Establishing a standardised approach for the measurement of neonatal noxious-evoked brain activity in response to an acute somatic nociceptive heel lance stimulus.

BACKGROUND: 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 for blood tests. 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 pharmacological and non-pharmacological methods to treat neonatal pain. This study aimed to test whether a measure of noxious-evoked EEG activity called the noxious neurodynamic response function (n-NRF), that was originally derived in a sample of term-aged infants at the Oxford John Radcliffe Hospital, UK, in 2017, can reliably distinguish noxious from non-noxious events in two independent datasets collected at University College London Hospital and at Royal Devon & Exeter Hospital. We aimed to reproduce three published results that use this measure to quantify noxious-evoked changes in brain activity. We used the n-NRF 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 postmenstrual age (PMA) in premature infants up to 37 weeks PMA. Positive replication of these studies will build confidence in the use of the n-NRF as a valid and reliable pain-related outcome which could be used to evaluate analgesic efficacy in neonates. The protocol for this study was published following peer review (https://doi.org/10.17605/OSF.IO/ZY9MS). RESULTS: The n-NRF magnitude to a noxious heel lance stimulus was significantly greater than to a non-noxious control heel lance stimulus in both the UCL dataset (n = 60; mean difference .88; 95% confidence interval (CI) .64-1.13; p < .0001) and the Exeter dataset (n = 31; mean difference .31; 95% CI .02-.61; p = .02). The mean magnitude and 90% bootstrap confidence interval of the n-NRF evoked by the heel lance did not meet our pre-defined equivalence bounds of 1.0 ± .2 in either the UCL dataset (n = 72; mean magnitude 1.33; 90% bootstrapped CI 1.18-1.52) or the Exeter dataset (n = 35; mean magnitude .92, 90% bootstrapped CI .74-1.22). The magnitude of the n-NRF to the noxious stimulus was significantly positively correlated with PMA in infants up to 37 weeks PMA (n = 65; one-sided Pearson's R, adjusted for site: .24; 95% CI .06-1.00; p = .03). CONCLUSIONS: We have reproduced in independent datasets the findings that the n-NRF response to a noxious stimulus is significantly greater than to a non-noxious stimulus, and that the noxious-evoked EEG response increases with PMA. The pre-defined equivalence bounds for the mean magnitude of the EEG response were not met, though this might be due to either inter-site differences such as the lack of calibration of devices between sites (a true negative) or underpowering (a false negative). This reproducibility study provides robust evidence that supports the use of the n-NRF as an objective outcome for clinical trials assessing acute nociception in neonates. Use of the n-NRF in this way has the potential to transform the way analgesic efficacy studies are performed.

Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK.

BACKGROUND: Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. METHODS: Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). FINDINGS: Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. INTERPRETATION: Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. FUNDING: Wellcome Trust and Bliss.

Continuous non-invasive measurement of cardiac output in neonatal intensive care using regional impedance cardiography: a prospective observational study.

OBJECTIVES: To compare agreement between echocardiography and regional impedance cardiography (RIC)-derived cardiac output (CO), and to construct indicative normative ranges of CO for gestational age groups. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort observational study performed in a tertiary centre in London, UK, including neonates born between 25 and 42 weeks' gestational age. EXPOSURES: Neonates on the postnatal ward had 2 hours of RIC monitoring; neonates in intensive care had RIC monitoring for the first 72 hours, then weekly for 2 hours, with concomitant echocardiography measures. MAIN OUTCOMES AND MEASURES: RIC was used to measure CO continuously. Statistical analyses were performed using R (V.4.2.2; R Core Team 2022). RIC-derived CO and echocardiography-derived CO were compared using Pearson's correlations and Bland-Altman analyses. Differences in RIC-derived CO between infants born extremely, very and late preterm were assessed using analyses of variance and mixed-effects modelling. RESULTS: 127 neonates (22 extremely, 46 very, 29 late preterm and 30 term) were included. RIC and echocardiography-measured weight-adjusted CO were correlated (r=0.62, p<0.001) with a Bland-Altman bias of -31 mL/min/kg (limits of agreement -322 to 261 mL/min/kg). The RIC-derived CO fell over 12 hours, then increased until 72 hours after birth. The 72-hour weight-adjusted mean CO was higher in extremely preterm (424±158 mL/min/kg) compared with very (325±131 mL/min/kg, p<0.001) and late preterm (237±81 mL/min/kg, p<0.001) neonates; this difference disappeared by 2-3 weeks of age. CONCLUSIONS: RIC is valid for continuous, non-invasive CO measurement in neonates. Indicative normative CO ranges could help clinicians to make more informed haemodynamic management decisions, which should be explored in future studies. TRIAL REGISTRATION NUMBER: NCT04064177.

Cardiac Output Measurement in Neonates and Children Using Noninvasive Electrical Bioimpedance Compared With Standard Methods: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review and meta-analyze the validity of electrical bioimpedance-based noninvasive cardiac output monitoring in pediatrics compared with standard methods such as thermodilution and echocardiography. DATA SOURCES: Systematic searches were conducted in MEDLINE and EMBASE (2000-2019). STUDY SELECTION: Method-comparison studies of transthoracic electrical velocimetry or whole body electrical bioimpedance versus standard cardiac output monitoring methods in children (0-18 yr old) were included. DATA EXTRACTION: Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Mean differences of cardiac output, stroke volume, or cardiac index measurements were pooled using a random-effects model (R Core Team, R Foundation for Statistical Computing, Vienna, Austria, 2019). Bland-Altman statistics assessing agreement between devices and author conclusions about inferiority/noninferiority were extracted. DATA SYNTHESIS: Twenty-nine of 649 identified studies were included in the qualitative analysis, and 25 studies in the meta-analyses. No significant difference was found between means of cardiac output, stroke volume, and cardiac index measurements, except in exclusively neonatal/infant studies reporting stroke volume (mean difference, 1.00 mL; 95% CI, 0.23-1.77). Median percentage error in child/adolescent studies approached acceptability (percentage error less than or equal to 30%) for cardiac output in L/min (31%; range, 13-158%) and stroke volume in mL (26%; range, 14-27%), but not in neonatal/infant studies (45%; range, 29-53% and 45%; range, 28-70%, respectively). Twenty of 29 studies concluded that transthoracic electrical velocimetry/whole body electrical bioimpedance was noninferior. Transthoracic electrical velocimetry was considered inferior in six of nine studies with heterogeneous congenital heart disease populations. CONCLUSIONS: The meta-analyses demonstrated no significant difference between means of compared devices (except in neonatal stroke volume studies). The wide range of percentage error reported may be due to heterogeneity of study designs, devices, and populations included. Transthoracic electrical velocimetry/whole body electrical bioimpedance may be acceptable for use in child/adolescent populations, but validity in neonates and congenital heart disease patients remains uncertain. Larger studies in specific clinical contexts with standardized methodologies are required.