Development, prevalence and treatment of blood pressure abnormalities in spinal cord injury Min Yin Goh ORCID: 0000-0003-2517-7745 Doctor of Philosophy August 2019 Department of Medicine, Austin Health Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy Abstract Disorders of blood pressure control arise from disruption of the autonomic nervous system and result in symptomatic orthostatic hypotension and large fluctuations in blood pressure. Ambulatory blood pressure monitoring is used in the general population for assessment of blood pressure control and to detect episodes of hypotension. In spinal cord injury (SCI), impaired control of the sympathetic nervous system leads to orthostatic intolerance and autonomic dysreflexia. Smaller studies in restricted populations have examined ambulatory pressures in SCI and observed abnormalities in diurnal blood pressure variation in complete cervical SCI. Altered diurnal blood pressure is associated with abnormalities in diurnal urine production and orthostatic intolerance in autonomic failure. This triad may also occur in SCI to explain the orthostatic intolerance. A retrospective examination of ambulatory pressures of patients with SCI referred for clinically significant blood pressure disorders revealed a high prevalence of abnormalities in diurnal blood pressure and urine production in acute and chronic tetraplegia and in acute paraplegia. To characterise the course of diurnal blood pressure, urine production and orthostatic symptoms in SCI, two prospective studies were performed. First, consecutive patients admitted with acute SCI were screened for recruitment, and consenting volunteers were compared with immobilised and mobilising controls. In the second study, people with chronic SCI (>1 year) living in the community were compared with mobilising controls. Compared with mobilising and immobilised controls, there was a high prevalence of abnormal diurnal blood pressure variation in SCI. The abnormalities were most prevalent and marked in higher and earlier SCI. Abnormalities persisted over time in both complete and incomplete cervical SCI. Abnormalities in high paraplegia were no different to that of cervical SCI in early SCI, but were no different to that of controls in chronic SCI. Nocturnal hypertension occurred in the absence of day hypertension in i SCI, thus clinic pressures may miss elevation in blood pressures and ambulatory monitoring may be beneficial in assessment of blood pressure in SCI. Abnormalities in diurnal urine production were present and persisted over time in cervical SCI, but appeared to improve over time with thoracic SCI, mirroring changes in diurnal blood pressure. Orthostatic hypotension and orthostatic intolerance were more prevalent in SCI than in controls. Mild orthostatic intolerance is common in chronic SCI and a small proportion had more severe symptoms. A single centre study to investigate a drug treatment for orthostatic intolerance in the setting of a loss of diurnal blood pressure variation was unsuccessful due to low recruitment rates. As life expectancy increases in the SCI population, there is evidence of increased rates of cardiovascular disease. Similar to the general population, the loss of diurnal blood pressure variation and elevated nocturnal pressures may be a contributor to the increased cardiovascular disease in SCI, and thus a potential therapeutic target. Ambulatory blood pressure monitoring may be useful to detect these changes and examination of a larger SCI population with a longer duration of follow up for cardiovascular disease may help to determine this. ii Declaration This is to certify that: i. this thesis comprises only my original work towards the Doctor of Philosophy except where indicated in the preface; ii. due acknowledgement has been made in the text to all other material used; and iii. this thesis is fewer than 100,000 words in length, exclusive of tables, maps, bibliographies and appendices. _______________ Min Yin Goh iii Preface Studies in this thesis were conducted as part of a large project comprising many programs, funded by the Victorian Neurotrauma Initiative which supports research in traumatic brain and spinal cord injury (SCI). A/Prof Chris O’Callaghan and Ms Melinda Millard were responsible for the concept and design for Studies 2 and 3, with input from associate investigators, A/Prof Doug Brown, Prof David Berlowitz and Dr Edmund Wong. I provided input to protocol revisions. I set up Studies 1 and 4 together with A/Prof Chris O’Callaghan, Ms Melinda Millard and A/Prof Doug Brown. Screening and recruitment for all inpatients and some outpatients for Studies 2, 3 and 4 was done by Ms Melinda Millard and Ms Janette Alexander, the Spinal Research Liaison Coordinators, as there