CATECHOLAMINES AS INDEPENDENT PREDICTORS OF OUTCOME IN MODERATE AND SEVERE TRAUMATIC BRAIN INJURY (TBI). THE COMA-TBI STUDY By Luis Teodoro da Luz A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Sciences University of Toronto © Copyright by Luis Teodoro da Luz 2015 i Catecholamines as Independent Predictors of Outcome in Moderate and Severe Traumatic Brain Injury (TBI). The COMA-TBI Study Luis Teodoro da Luz Master of Science Institute of Medical Sciences University of Toronto 2015 1. Abstract Introduction: High levels of catecholamines post brain trauma are associated with severity of injury and neurological outcome. We aimed to overcome methodological limitations of previous studies and demonstrate an independent association between circulating catecholamine levels with neurological outcome in patients with isolated brain injury. Methods: Multi site, prospective observational blinded cohort study. After enrollment, patients had catecholamine levels measured on admission and the independent association with a 6-month neurological outcome was assessed using the Glasgow Outcome Scale Extended. Multivariate logistic regression models estimated the adjusted odds ratio for prediction of unfavorable outcome. Results: 181 patients were enrolled and admission catecholamines were measured. High admission levels were independently associated with severity of injury and with unfavorable outcome. Conclusion: We demonstrated the natural history of catecholamine release early post brain injury and an independent association with unfavorable outcome in a dose response fashion. Catecholamines are biomarkers of outcome in moderate to severe traumatic brain injury. ii 2. Acknowledgments This thesis is dedicated to Flavio Henrique Duarte de Araujo, my partner of life, for showing me that there is much more to discover and achieve when leaving our comfort zone. Thanks for the constant emotional support, respect, companionship and love. I also dedicate this thesis to my parents Sebastião Teodoro da Luz (in memoriam) and Inácia Rosa da Luz, both very simple and respectful people. From mom and dad I learned how to be humble and strong at the same time, characteristics I think are important to face difficulties in life. I would like to express my deep gratitude to my supervisor Dr. Sandro Rizoli for his continuous support, patience, and helpful advice, for opening the door to a wide range of opportunities. His continuous efforts have made this project possible. I would also like to thank Dr. Andrew Baker and Dr. Leodante da Costa for their insightful feedback and strong guidance to ensure my work was moving in the right path. I would also like to extend my thanks to the members of my outstanding thesis committee members Dr. John Marshal, Dr. Sunit Das, and Dr. Eric Ley. The COMA-TBI study would not have been possible without a large team of experts that was fundamental in all phases of the study. I would like to express my immense gratitude to the strong work of all members. This unique team is represented by Dr. Capone Neto, Dr. Bartolomeu Nascimento, Dr. Gordon Rubenfeld, Dr. Kenji Inaba, Dr. Alex Di Battista, Dr. Jane T-Vranic, Dr Adic Perez, Dr. Mitra Arjang, Shawn Rhind, Sandy Trpcic, Brandon Lejnieks, Arimie Min, Yangmei Li and Monica Wong. iii 3. Contributions The idea of the COMA-TBI study initiated around 2010. In 2011 the project was written and applications for funding and Research Ethics Board approval were submitted. Patient enrollment started in late 2011. Dr. Luis Teodoro da Luz initiated his contribution to the study in 2013 when enrollment was finalizing. Dr. da Luz was involved in updating the research project, reviewing, cleaning and critically analyzing clinical data, coordinating finalization of the data with the research assistants and managers from the 3 study sites. Dr. da Luz was involved in the team effort of performing the statistical analysis and fully responsible for the production of the thesis dissertation. Dr da Luz is also an important contributor in writing the main manuscripts using the COMA-TBI study data. Dr. Sandro Rizoli was the principal investigator of the study, contributing with all aspects of the trial, from generating the research question, to study design, production of study protocol and application for funding. Dr. Rizoli also coordinated the diverse teams from the 3 different centers, and was involved in all phases of the study and reviewed the statistics analyses, results, the thesis dissertation and the COMA-TBI manuscript. Dr. Capone Neto contributed to the research question, design, study protocol production, consent forms, application for funding, and for REB approval. Dr. Capone Neto also reviewed the statistical approach and results. Dr. Alex Di Battista and