Durham E-Theses Hilo Trial: A Comparative Study of High versus Low Tidal Volume in Very Low Birth Babies with Respiratory Distress Syndrome GUPTA, ANUPAM How to cite: GUPTA, ANUPAM (2019) Hilo Trial: A Comparative Study of High versus Low Tidal Volume in Very Low Birth Babies with Respiratory Distress Syndrome, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/13320/ Use policy This work is licensed under a Creative Commons Attribution Non-commercial No Derivatives 2.0 UK: England & Wales (CC BY-NC-ND) Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 Hilo Trial: A Comparative Study of High versus Low Tidal Volume in Very Low Birth Babies with Respiratory Distress Syndrome Dr Anupam Gupta MBBS MD (Paediatrics) MRCPCH PGCertCH (Glasgow) A thesis presented for the degree of Doctor of Philosophy School of Medicine, Pharmacy and Health The University of Durham United Kingdom July 2019 Hilo Trial: A Comparative Study of High versus Low Tidal Volume in Very Low Birth Babies with Respiratory Distress Syndrome Dr Anupam Gupta MBBS MD (Paediatrics) MRCPCH PGCertCH (Glasgow) Abstract Background Preterm infants often require mechanical ventilation. Volume targeted ventila- tion has been shown to reduce both complications and the duration of required mechanical ventilation. The recommended tidal volumes vary from 4-8 mL/kg, but the optimal tidal volume remains elusive. Aims and objectives To compare volume ventilation at a lower (4-5 mL/kg) with a higher (7-8 mL/kg) tidal volume during volume guarantee ventilation (VG) of respiratory distress syndrome (RDS) in very preterm infants. Methodology The randomised trial was conducted at North Tees Hospital in North East England from 2013 to 2016. Babies <32 weeks’ gestation or <1500 grams birthweight requiring mechanical ventilation within 12 hours of life from RDS were included in the study. Babies were randomised to receive lower (4-5 mL/kg) or higher (7-8 mL/kg) tidal volume using Volume Guarantee (VG). The primary outcome was the time to achieve a 25% reduction from the initial peak inspiratory pressure (PIP). Secondary outcomes included the duration of mechanical ventilation, as well as respiratory and non-respiratory complic- ations. Results Babies in both groups were similar at baseline with regard to maternal, demo- graphic and clinical characteristics. There was no difference in the primary i outcome of time difference to reach a 25% reduction in baseline peak pres- sure between the two groups. There were no differences in short term sec- ondary outcomes (air leak, pulmonary haemorrhage, sepsis, IVH, NEC, PDA and ROP) or medium term complications (Bronchopulmonary Dysplasia at 28 days’ life and 36 weeks PMA, severity of Bronchopulmonary Dysplasia, amount of home oxygen, survival to discharge and survival without Bronchop- ulmonary Dysplasia at 36 weeks PMA). The minute volume, paCO2 or FIO2 requirements were not significantly different either. Summary and conclusions This trial did not find statistically significant differences between lower versus higher tidal volume delivery in a population of 70 infants with RDS. It is possible that both tidal volume ranges selected for study are at functional residual capacity and this might be one reason for negative results of the study. Supervisors: Professor Samir Gupta and Professor A. P. S. Hungin ii Dedicated to My Parents Acknowledgements I wish to thank my supervisors Professor Samir Gupta and Professor Pali Hungin. It would be an understatement to state that this would not have been completed without their guidance and support. Professor Samir Gupta’s drive and clear think- ing have contributed enormously to ensuring this project addresses the critical clin- ical questions. It has been a privilege to be supervised by Professor Hungin. He has been the driving force behind the thesis. This was a clinical project and therefore required help and cooperation from my colleagues at the neonatal unit at University Hospital of North Tees. Dr. Hariku- mar, my mentor and a senior consultant colleague in the department helped me immensely by his inputs in the protocol and implementation. He took an active interest in ensuring that in my absence the robust methodology was followed and for that, I am grateful. My other consultant colleagues, Dr. Janakiraman, Dr. Job and Dr. Reichert, were incredibly supportive in identifying, enrolling and following the protocol. I also would like to acknowledge their significant contribution to this work by supporting my training and development both in clinical practice and in my research. I can never thank enough my research nurse, Ms. Wendy