Baxter Luke, van der Vaart Marianne, Cobo Maria M, Gunawan Patricia Y, Allegaert Karel, Davis Jonathan M, Turner Mark, Ward Robert M, Darsey Edress, Sheppard James P, Bhatt Aomesh, van den Anker John, Massaro An N, Walls Ramona L, Song Laura S, Singh Kanwaljit, Slater Rebeccah
Department of Paediatrics, University of Oxford, Oxford, UK.
Paediatric Neuroimaging Group Level2 Childrens Hospital, John Radcliffe Hospital, Oxford, UK.
Syst Rev. 2025 Jul 26;14(1):152. doi: 10.1186/s13643-025-02890-4.
There 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.
To 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.
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.
The protocol was registered with PROSPERO on 14 July 2023: CRD42023444809.
有几个重大挑战限制了我们测试新生儿疼痛治疗镇痛效果的能力，新生儿镇痛药物研究进展停滞。一个重要问题是临床疼痛评估依赖于基于传统行为和生命体征的测量方法，且排除了基于大脑的新型生物标志物。在本综述方案中，我们概述了评估基于脑电图（EEG）的反应生物标志物在评估新生儿急性躯体伤害性疼痛方面的可靠性、有效性和可解释性的策略。
为了标准化脑电图分析并得出感兴趣的结果，我们将使用来自月经龄34 - 44周新生儿的数据进行个体参与者数据（IPD）荟萃分析，这些新生儿在急性躯体伤害性皮肤破损程序中记录了脑电图。通过搜索六个数据库（MEDLINE、Embase、CINAHL、Web of Science、Scopus、谷歌学术）、两个临床试验注册平台（ClinicalTrials.gov、世界卫生组织国际临床试验注册平台）以及咨询专家意见来识别已发表文献和灰色文献中的相关数据。我们将通过将提供的数据与文献中的数据描述进行交叉核对、识别重复和无意义的值以及提取质量控制指标来评估可用性偏差、数据准确性和数据质量。数据将通过两阶段的IPD荟萃分析，采用按地点分组的随机效应建模方法进行综合。可靠性（评分者间和评分者内）结果将以Gwet's AC1系数衡量。有效性（已知组和已知刺激）结果将以临床意义上不同刺激之间的脑电图反应幅度差异衡量。可解释性将通过提供原始单位和标准化单位的规范值来解决。
本研究的目的是建立一种基于特定脑电图的反应生物标志物在评估新生儿急性躯体伤害性疼痛方面的可靠性、有效性和可解释性。它将概述现有数据以及脑电图在全球范围内如何用于评估新生儿急性疼痛。如果有足够的个体参与者数据可用且结果可靠、有效且可解释，这项工作将支持在评估新生儿镇痛效果的临床试验中使用基于脑电图的结果测量作为主要终点。
该方案于2023年7月14日在PROSPERO注册：CRD42023444809。
