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Electroencephalography (EEG) can be used in neonates to measure brain activity changes that are evoked by noxious events, such as clinically-required immunisations, cannulation and heel lancing. EEG provides an alternative approach to infer pain experience in infants compared with more commonly used behavioural and physiological pain assessments. Establishing the generalisability and construct validity of these measures will help corroborate the use of brain-derived outcomes to evaluate the efficacy of new or existing drugs to treat neonatal pain. This study aims to test whether a measure of noxious-evoked EEG activity, that was originally derived in a sample of term-aged infants at the Oxford John Radcliffe Hospital in 2017, can reliably distinguish noxious from non-noxious events in two independent datasets retrospectively collected at University College London Hospital and prospectively collected at Royal Devon & Exeter Hospital. We aim to reproduce three published results that use this measure to quantify noxious-evoked changes in brain activity. We will use this EEG measure to quantify noxious-evoked brain activity to test (i) whether significantly larger noxious-evoked activity is recorded in response to a clinical heel lance compared to a non-noxious control heel lance procedure; (ii) whether the magnitude of the activity evoked by a noxious heel lance is equivalent in independent cohorts of infants; and (iii) whether the magnitude of the noxious-evoked brain activity increases with age in premature infants up to 37 weeks postmenstrual age. Positive replication of these studies will build confidence in the use of brain-derived signals as valid and reliable pain-related outcomes which could be used to evaluate analgesic efficacy in neonates.

Objectives This study examined a more effective pain management method, without sucrose, on heel lance in preterm infants using the Premature Infant Pain Profile (PIPP). Design In a nonblinded, randomized controlled, two-period, two-sequence crossover trial, 25 infants were randomly allocated to intervention (a Brahms lullaby with non-nutritive sucking, facilitated tucking and holding) or standard care (facilitated tucking and holding). Setting Local Perinatal Medical Centre’s NICU in Japan, July 2014 until June 2015. Outcome measures The primary outcome variable was PIPP, and secondary outcomes were heart rate (HR), oxygen saturation, and abnormal HR (> baseline mean plus 2 SDs, or

To clarify the possibility of event-related potential (ERP) evoked by heel lance in neonates as an index of pain assessment, knowledge acquired by and problems of the methods used in studies on ERP evoked by heel lance in neonates were systematically reviewed, including knowledge about Aδ and C fibers responding to noxious stimuli and Aβ fibers responding to non-noxious stimuli. Of the 863 reports searched, 19 were selected for the final analysis. The following points were identified as problems for ERP evoked by heel lance in neonates to serve as a pain assessment index: (1) It is possible that the ERP evoked by heel lance reflected the activation of Aβ fibers responding to non-noxious stimuli and not the activation of Aδ or C fibers responding to noxious stimulation; (2) Sample size calculation was presented in few studies, and the number of stimulation trials to obtain an averaged ERP was small. Accordingly, to establish ERP evoked by heel lance as a pain assessment in neonates, it is necessary to perform a study to clarify ERP evoked by Aδ- and C-fiber stimulations accompanied by heel lance in neonates.

Background Orally administered sucrose is effective and safe in reducing pain intensity during single, tissue-damaging procedures in neonates, and is commonly recommended in neonatal pain guidelines. However, there is wide variability in sucrose doses examined in research, and more than a 20-fold variation across neonatal care settings. The aim of this study was to determine the minimally effective dose of 24% sucrose for reducing pain in hospitalized neonates undergoing a single skin-breaking heel lance procedure. Methods A total of 245 neonates from 4 Canadian tertiary neonatal intensive care units (NICUs), born between 24 and 42 weeks gestational age (GA), were prospectively randomized to receive one of three doses of 24% sucrose, plus non-nutritive sucking/pacifier, 2 min before a routine heel lance: 0.1 ml (Group 1; n = 81), 0.5 ml (Group 2; n = 81), or 1.0 ml (Group 3; n = 83). The primary outcome was pain intensity measured at 30 and 60 s following the heel lance, using the Premature Infant Pain Profile-Revised (PIPP-R). The secondary outcome was the incidence of adverse events. Analysis of covariance models, adjusting for GA and study site examined between group differences in pain intensity across intervention groups. Results There was no difference in mean pain intensity PIPP-R scores between treatment groups at 30 s (P = .97) and 60 s (P = .93); however, pain was not fully eliminated during the heel lance procedure. There were 5 reported adverse events among 5/245 (2.0%) neonates, with no significant differences in the proportion of events by sucrose dose (P = .62). All events resolved spontaneously without medical intervention. Conclusions The minimally effective dose of 24% sucrose required to treat pain associated with a single heel lance in neonates was 0.1 ml. Further evaluation regarding the sustained effectiveness of this dose in reducing pain intensity in neonates for repeated painful procedures is warranted. Trial registration ClinicalTrials.gov: NCT02134873. Date: May 5, 2014 (retrospectively registered).