ASYMPTOMATIC THROMBOSIS FOLLOWING THE USE OF CENTRAL VENOUS CATHETERS IN CHILDREN Sophie Elizabeth Jones A research thesis submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy May 2017 Department of Paediatrics Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne i Abstract Central venous catheters (CVCs) are the major cause of thrombosis in acutely unwell neonates and children. This thesis reports the outcomes of a prospective study of 189 children in a paediatric intensive care unit (PICU) that aimed to determine the frequency of asymptomatic CVC-related thrombosis during hospital admission, and the incidence of residual CVC-related thrombosis and clinically significant post thrombotic syndrome (PTS) two years following CVC placement. The study also sought to identify risk factors predictive of CVC-related thrombosis and clinically significant PTS and determine the utility of ultrasound screening for asymptomatic CVC-related thrombosis in acutely unwell children. This study is distinct from previous work as children in this cohort identified to have asymptomatic CVC-related thrombosis were not treated and were followed for two years to determine the natural history of asymptomatic thrombosis. The incidence of asymptomatic CVC-related thrombus during hospital admission was 21.2% (n=31), despite over 80% of the cohort having received thromboprophylaxis. One child had a symptomatic CVC-related thrombosis. Sixteen children had new or residual thrombus identified on the follow-up ultrasound, performed a mean of 26 months post CVC placement. Of 126 PTS assessments completed at follow-up, 10.3% of children were diagnosed with mild PTS as classified by both the Manco-Johnson instrument and Modified Villalta scale. Only two children were identified to have clinically significant PTS (Manco-Johnson instrument only), one of whom had a symptomatic CVC-related thrombosis. Whilst over one fifth of the cohort had asymptomatic CVC-related thrombosis, only one of these children developed clinically significant PTS. There were no clinical embolic phenomenon or deaths attributable to CVC-related thrombosis. These findings suggest that ultrasound screening for asymptomatic CVC-related thrombosis is not indicated in children in PICU as, despite no treatment (in all but one child), the incidence of any thrombosis-associated morbidity was extremely low. In ii addition, the study’s findings support previous evidence that thromboprophylaxis provides no protection against CVC-related thrombosis in children. Neither D-dimer nor Factor VIII were predictive of CVC-related thrombosis. However, this study identified that children with femoral CVCs had a significantly higher incidence of residual thrombosis and thrombosis-associated morbidity. Children with femoral CVCs were also significantly more likely to have a higher PIM2 probability of death, cardiac arrest, hypotension, elevated D-dimer and Factor VIII compared to children with jugular CVCs. Whether the placement of the CVC in the femoral veins or the apparent higher acuity of this sub-group of patients is the mediator of increased risk (residual thrombosis and morbidity) compared to jugular CVC placement remains unclear. This study contributes novel insights into the natural history of asymptomatic CVC-related thrombosis, demonstrating a very low morbidity associated with jugular CVC placement. This study informs future clinical research targeting children most at risk of long-term CVC-related thrombosis associated morbidity. Specifically, further investigation of similar cohorts of children to those in whom femoral CVC placement occurred in this study is needed to elucidate risk factors for poor outcomes and the potential for a risk stratified approach to the treatment of asymptomatic CVC related thrombosis. iii Declaration This is to certify that: The thesis comprises only my original work towards the degree of Doctor of Philosophy. Due acknowledgement has been made in the text to all other material used. The thesis is fewer than 100,000 words in length, exclusive of tables, maps, bibliographies and appendices. Sophie Elizabeth Jones May 2017 iv Preface Jones, S. RCH Foundation Grant from the Bank of Queensland Jones, S. MCRI Clinical Sciences theme funding Jones, S. Australian College of Nursing, Centaur Grant 2013 v Acknowledgements There are many people who assisted me along the PhD journey and were very generous with their time and knowledge who I wish to thank and acknowledge. To my primary supervisor Professor Paul Monagle – your ability to get to identify the crux of any issue and eloquently describe and educate those around you with ease always amazes me. Thank you for supporting me to undertake a PhD, assisting me to find a topic that I was passionate about and for always having faith in my ability to complete the study. You always knew how to motivate me and ease my