Title: Developing better treatments for birth related brain injury
Funder: Department of Health and Social Care

Abstract: My fellowship will involve two studies intended to improve the neurological outcome of babies with hypoxic-ischemic encephalopathy (HIE) in the NHS. In the first study, I will explore the physiological effects of high dose Erythropoietin (Epo) alongside cooling therapy, on magnetic resonance spectroscopy (MRS) thalamic N-acetyl aspartate (NAA) levels at 1 week, and neurodevelopmental outcomes at 18 months in 60 babies with moderate or severe HIE, recruited from 7 NHS hospitals. HIE is the commonest cause of disability in term babies in the UK, with major neurodisability including cerebral palsy occurring in 30% of the affected infants, despite cooling therapy. The NHS costs to provide for complex care needs of a disabled child exceeds 20m. In my NIHR Clinician Scientist fellowship, I showed that MRS thalamic NAA levels one week after birth predicts outcome at 2 years after HIE with an AUC of 0.99. Hence using NAA as a surrogate end point will accelerate clinical translation of new treatments. Epo is one of the most promising adjunct neuroprotectant therapies in animal models and in preliminary clinical studies, with a wide therapeutic window of 24 hours. Hence, if successful, this project may eventually introduce a new treatment for HIE with a potential NHS saving of 100 million per annum. The aim of the second study is to examine if non-pharmacological interventions (e.g. non-nutritive sucking, swaddling, positioning, maternal touching and holding, and reducing light and noise) can reduce the intensive care stays in babies with HIE. Most NHS hospitals use pre-emptive morphine to reduce the discomfort and back ground stress of cooling. Parents of cooled babies have major concerns with this practice. With recent data on lack of neuro-protective benefits of pre-emptive opioid sedation, and potential harms, this practice need to be re-assessed. This study will be conducted in two phases, recruiting 40 babies undergoing cooling at Imperial NHS Trust in each phase. In the first phase the current policy of routine pre-emptive morphine infusion will be continued. In the second phase, the non-pharmacological interventions will be used instead of pre-emptive morphine, with an option of rescue bolus dose of morphine. The background stress and discomfort will be quantified using continuous heart rate variability (HRV) measurement, hourly clinical score of sedation (N-PASS), and 6 hourly salivary cortisol for the first 80 hours, in both phases. In addition, salivary cortisol and HRV will be collected before and after the non-pharmacological intervention and morphine bolus in the second phase. Primary outcome is the duration of hospital stay. Secondary outcomes include the duration of ventilatory support, total morphine dose per baby, salivary cortisol levels and the thalamic NAA levels. A reduction in intensive care stay of babies with HIE by 2 days will save approximately 24 million per annum to the NHS. Both studies were developed jointly with parents, and they will continue to be involved in all aspects of the work. The work will be disseminated through our parent groups, Hope for HIE and BLISS charity, in addition to conferences and peer reviewed publications.

Lay abstract: First aim of my project is to examine if high dose erythropoietin (Epo) reduces brain injury related to oxygen deprivation around the time of birth. Birth asphyxia related brain injury occurs in 1 in 300 babies born in the UK leading to lifelong disability. Although cooling therapy improves outcome in some, it does not work in all, and many cooled babies still develop disability. Developing new medicines to reduce brain injury takes a very long time, as the effect of these medicines are apparent only during later child hood. I have recently reported that the levels of a compound called N-acetyl aspartate (NAA) in the baby's brain, can accurately predict whether or not they will develop disability in later life. In this work, Epo injections will be given to 60 babies with birth asphyxia related brain injury undergoing cooling therapy in seven NHS hospitals, during the first week after birth. All babies will have an MRI scan to examine if Epo increases the level of NAA at 1 week and reduces neurodisability at 18 months. If effective, Epo would be eventually used as a new treatment for babies with brain damage related to birth asphyxia in the NHS, so that later disability can be prevented.The second aim of my fellowship is to examine if discomfort of cooling in babies with birth asphyxia can be reduced by effective use of non-medicinal treatments like cuddling, positioning, pacifiers, reducing noise and light, so that the morphine use in these babies can be reduced. Presently, most NHS hospitals routinely sedate babies with high doses of morphine to reduce shivering and discomfort from cooling therapy. In contrast, parents have major concerns with use of morphine in their babies. This study will be conducted in two parts. In the first part, the background stress and discomfort levels in 40 babies undergoing cooling therapy over a one-year period at Imperial NHS trust will be examined. Stress in babies will quantified by measuring the levels of a stress hormone (cortisol) in saliva, and the variability of heart rhythm (higher variability indicates lower stress), in addition to clinical scoring of pain and agitation. In the second part, I will introduce the non-medicinal analgesic/sedation package in close partnership with parents and the nursing staff, instead of routine morphine treatment in the subsequent 40 babies undergoing cooling therapy. If this method can keep babies comfortable and reduce the morphine use, babies may require shorter time on breathing support, and can be discharged home earlier. I have had extensive discussions with parents of babies with brain injury in developing these studies, and they will continue to be involved in all aspects of the work. This is particularly important for the morphine study, as parental views on morphine use in babies is in contrast with the current medical and nursing views. The work will be disseminated through our parent groups, Hope for HIE and BLISS charity, in addition to medical conferences and peer reviewed publications. These projects will help me to gain further experience in clinical trials, address some key gaps in my training and to undertake the necessary training to take on senior academic leadership role. During the course of this fellowship, I hope to secure a chair position in perinatal neuroscience and to establish myself as a world leader in this field. The lack of senior clinical academics working on perinatal brain injury is a key factor for lack of progress in this field. The fellowship will allow me to address this gap, and to establish a world leading research group focused on improving outcomes of babies with birth asphyxia.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;NEUROLOGICAL