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.

Parental experience of neonatal pain research while participating in the Parental touch trial (Petal).

ABSTRACT: Parental involvement in neonatal comfort care is a core component of family-centred care. Yet, parents experience a range of positive and negative feelings when providing pain-relieving interventions for their infants. Parents of infants who participated in the Parental touch trial ( Petal ), a multicentre randomised controlled trial investigating the impact of gentle parental touch on neonatal pain, were asked to complete an anonymous survey. This survey aimed to (1) explore parent-reported motivations in deciding to participate in the Petal trial; (2) understand parent-reported experiences related to trial participation; (3) understand parents' willingness to participate in future studies; and (4) evaluate parent-reported feelings while they were delivering a gentle touch intervention either before or after a clinically necessary blood test. One hundred six parents (1 parent per infant) took part in the survey. Primary motivators for participation were altruistic. Parents most frequently reported that they wanted their child to take part in the research because it has a potential benefit to babies in the future and because they wanted to improve scientific understanding. Parents reported that providing gentle touch to their children during painful procedures was associated with positive emotions, such as feeling "useful" (64%) and "reassured" (53%). Furthermore, nearly all parents (98%) were pleased to have participated in the Petal trial and would consider, or maybe consider, participating in further research studies. These results underscore the importance of structuring trials around parental involvement and providing opportunities for parents to be involved in providing comfort to their infants during necessary painful clinical procedures.

Multicentre, randomised controlled trial to investigate the effects of parental touch on relieving acute procedural pain in neonates (Petal).

INTRODUCTION: Newborn infants routinely undergo minor painful procedures as part of postnatal care, with infants born sick or premature requiring a greater number of procedures. As pain in early life can have long-term neurodevelopmental consequences and lead to parental anxiety and future avoidance of interventions, effective pain management is essential. Non-pharmacological comfort measures such as breastfeeding, swaddling and sweet solutions are inconsistently implemented and are not always practical or effective in reducing the transmission of noxious input to the brain. Stroking of the skin can activate C-tactile fibres and reduce pain, and therefore could provide a simple and safe parent-led intervention for the management of pain. The trial aim is to determine whether parental touch prior to a painful clinical procedure provides effective pain relief in neonates. METHODS AND ANALYSIS: This is a multicentre randomised controlled trial. A total of 112 neonates born at 35 weeks' gestation or more requiring a blood test in the first week of life will be recruited and randomised to receive parental stroking either preprocedure or postprocedure. We will record brain activity (EEG), cardiac and respiratory dynamics, oxygen saturation and facial expression to provide proxy pain outcome measures. The primary outcome will be the reduction of noxious-evoked brain activity in response to a heel lance. Secondary outcomes will be a reduction in clinical pain scores (Premature Infant Pain Profile-Revised), postprocedural tachycardia and parental anxiety. ETHICS AND DISSEMINATION: The study has been approved by the London-South East Research Ethics Committee (ref: 21/LO/0523). The results will be widely disseminated through peer-reviewed publications, international conferences and via our partner neonatal charities Bliss and Supporting the Sick Newborn And their Parents (SSNAP). If the parental tactile intervention is effective, recommendations will be submitted via the National Health Service clinical guideline adoption process. STUDY STATUS: Commenced September 2021. TRIAL REGISTRATION NUMBER: NCT04901611; 14 135 962.

Air travel with pneumocephalus: a systematic review.

