full report, to evaluate whether there will be data on infants who are mechanically ventilated that may be included in this review.

AQS: ages and stages questionnaire; ASA: American Society of Anesthesiologists; BSAS: bedside shivering assessment scale; EMLA: eutectic mixture of local anaesthetic; GMA: generalised motor assessment scores; HINE: Hammersmith infant neurological exam; IRB: Institutional Review Board; MOAAS score: modified observer's alertness/sedation scale; N‐PASS: neonatal pain, agitation, and sedation scale; PDMS‐2: Peabody developmental motor skills; RCT: randomised controlled trial; TH: therapeutic hypothermia; TIMP: test of infant motor performance.

Characteristics of ongoing studies [ordered by study ID]

CTRI/2022/01/039656.

Study name	Dexmedetomidine versus fentanyl for sedation in neonates undergoing surgery: a blinded randomized controlled trial
Methods	Design: parallel‐group RCT Single/multicentre: single centre Country: India
Participants	Inclusion criteria > 35 weeks' gestation Undergoing surgery Exclusion criteria Bradycardia (HR < 100) Hypotension and a requirement of more than 2 inotropes Sample size: 76
Interventions	Intervention: dexmedetomidine. Dexmedetomidine infusion will be started at a maintenance infusion rate of 0.3 μg/kg/hr. Infusion rate will be increased by 0.1 μg/kg/hr to a maximum of 1 μg/kg/hr. Control: fentanyl infusion. Fentanyl infusion will be started at 2 μg/kg/hr and increased to a maximum of 4 μg/kg/hr.
Outcomes	Primary outcomes Percentage of neonates with N‐PASS score 3 at any time during the study (Morgan 2020) Secondary outcomes Requirement of midazolam or fentanyl boluses
Starting date	21 January 2022
Contact information	Dr Shivani Dogra, shivanidogra2003@yahoo.com
Notes	Status of study: the trial status is "not yet recruiting" as of 14 November 2023.

NCT05324891.

Study name	Dexmedetomidine versus fentanyl for sedation of postoperative mechanically ventilated neonates
Methods	Design: RCT Single/multicentre: single centre Country: Egypt
Participants	Inclusion criteria Neonates that require postoperative ventilation Exclusion criteria Major congenital cardiovascular anomalies Chromosomal anomalies Grade IV intraventricular haemorrhage Tracheoesophageal fistula with a wide gap (distance between proximal and distal ends > 2 cm) Sample size: 40
Interventions	Intervention: dexmedetomidine infusion Control: fentanyl infusion Co‐interventions Infants in both groups received open‐label intravenous fentanyl boluses at a dose of 1 µg/kg, as an adjuvant analgesic when the pain score was > 3 points. The dose was repeated, based on pain score assessment, at a minimum interval of 2–4 hours. Infants who became agitated received midazolam bolus at a dose of 0.1 mg/ kg/dose IV as an adjuvant sedative When 2 boluses of midazolam failed to control agitation, infants received pancuronium IV at a dose of 0.1 mg/kg as a skeletal muscle relaxant
Outcomes	Primary outcome Assessment of N‐PASS immediately after the operations, then every 12 hours till 5 days (Morgan 2020) Secondary outcomes Plasma cortisol level Need for adjuvant analgesics or sedatives Need for skeletal muscle relaxant Time to extubation Days of mechanical ventilation Time to reach 100 mL/kg/day enteral feed Length of hospital stay Mortality Death Adverse effects of the sedative drugs Hypotension, bradycardia, chest wall rigidity, feeding intolerance, withdrawal signs, re‐intubation within 48 hours Culture‐proven sepsis
Starting date	January 2016
Contact information	Not provided on the trial registration website (clinicaltrials.gov/study/NCT05324891?tab=history&a=1)
Notes	Status of study: according to the trial register record, the trial started in January 2016, and was completed on 30 August 2017. However, no results were posted on the trial register site, and no relevant abstract or full publication could be found after we searched using a combination of keyword, title, and institution. Last update: the last update on the trial register was posted on 13 April 2022. Reason classified as ongoing: there is no contact information given in the trial register, which precluded a direct enquiry to the study authors to request further information. We decided to keep the current record as ongoing, and exclude if there is no abstract or full text published, or no other way of requesting study information by the next review update.

HR: heart rate; IV: intravenous; N‐PASS: neonatal pain, agitation, and sedation scale; randomised controlled trial.

Differences between protocol and review

We have made the following changes to the published protocol (Ibrahim 2016).

1. In the Background section, we have updated some references on epidemiology and guideline recommendations.

2. Under Types of outcome measures, we amended the wording of the two primary outcomes slightly, as follows.

   1. Primary outcome 1: from "Sedation..." to "Level of sedation..."

   2. Primary outcome 2: from "Analgesia..." to "Level of analgesia..."

   3. Primary outcomes: we revised the statement on time point of outcome evaluation, from "30 minutes and 3 hours post‐administration of the drug in question", which appeared over‐specific as a result of our inadvertent choice of wording, to a more realistic range of time points: "We planned to report the mean values of the sedation and analgesia scales. Typical time points of assessment range from 30 minutes to three hours after administration of the drug in question."

   4. Secondary outcomes: we revised the outcome statement on mortality based on a peer reviewer's comment to offer a wider coverage on the relevant period of outcome measurement. Original statement: "Neonatal mortality (death within 28 days of birth) and all‐cause mortality (death within 28 days of completion of therapy)."; revised statement: "Mortality before hospital discharge and mortality within 28 days of completion of therapy."

   5. Secondary outcomes: we expanded our definition of bradycardia in response to peer reviewer's comment. Original statement: "bradycardia: defined as heart rate less than 100 beats per minute"; revised statement: "Bradycardia, defined as a decrease in heart rate by more than 30% below baseline, or a heart rate below 100 beats per minute, for 10 seconds or longer (Ballout 2017)."

3. We updated the Assessment of risk of bias in included studies section.

4. In the review we refer to certainty rather than quality of the evidence.

5. We updated the risk of bias tool in Appendix 3.

6. Under Summary of findings and assessment of the certainty of the evidence, we removed the mention of GRADEpro GDT as we used RevMan Web to construct the summary of the findings table (RevMan Web 2023). We replaced the GRADEpro GDT reference with that of RevMan web.

Contributions of authors

Conception and design of review: NML, KT, Dr Masitah Ibrahim
Co‐ordination of review processes: NML, KT
Search: MF
Selection of studies: JYL, CJK, NML, OR
Data collection: JYL, CJK
Data analysis and interpretation: NML, OR
Writing: NML, OR, MF

Sources of support

Internal sources

• Monash University, Australia

  Provided intramural support for this review

• Taylor's University, Malaysia

  Provided intramural support for this review

External sources

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

Declarations of interest

JYL has declared that they have no conflict of interest.
CJK has declared that they have no conflict of interest.
NML is an Associate Editor at Cochrane Clinical Answers, an Associate Editor at Cochrane Neonatal, and a Sign‐off Editor at Cochrane Central Editorial Services, but was not involved in the editorial process for this review.
OR has declared that they have no conflict of interest.
MF is a Managing Editor and Information Specialist for Cochrane Neonatal, but was not involved in the editorial acceptance or assessment of this review.
KK has declared that they have no conflict of interest.
Dr Masitah Ibrahim has declared that they have no conflict of interest.

New