Evidence map›Paper›PMID 40713869›Full record

ArticleSystematic reviews2025

Is noxious stimulus-evoked electroencephalography response a reliable, valid, and interpretable outcome measure to assess analgesic efficacy in neonates? A systematic review and individual participant data (IPD) meta-analysis protocol.

Luke Baxter, Marianne van der Vaart, Maria M Cobo, Patricia Y Gunawan, Karel Allegaert, Jonathan M Davis, Mark Turner, Robert M Ward, Edress Darsey, James P Sheppard and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Systematic reviews, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Fetal Pain Perception:Annals of the Child Neurology Society · 2026
    Review
  3. Review
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Luke BaxterDepartment of Paediatrics, University of Oxford, Oxford, UK. luke.baxter@paediatrics.ox.ac.uk.ORCID 0000-0001-9548-7162
Marianne van der VaartDepartment of Paediatrics, University of Oxford, Oxford, UK.
Maria M CoboDepartment of Paediatrics, University of Oxford, Oxford, UK.
Patricia Y GunawanDepartment of Paediatrics, University of Oxford, Oxford, UK.
Karel AllegaertDepartment of Development and Regeneration, KU Leuven, Leuven, Belgium.
Jonathan M DavisDepartment of Pediatrics, Tufts Medical Center, Boston, MA, USA.
Mark TurnerDepartment of Womens and Childrens Health, University of Liverpool, Liverpool, UK.
Robert M WardDepartment of Pediatrics, University of Utah School of Medicine, Salt Lake City, USA.
Edress DarseyPediatric Center of Excellence, Pfizer, NY, USA.
James P SheppardNuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
Aomesh BhattDepartment of Paediatrics, University of Oxford, Oxford, UK.
John van den AnkerDepartment of Paediatrics, University of Oxford, Oxford, UK.
An N MassaroOffice of Pediatric Therapeutics, Food and Drug Administration (FDA), Silver Spring, MD, USA.
Ramona L WallsCritical Path Institute, Data Collaboration Center, Tucson, AZ, USA.
Laura S SongCritical Path Institute, Data Collaboration Center, Tucson, AZ, USA.
Kanwaljit SinghINC, Critical Path Institute (C-Path), Tucson, AZ, USA.
INC Pain Working Group
Rebeccah SlaterDepartment of Paediatrics, University of Oxford, Oxford, UK.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundThere are several major challenges limiting our ability to test analgesic efficacy for treatment of neonatal pain, and progress in analgesic drug studies in neonates has stalled. One significant issue is the reliance of clinical pain assessments on traditional behavioural and vital signs-based measures and the exclusion of novel brain-based biomarkers. In this review protocol, we outline our strategy to assess the reliability, validity, and interpretability of an electroencephalography (EEG)-based response biomarker for assessment of acute somatic nociceptive pain in neonates.

methodsTo standardise EEG analysis and generate the outcome of interest, we will perform an individual participant data (IPD) meta-analysis using data from neonates aged 34-44-week postmenstrual age that have had EEG recorded during acute somatic nociceptive skin-breaking procedures. Relevant data from both published and grey literature will be identified by searching six databases (MEDLINE, Embase, CINAHL, Web of Science, Scopus, Google Scholar), two clinical trial registry platforms (ClinicalTrials.gov, WHO ICTRP), and by consulting expert opinion. We will assess availability bias, data accuracy, and data quality by cross-referencing provided data with data descriptions in the literature, identifying duplicates and nonsensical values, and extracting quality control metrics. Data will be synthesised via a two-stage IPD meta-analysis using a random effects modelling approach grouped by site. Reliability (inter- and intra-rater) outcomes will be measured as Gwet's AC1 coefficient. Validity (known-groups and known-stimuli) outcomes will be measured as EEG response magnitude differences between clinically meaningfully different stimuli. Interpretability will be addressed by providing normative values, in both original and standardised units. DISCUSSION: The purpose of this study is to establish the reliability, validity, and interpretability of a specific EEG-based response biomarker for assessing acute somatic nociceptive pain in neonates. It will provide an overview of available data and how EEG is being used globally to assess acute neonatal pain. If sufficient IPD are made available and the outcome is reliable, valid, and interpretable, this work will support the use of EEG-based outcome measures as primary endpoints in clinical trials assessing analgesic efficacy in neonates. SYSTEMATIC REVIEW REGISTRATION: The protocol was registered with PROSPERO on 14 July 2023: CRD42023444809.

Indexed as

AnalgesicsElectroencephalographyNociceptive PainOutcome Assessment, Health CarePain MeasurementHumansInfant, NewbornMeta-Analysis as TopicReproducibility of ResultsSystematic Reviews as TopicAnalgesicsBiomarkersBrainElectroencephalographyIndividual participant dataInterpretabilityMeta-analysisNeonatePainReliabilityValidity

Identifiers

PMID40713869
PMCPMC12296588

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.