Title: Real-time non-invasive bedside monitoring of heart rate variability to improve clinical decision and reduce stress in babies with hypoxic ischaemic encephalopathy
Funder: Health Education England

Abstract: Title:Real-time non-invasive bedside monitoring of heart rate variability to improve clinical decision and reduce stress in babies with hypoxic ischaemic encephalopathy Background: Hypoxic ischaemic encephalopathy (HIE) is the single most common cause of death and lifelong neurodisability in term babies. Although cooling treatment improves outcomes for these babies, early identification (within six hours of birth) of at risk infants' remains challenging. Consequently, not all babies who need treatment will receive it and other babies receive treatment unnecessarily. Furthermore, neuroprotection from cooling may be lost if baby remains stressed during treatment, but accurate methods of measuring stress in babies are lacking. This results in suboptimal care of babies with HIE. Real-time stress monitoring would allow intervening towards stress reduction, such as by tailoring neonatal neurodevelopmental care or optimising sedation. This could improve the outcome of babies. Complexity analysis of heart rate variability (HRV), obtained from electrocardiogram, can detect stress and illness. Recent promising evidence demonstrates that HRV can identify brain injury in babies. Nonetheless, no studies have examined the clinical applications of HRV to improve early decision-making and on-going clinical management in those babies. I hypothesize that complexity analysis of heart rate variability can help improve patient outcomes of babies with HIE by a) enhancing early identification of babies who need cooling treatment, and b) non-invasively monitoring neonatal stress levels in real-time, throughout treatment. Primary aim: To examine the accuracy of heart rate variability, within six hours of birth, to predict adverse neurodevelopmental outcome in encephalopathic babies. Secondary aims: To examine the relation between heart rate variability and stress in encephalopathic babies. To identify clinical interventions associated with reduced heart rate variability (increased stress) in encephalopathic babies. Methods: I will enrol 140 babies with HIE from five NHS hospitals. Electrocardiogram and vital signs will be obtained from routine clinical monitors during the first six hours of life, and post-processed using in-house Matlab based algorithms to describe HRV values. Babies will have brain magnetic resonance (MR) imaging within 2 weeks of age and neurodevelopmental assessment at 18 months of age (Primary aim). In a subgroup of 60 babies, I will continue electrocardiographic data and Neonatal Pain and Agitation scores collection for 120 hours and measure 12-hourly salivary cortisol and Neonatal Pain, Agitation and Sedation Scores, to describe stress (secondary aims). I will collect data about clinical events (video recorded) that could affect stress levels (secondary aims). Data analysis: To establish the clinical utility of HRV as a bedside decision tool, I will analyse early HRV values in babies with and without adverse outcomes (dichotomised), use ROC curves to identify thresholds and report prognostic accuracy (sensitivity, specificity, 95% confidence intervals) of early heart rate variability (primary aim) I will test the correlation between HRV and stress levels, using logistic regression to adjust for confounders. I will describe frequency measures of HRV during clinical procedures and identify clinical interventions associated with 25% changes in HRV (secondary aims) Potential benefit to patients and the NHS: I anticipate an immediate clinical application in the NHS, with minimal additional costs, as electrocardiography is a widely used for continuous monitoring in neonatal intensive care. This work may directly impact clinical care by: (a) improving access to treatment and the number of babies who benefit from being offered cooling; (b) maximising the therapeutic effect of cooling; (c) enabling tailored neonatal nursing care based on real-time monitoring of neonatal stress and (d) improving the long-term outcomes of babies with HIE. Consequently, I expect considerable economic impact on the NHS by improving the effectiveness of treatment and reducing the overall burden of HIE.

Lay abstract: Title:Using real-time non-invasive bedside monitoring of heart trace to improve clinical decision and reduce stress in babies with brain injury Aim: This study will find out if analysing heart trace in babies with brain injury, based on standard clinical monitors, can inform treatment decisions and monitor stress levels in real time Background: Hypoxic Ischaemic Encephalopathy (HIE) occurs due to a lack of oxygen and blood flow to the baby's brain around the time of birth, causing brain damage. This is the single most common cause of death and lifelong neurodisability in term babies and results in substantial economic burden to the NHS. In babies with HIE, cooling treatment, if started within six hours of birth reduces death and neurodisability by half. However, it is difficult to identify babies who need this treatment, soon after birth, as robust bedside tools are lacking. This time-window is crucial for making clinical decisions. Sometimes, babies who need treatment are missed while others will receive treatment unnecessarily. Even when we do correctly identify babies needing treatment, treatment becomes ineffective if the baby is stressed (either due to discomfort from cooling, different factors associated with the neonatal unit environment, or due to illness). Minimising stress may be possible with skilled nursing care or sedation, but there are no effective ways of real-time stress monitoring in babies at present. Furthermore, both under or over sedation may worsen brain damage. In a healthy state, there is some variability in the heart rate (heart rate variability). Heart rate variability is reduced in stress and during different diseases. Increasingly, heart rate variability is used as a clinical tool in the NHS to predict infection in premature babies. I conducted a systematic review to examine the use of heart rate variability in babies with HIE. Although these studies were small and mostly retrospective, a consistent association between heart rate variability and the long-term outcomes was noted. I obtained a one-year fellowship to examine the feasibility of monitoring early heart rate variability in HIE. My preliminary data suggests that heart rate variability obtained from standard clinical monitors can accurately identify brain injury. I will investigate if heart rate variability obtained within six hours of birth from standard clinical monitors can predict adverse neurodevelopment in babies with HIE. This would help clinical teams make better treatment decisions and ensuring all babies with who need cooling treatment will receive it. I will also examine if heart rate variability can measure neonatal stress in real-time, which could improve treatment response. Design and Methods: I will enrol 140 term babies with signs of brain injury from five NHS Neonatal Units. I will extract heart beat data from routine clinical monitoring, which will be post-processed to compute different features of heart rate variability using in-house algorithms. Babies will have one magnetic resonance imaging scan (MRI) within two weeks of life and a full neurodevelopmental examination at 18 months of age, as part of clinical care. I will compare values of heart rate variability with how much brain injury and developmental problems the baby had. In a subgroup of 60 babies, I will compare heart rate variability with hourly pain and agitation scores (NPASS) and potentially painful clinical interventions (video recorded) for the first 5 days after birth. In addition, I will examine the relation between heart rate variability and salivary cortisol (which is produced by the body during stress), obtained 12 hourly during 5 days. Benefits: My research will have an immediate clinical application in the NHS, with minimal additional costs, as heart monitoring is widely used in neonatal units. Heart rate variability monitoring will not only enable accurate and early identification of babies who need cooling but also improve the treatment effect by monitoring stress. This will also allow tailored nursing, improving the care provided to babies. This will result in substantial savings to the NHS. Patient and Public Involvement: I involved Bliss UK Charity and Hope for HIE and spoke to 15 parents of babies with HIE who helped refining the research question and incorporated their input in this application. Parents are helping me to design study documents. Parents will be involved throughout this study and integrate the steering committee. Dissemination: Publication in peer-reviewed and open access journals; Local presentations (maternity and neonatal services), Imperial website, parent groups, across the neonatal care network, scientific meetings and international conferences; Link via Bliss and Hope for HIE, Scope and Cerebra; Social media such as twitter and podcasting short videos Imperial College Science Festival.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CARDIOVASCULAR