were several concurrent studies recruiting these patients. Ms Melinda Millard assisted with participant recruitment and assessment through the project. Dr Edmund Wong performed assessments in 2010 prior to my starting with the project. Dr Mariannick Le Guen assisted with data collection from a few participants who were also undertaking a research study she was conducting. Ms Samantha Lawford and Ms Stephanie Zhao assisted with patient list cleaning and telephone screening for Study 4. Mr Oliver Lukis assisted with data entry. I carried out participant assessments, and recruitment and screening of the outpatients not covered by the Spinal Research Liaison Co-ordinators; some of this was done in 2011 and 2012, prior to my enrolment towards the degree in 2013. Prof David Berlowitz, Dr Rachel Schembri and Dr Marnie Graco assisted with access to a database, database setup and maintenance, and a statistician during the studies. Statisticians Dr Steve Vander Hoorn provided guidance in data cleaning, manipulation and preliminary data analysis planning, and Dr Sue Finch provided guidance with data analysis. With this assistance, I set up and maintained the database, extracted information for data analysis, performed data cleaning, manipulation and analysis; data analysis and interpretation was conducted with A/Prof Chris O’Callaghan. iv Collaboration with other research programs run by Prof Mary Galea, Dr Jo Spong, Dr Mariannick Le Guen and Prof Ego Seeman facilitated participant recruitment. I collected data for the three publications included in this thesis, with help as described above, did the data cleaning, manipulation and analysis with guidance from statisticians as above, wrote initial drafts of all papers and revised manuscripts after feedback from all co-authors and reviewers. A/Prof Chris O’Callaghan helped with data interpretation for all papers. All co-authors as listed on the co-author authorisation forms were involved in manuscript revision. The three articles included in Chapters 3, 4 and 5 were published online in Spinal Cord on 11 November 2014, 28 June 2016 and 2 March 2018 respectively. Funding Funding for these studies was provided by the Victorian Neurotrauma Initiative (VNI) and Transport Accident Commission (TAC) (DP174). I was supported by a scholarship (Australian Postgraduate Award, APA) through the University of Melbourne and a stipend through the Spinal Research Institute. v Acknowledgements My heartfelt thanks to many for their support through these studies: A/Prof Chris O’Callaghan for continued and invaluable support, guidance, encouragement and patience; Prof Albert Frauman for advice and supervision; Prof Ingrid Scheffer and Dr Willian Korim as my advisory committee. Ms Jo Mayall, for help with university related queries. Ms Melinda Millard for all project related tasks and continued support; Ms Janette Alexander for co-ordinating participant recruitment and assessments. The Departments of Clinical Pharmacology and Medicine, especially Dr Edmund Wong, Ms Samantha Lawford, Ms Stephanie Zhao, Ms Lesa Marr, Dr Andrew Ellis, Ms Jenni Caulfield for help with research related tasks. Mr Oliver Lukis, for help with data entry. The Spinal Unit and the Spinal Research Institute (SRI), with special mention to A/Prof Doug Brown and Dr Andrew Nunn; staff at the Spinal Units for their help and patience with my repeated requests for urine collection and scheduling of monitors/interviews. Prof David Berlowitz, Dr Rachel Schembri, Dr Marnie Graco and the IBAS for access to a database, statistician and support. Dr Steve Vander Hoorn and Dr Sue Finch for statistics related guidance, and the former for introduction to the world of R. The SCI Autonomic Group and the VNI Program and other collaborators, for facilitating recruitment of participants - Prof John Furness, A/Prof James Brock, Prof Mary Galea, Dr Jo Spong, Dr Mariannick Le Guen, Prof Ego Seeman. Participants for their time and effort, and giving me a glimpse into life with SCI. Family, friends and rats, for being there for me. The Transport Accident Commission (TAC) and Victorian Neurotrauma Initiative (VNI) for project funding; APA scholarship through the University of Melbourne and the SRI for financial support. vi Table of Contents Abstract ........................................................................................................................ i Declaration ................................................................................................................. iii Preface ........................................................................................................................ iv Acknowledgements ...................................................................................................