Dr. Shawn Rhind were instrumental in all phases of the trial, from concept to creation to analysis and more recently, in writing and disseminating the results of the trial. Dr Rhind participated in the concept and writing of the project, arranging for funding, managed the conduction of all laboratorial experiments from sample iv collection to results. Drs Di Battista and Rhind have a major role in the analysis of the data, particularly that of the laboratorial results, and writing of the main manuscripts using the COMA-TBI data. Dr Di Battista is using part of the COMA-TBI data for his PhD work. Dr. Gordon Rubenfeld and Dr. Martin Chapman made important contributions to the initial concept and its writing by critically reviewing it. Their major contribution was to the methodology for the trial. They participated in the applications for funding and Research Ethic Board approval. They also participated on the initial phases of the clinical trial. Mrs. Sandy Trpcic was instrumental in managing the entire project, from conception to finalization. Mrs. Trpcic has coordinated the efforts from the 3 sites and ascertained that all regulations were followed and all aspects of the work were done. At SHSC: Dr. Adic Perez was the research coordinator with the important role of acquiring the data, storing it and making the results available whenever needed. At SMH: Dr. Jane Topolovec-Vranic was the Principal Investigator and was heavily support by Dr. Andrew Baker. Dr Baker was instrumental in all phases of the study, from its conception and writing, to final analysis. Mrs. Yangmei Li and Marlene dos Santos were the research coordinators responsible for all aspects of the trial, including all regulatory steps, from patient enrollment, consenting, data acquisition, and blood sample handling. At LA County: Dr. Kenji Inaba was responsible for coordinating all aspects of the trial. Mrs. Monica Wong was the local research coordinator, coordinating enrollment, consenting, data acquisition and blood sample handling. v 4. Table of Contents Page 1. Abstract __________________________________________________ ii 2. Acknowledgements _________________________________________ iii 3. Contributions ______________________________________________ iv 4. List of Tables _____________________________________________ viii 5. List of Figures _____________________________________________ ix 6. List of Appendices _________________________________________ x 7. List of Abbreviations ________________________________________ xi CHAPTER 1 – LITERATURE REVIEW ____________________________ 1 1.1 Introduction _________________________________________ 1 1.2. Catecholamines _____________________________________ 3 1.2.1. History of catecholamine Research _____________________ 3 1.2.2. Pharmacology _____________________________________ 3 1.2.2.1. Epinephrine and Norepinephrine Synthesis _____________ 3 1.2.2.2. Epinephrine and Norepinephrine Storage _______________ 4 1.2.2.3. Epinephrine and Norepinephrine Release ______________ 4 1.2.2.4. Termination of Action ______________________________ 4 1.2.2.5. Receptors and Specific Actions ______________________ 5 1.2.3. Catecholamines in Traumatic Brain Injury ________________ 8 1.2.3.1. Effects in the Brain ________________________________ 8 1.2.3.2. Paroxysmal Sympathetic Storm ______________________ 12 1.2.3.3. Effects in the Cardiovascular System __________________ 14 1.2.3.4. Effects in the Lungs _______________________________ 15 1.2.3.5. Effects in Inflammation _____________________________ 16 1.3. Catecholamines and Current TBI Therapeutic Strategies ______ 20 1.4. Prediction of Outcome after TBI _________________________ 26 1.4.1. Age ______________________________________________ 26 1.4.2. Pupillary Diameter and Light Reflex _____________________ 28 1.4.3. Hypotension _______________________________________ 29 vi 1.4.4. Glasgow Coma Scale _______________________________ 32 1.4.5. Computed Tomography (CT) Findings __________________ 33 1.4.5.1. Abnormal CT _____________________________________ 33 1.4.5.2. Classification of TBI according to CT findings ___________ 34 1.4.6. Additional Strategies to Determine Outcome ______________ 37 1.4.6.1. Clinical Assessment _______________________________ 37 1.4.6.2. Neuroimaging ____________________________________ 41 1.4.6.3. Brain Physiology/Metabolism ________________________ 42 1.4.6.4. Electrophysiology _________________________________ 43 1.4.6.5. Serum Biomarkers ________________________________ 44 1.4.6.6. Laboratory Parameters _____________________________ 46 1.4.6.7. Therapeutic Interventions ___________________________ 47 1.4.7. The Role of Catecholamines as Outcome Predictors _______ 48 CHAPTER 2 – THE COMA-TBI STUDY____________________________