We will conduct a systematic review using the standard methods of the Cochrane Neonatal Review Group. We will search for all randomized and quasi-randomized controlled trials. We will also include observational studies, as we expect to identify few randomized trials and to better explore potential harms. The methodology will follow the criteria and standard methods of the Cochrane Handbook [28] and the reporting guidelines by the Preferred Reporting Items for Systematic Review and Meta-Analyses for Protocols (PRISMA-P) (Additional file 1). Ethical approval is not needed for a systematic review. The review is registered in PROSPERO (registration number: CRD42020205755).
Types of participants
Late preterm (i.e., 34–36 weeks’ gestational age) and full-term (i.e., more than 36 weeks’ gestational age) newborn infants undergoing any type of TH for hypoxic-ischemic encephalopathy.
Types of interventions
We will include studies using any type of drugs or any type of non-pharmacological intervention used for the management of pain and/or sedation during TH. We will include any dose, duration, and route of administration. Pharmacological interventions include any opioids, e.g., morphine; alpha-2 agonists, e.g., clonidine; and benzodiazepines, e.g., midazolam. Non-pharmacological interventions include non-nutritive sucking, sweet solutions (oral glucose or sucrose), swaddling, musical therapy, therapeutic touch/massage, sensorial saturation, or acupuncture.
Types of outcome measures
Primary outcomes are analgesia and sedation assessed with validated pain scales in the neonatal population (the Echelle Douleur Inconfort Nouveau-ne (EDIN) Scale, the COMFORTneo, Faces Pain Scale-Revised, the Neonatal Pain, Agitation and Sedation Scale (N-PASS), Pain Assessment Tool, the Astrid Lindgren and Lund Children’s Hospital’s Pain and Stress Assessment scale for Preterm and Sick Newborn Infants (ALPS-neo), the Neonatal Facial Coding System (NFCS), the CRIES (acronym for Crying, Requires oxygen, Increased vital signs, Expression, Sleepless) Scale [29, 30], circulatory instability requiring medical therapy (inotropes, vasopressors, and/or fluid boluses), mortality to discharge and neurodevelopmental disability, defined as cerebral palsy, developmental delay (Bayley Scales of Infant Development - Mental Development Index Edition II (BSID-MDI-II), Bayley Scales of Infant and Toddler Development - Edition III Cognitive Scale (BSITD-III), Griffiths Mental Development Scale - General Cognitive Index (GCI) assessment greater than two standard deviations (SDs) below the mean), intellectual impairment (intelligence quotient (IQ) greater than two SDs below the mean), blindness (vision less than 6/60 in both eyes), or sensorineural deafness requiring amplification.
The secondary outcomes are neonatal mortality; duration of hospital stay; days to reach full enteral feeding; analgesia assessed with neurophysiological measures such as NIRS (near-infrared spectroscopy) or GSR (galvanic skin response); focal gastrointestinal perforation; episodes of bradycardia (heart rate < 80 beats/min); signs of distress, e.g., heart rate > 100 beats/min; and neurodevelopmental disability.
Search methods
We will search for studies in the following databases: CINAHL, ClinicalTrials.gov, Cochrane Library, Embase, PubMed, Scopus, Web of Science, and conference proceedings with no restrictions for time and language (search strategy is shown in Additional file 2). We will also perform a manual search through references in the found articles.
Selection of studies
Two independent researchers will independently screen the titles and abstracts followed by a full-text screening using an online tool for the preparation of systematic reviews [31]. Disagreements will be solved by a third researcher or in discussion with the group, as proposed by the Cochrane Handbook [28].
Data extraction and management
Data will be extracted using a data extraction form by two authors independently. Disagreements will be solved by a third researcher or in discussion with the group. The following data will be extracted:
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Administrative details (author(s), year of publication)
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Details of the study: design, type, duration, country and location of study, funding, informed consent, and ethical approval
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Details of participants: birth weight, gestational age, number of participants, and HIE severity
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Details of intervention and comparator: type of drug/non-pharmacological intervention and dosages
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Details of outcomes, as listed in types of outcome measures
Should any queries arise or in cases where additional data are required, we will contact the study investigators/authors for clarification.