INTRODUCTION: Concerns arise when patients with pneumocephalus engage in air travel. How hypobaric cabin pressure affects intracranial air is largely unclear. A widespread concern is that the intracranial volume could relevantly expand during flight and lead to elevated intracranial pressure. The aim of this systematic review was to identify and summarise models and case reports with confirmed pre-flight pneumocephalus. METHODS: The terms (pneumocephalus OR intracranial air) AND (flying OR fly OR travel OR air transport OR aircraft) were used to search the database PubMed on 30 November 2021. This search returned 144 results. To be included, a paper needed to fulfil each of the following criteria: (i) peer-reviewed publication of case reports, surveys, simulations or laboratory experiments that focussed on air travel with pre-existing pneumocephalus; (ii) available in full text. RESULTS: Thirteen studies met the inclusion criteria after title or abstract screening. We additionally identified five more articles when reviewing the references. A notion that repeatedly surfaced is that any air contained within the neurocranium increases in volume at higher altitude, much like any extracranial gas, potentially resulting in tension pneumocephalus or increased intracranial pressure. DISCUSSION: Relatively conservative thresholds for patients flying with pneumocephalus are suggested based on models where the intracranial air equilibrates with cabin pressure, although intracranial air in a confined space would be surrounded by the intracranial pressure. There is a discrepancy between the models and case presentations in that we found no reports of permanent or transient decompensation secondary to a pre-existing pneumocephalus during air travel. Nevertheless, the quality of examination varies and clinicians might tend to refrain from reporting adverse events. We identified a persistent extracranial to intracranial fistulous process in multiple cases with newly diagnosed pneumocephalus after flight. Finally, we summarised management principles to avoid complications from pneumocephalus during air travel and argue that a patient-specific understanding of the pathophysiology and time course of the pneumocephalus are potentially more important than its volume.

Early life serum neurofilament dynamics predict neurodevelopmental outcome of preterm infants.

BACKGROUND AND PURPOSE: To determine whether neurofilament light chain (NfL), a promising serum and cerebrospinal fluid (CSF) biomarker of neuroaxonal damage, predicts functional outcome in preterm infants with neonatal brain injury. METHODS: Our prospective observational study used a sensitive single-molecule array assay to measure serum and CSF NfL concentrations in preterm infants with moderate to severe peri/intraventricular hemorrhage (PIVH). We determined temporal serum and CSF NfL profiles from the initial diagnosis of PIVH until term-equivalent age and their association with clinical and neurodevelopmental outcome until 2 years of age assessed by Bayley Scales of Infant Development (3rd edition). We fitted univariate and multivariate logistic regression models to determine risk factors for poor motor and cognitive development. RESULTS: The study included 48 infants born at < 32 weeks of gestation. Median serum NfL (sNfL) at PIVH diagnosis was 251 pg/mL [interquartile range (IQR) 139-379], decreasing markedly until term-equivalent age to 15.7 pg/mL (IQR 11.1-33.5). CSF NfL was on average 113-fold higher (IQR 40-211) than corresponding sNfL values. Additional cerebral infarction (n = 25)-but not post-hemorrhagic hydrocephalus requiring external ventricular drainage (n = 29) nor any other impairment-was independently associated with sNfL. Multivariate logistic regression models identified sNfL as an independent predictor of poor motor outcome or death at 1 and 2 years. CONCLUSIONS: Serum neurofilament light chain dynamics in the first weeks of life predict motor outcome in preterm infants with PIVH.

Combinatory Multifactor Treatment Effects on Primary Nanofiber Oligodendrocyte Cultures.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected axons, but in MS this endogenous repair mechanism frequently fails, leaving axons increasingly vulnerable to the detrimental effects of inflammatory and metabolic stress. Understanding the molecular basis of remyelination and remyelination failure is essential to develop improved therapies for this devastating disease. However, recent studies suggest that this is not due to a single dominant mechanism, but rather represents the biological outcome of multiple changes in the lesion microenvironment that combine to disrupt oligodendrocyte differentiation. This identifies a pressing need to develop technical platforms to investigate combinatory and/or synergistic effects of factors differentially expressed in MS lesions on oligodendrocyte proliferation and differentiation. Here we describe protocols using primary oligodendrocyte cultures from Bl6 mice on 384-well nanofiber plates to model changes affecting oligodendrogenesis and differentiation in the complex signaling environment associated with multiple sclerosis lesions. Using platelet-derived growth factor (PDGF-AA), fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein 4 (BMP4) as representative targets, we demonstrate that we can assess their combinatory effects across a wide range of concentrations in a single experiment. This in vitro model is ideal for assessing the combinatory effects of changes in availability of multiple factors, thus more closely modelling the situation in vivo and furthering high-throughput screening possibilities.