concerns along the way. Your approach to the family/ work balance gave me the confidence to keep going but motivated me to give this my all. To Professor Fiona Newall – all that you have achieved and continue to achieve is an inspiration. Your efficiency and work output constantly astounds me. I hope to have learnt a lot from you about how to collaborate with and mentor others. Thank you for your constant support, friendship, encouragement and enthusiasm. Your support was integral to me taking on this PhD and I thank you for your faith in me. Fiona and Paul - I feel extremely fortunate to have worked with you both for the last seven years. I have learnt and continue to learn so much from you, both as a student and a colleague. I consider you both to be mentors and hope we can continue to work together in the future. To Warwick Butt, thank you for your support and encouragement over the last four years. Your practical advice and insight into the patient population was invaluable. To Dr Janine Campbell and Dr Rochelle Wynne – thank you both for taking the time to be members of my advisory panel and for providing helpful feedback and critique of the study. A/Prof Trevor Duke – thank you for taking on the role of chair of my advisory panel and for sharing your knowledge, supporting my progress and ensuring I was realistic about my timelines. I very much appreciate the time you gave to this role and for you investment in me and the study. vi Dr Tim Cain – you were on board and invested in this study and its aims from day one. Thank you so much for taking such a keen interest and for all the time you have dedicated to the study on top of your existing workload. Your expert knowledge has been invaluable and I really couldn’t have finished the study without your input. I hope you are happy with the results. Ms Tania Griffiths – Tania, how do I thank you for all those hours of scanning wriggly toddlers? Thank you for giving up many of your Saturdays to complete the follow up ultrasounds and for taking on a huge job on top of your clinical workload. Thanks not only for your time but for your interest, enthusiasm and commitment to the study. There is absolutely no way this study would have been completed without you. Cain Brockley and Sara Kernick and the sonography team: Cain and Sara thank you for the huge number of ultrasounds you performed in the midst of your busy clinical days. I am so grateful for your interest and the efforts you went to performing the ultrasounds for the study. Thanks for all your time. Dr Padma Rao – thank you for your support both in terms of your own time to report the ultrasounds and also the departments support of the study. Without the efforts of the medical imaging department this study would not have been possible. To the cardiac surgical, cardiology and ICU teams for their support of the study and for allowing me access to their patients. Especially to the PICU nurses for assisting me during recruitment by contacting me and supporting parents by answering questions about the study. Lyn Marshall – your support and input during recruitment was crucial to me achieving the participant numbers that I did. Thanks for your interest and commitment when your days were already so busy. Carmel Delzoppo – thank you for supplying data at short notice with efficiency and ease. Your time is much appreciated. Eliza Mertyn, Siobhan McLoughlin, Wincy Au-Yang, Siying Wang – thank you all for your contributions to the study in the form of data entry and database development. Your hard work made my life so much easier and I sincerely appreciate your efforts. vii Jikke Rutgers – you were an invaluable addition to our research team and a pleasure to work with. Thank you so much for your dedication to the project and your attention to detail. The Haematology Research group, especially Chantal Attard, Vicky Karlaftis and A/Prof Vera Ignjatovic – thank you for always been available and ready to answer all my silly little questions, listening to me vent or guiding me along the way. Your knowledge is incredible and I feel very lucky to be part of such a supportive team. Clinical Haematology team and especially Julia Ekert and Janine Furmedge – thank you for your constant encouragement and support. You really helped to keep me motivated but also helped me to have perspective throughout the project. A/Prof Susan Donath – thank you for your time and for advising me on all statistical matters. I appreciate your patience and admire your knowledge. Thanks for your generosity in sharing your expertise with me and ensuring I was on the right path with the project. Dr Johnny Millar, A/Prof Yves D’Udekem, Dr Chris Barnes – thank you for your input and expertise offered throughout the project. Theo Lontos, Lidia De Rosa and Janet Burgess – Thank you to Theo for all the time and effort you put in to processing the samples for the study.