Assessment of risk of bias in the included studies
Two researchers will independently assess the risk of bias (low, high, or unclear) of all included studies using the Cochrane “Risk of Bias” tool. Any disagreements will be resolved by discussion in the group. The two researchers will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane “Risk of Bias” tool for the following domains:
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Sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants and personnel (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective reporting (reporting bias)
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Any other bias
For the included observational studies, we will use the “Risk of Bias in non-randomized Studies – of Interventions (ROBINS-I) tool to assess the risk of bias [32]. Two researchers will independently assess the risk of bias (low, moderate, serious, critical, no information) of all included observational studies using the ROBINS-I tool for the following domains:
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Bias due to confounding
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Bias in the selection of participants for the study
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Bias in the classification of interventions
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Bias due to deviations from intended interventions
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Bias due to missing data
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Bias in the measurement of outcomes
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Bias in the selection of the reported result
In the confounding domain, we will take into account the following confounding factors: sex, Apgar score, severity of HIE, mode of delivery, and gestational age.
Strategy for data synthesis
We will summarize all eligible studies in Review Manager 5.4. We will utilize the standard methodologies for meta-analysis as described in the Cochrane Handbook for Systematic Reviews of Interventions [28]. We will use the random-effect model and present all our results with 95% CI. We will calculate the RR, RD, and NNTB or NNTH if RD is significant, each with 95% CI, for categorical outcomes, and MD with 95% CI for continuous outcomes. 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, following the Synthesis without meta-analysis (SWiM) Guidelines [33]. We will not pool randomized studies and observational studies in the same analyses.
We plan to assess clinical heterogeneity by comparing the distribution of important participant factors between trials and trial factors (randomization concealment, blinding of outcome assessment, loss to follow-up, treatment type, co-interventions). We will assess statistical heterogeneity by examining the I2 statistic [28], a quantity that describes the proportion of variation in point estimates that is due to variability across studies rather than sampling error.
We will interpret the I2 statistic as described by Higgins 2019:
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< 25%: no heterogeneity
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25 to 49%: low heterogeneity
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50 to 74%: moderate heterogeneity
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≥ 75%: high heterogeneity
We will consider statistical heterogeneity to be substantial when I2 is greater than 50%. In addition, we will employ the χ2 test of homogeneity to determine the strength of evidence that heterogeneity is genuine. We will explore clinical the variation across studies by comparing the distribution of important participant factors among trials and trial factors (randomization concealment, blinding of outcome assessment, loss to follow-up, treatment type, and co-interventions). We will consider a threshold P value of less than 0.1 as an indicator of whether heterogeneity (genuine variation in effect sizes) is present.
Assessment of reporting biases
We will investigate publication by using funnel plots if at least 10 clinical trials are included in the systematic review [28, 34].
Certainty of evidence
We will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, as outlined in the GRADE Handbook, to assess the certainty of evidence for the primary outcomes of this review (see above).
Two authors will independently assess the certainty of the evidence for each of the primary outcomes specified above, in the section types of outcomes. We will consider evidence from randomized controlled trials as high but downgrade the evidence by one level for serious (or two levels for very serious) limitations 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 consider evidence from observational studies as low but upgrade the evidence (one or two levels) based upon the following: large magnitude of an effect, dose-response gradient, and effect of plausible residual confounding. We will use the GRADEpro Guideline Development Tool to create a “summary of findings” table to report the certainty of the evidence for randomized studies and observational studies, respectively.
Sensitivity analysis
We will conduct sensitivity analyses to explore the effect of the methodological quality of the trials, checking to ascertain if studies with a high risk of bias overestimate the effect of treatment.
Analysis of subgroups or subsets:
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Severity of HIE, based on the Sarnat staging
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High versus low dose of the intervention (thresholds will be set post hoc)
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By route of administration, e.g., enteral or intravenous