Cheadle, who helped me with preparing the randomising envelopes, distributing leaflets and taking consent from parents in my absence. I owe an enormous debt of gratitude to the exceptional nursing staffof the neonatal unit of University Hospital of North Tees (UHNT). Working in the unit has been a genuine pleasure and, at times, a welcome distraction from research work. They are caring, supportive, highly skilled, professional, and hard-working. There are far too many nursing colleagues and junior doctors to name everyone who helped me in identifying possible recruits, collecting tracheal aspirates and speaking to parents about the research. I want to mention help and contributions from Ms. Jayne Jobling, Ms. Lisa Linsel, Ms. Jodie Jenkins, Ms. Lisa Stoves, Ms. Shirley iv Lidgley, Ms. Sue Stones, Ms. Sam Davies, Dr. Sharon Probert, Dr. Anil Panicker and Dr. Soe thi Dar. I am also grateful to the Research and Development Department at the University Hospital of North Tees which helped me draft the research ethics application. The tracheal aspirates were stored at -80 degree centigrade and analysed locally by Ms. Liz Baker, the research scientist at UHNT and I am grateful to her. I am also grateful to Dr. Kasim Adetoyo, statistician at Durham University who helped with the statistics required with the thesis.The team at the former School of Medicine, Pharmacy and Health at Durham University provided much assistance in setting up this project, and I wish to acknowledge Ms. Veronica Crooks for her help and support. I would also like to express my gratitude to my Deanery colleagues, especially Dr. Lorna Gillespie, training programme director, and a consultant neonatologist to permit me to carry out this research work I am passionate about. Finally, it would be understatement to state that I am extremely grateful to my family and friends who have helped me in every step of the way to ensure that I complete this project satisfactorily. A special mention merits of Dr. Shobha Srivastava who helped me with proof reading and Dr. Atul Gupta who provided his expertise in thesis writing to help me achieve the desired formatting and backed me up with my small and big queries promptly. Their moral support and timely help made me feel supported and empowered to complete the project with the high standards set by all of us. Contents Declaration xiii List of Figures xiv List of Tables xvii Acronyms xix 1 Introduction 1 2 Resume of Literature 7 2.1 Premature babies and respiratory distress syndrome . 7 2.1.1 Very low birth weight infants . 7 2.1.2 Respiratory distress syndrome . 10 2.1.3 Pulmonary surfactant . 11 2.1.3.1 Pathophysiology . 11 2.1.4 Clinical manifestations and clinical course of RDS . 14 2.1.5 Prevention of respiratory distress syndrome . 14 2.1.5.1 Administration of antenatal corticosteroids . 15 2.1.5.2 Administration of exogenous surfactant . 15 2.1.5.3 Provision of assisted non-invasive ventilation . 17 2.1.6 Management of respiratory distress syndrome . 17 vi 2.1.6.1 Non invasive / Less invasive Ventilation . 18 2.1.6.2 Mechanical ventilation . 21 2.2 Volume Guarantee (VG) . 26 2.2.1 Newer Hybrid Modes . 26 2.2.1.1 Pressure regulated volume control (PRVC) . 26 2.2.1.2 Volume-assured pressure support (VAPS) . 27 2.2.1.3 Volume Guarantee (VG) . 27 2.2.2 Evidence in favour of volume guarantee . 28 2.2.2.1 SIMV+VG versus SIMV . 28 2.2.2.2 VG+SIPPV versus SIPPV . 30 2.2.2.3 PSV+ VG versus PSV . 30 2.2.2.4 PSV+VG versus SIMV . 31 2.3 Ventilator induced lung injury . 31 2.3.1 Definition . 32 2.3.2 Pathology . 32 2.3.3 Pathogenesis . 33 2.3.3.1 Alveolar over distension . 33 2.3.3.2 Alveolar collapse/Atelectotrauma . 35 2.3.3.3 Rheotrauma . 35 2.3.3.4 Biotrauma . 36 2.3.4 Prevention of Ventilator induced lung injury . 37 2.3.4.1 High PEEP . 38 2.3.4.2 High Frequency Ventilation . 39 2.3.4.3 Low tidal volume . 39 2.3.4.4 Lung protection strategies . 40 2.3.4.5 Preventing cyclic atelectasis . 40 2.4 Inflammatory markers of lung injury . 40 2.4.1 Cytokines . 41 2.4.1.1 Cytokines in VILI . 44 2.4.1.2 Interleukin 6 (IL-6) . 44 2.4.1.3 Interleukin 8 (IL-8) . 46 2.4.1.4 Tumour Necrosis Factor alpha (TNF-–) . 47 2.4.2 Experimental studies . 49 2.5 Tidal volume . 53 2.5.1 Lessons from animal studies . 53 2.5.2 Lessons from studies in adults . 54 2.5.3 Lessons from Paediatric studies . 56 2.5.4 Lessons from Neonatal studies . 57 3 Aims and Objectives 64 4 Methodology 69 4.1 Setting................................... 69 4.1.1 Subjects.............................. 69 4.1.2 Intervention . 70 4.1.2.1 Identification of potential recruits . 70 4.1.2.2 Inclusion Criteria .