Health and Social Development, Faculty of (Okanagan)
Health and Exercise Sciences, School of (Okanagan)
DSpace
UBCO
Sekhon, Mypinder Myp
Doctor of Philosophy - PhD
University of British Columbia
The pathophysiology of hypoxic ischemic brain injury comprises of an initial primary injury during circulatory arrest followed by the secondary injury following return of spontaneous circulation. Management strategies are aimed at mitigating the negative consequences of secondary injury to improve long term neurological outcome. This thesis aimed to: 1) delineate the underlying cerebrovascular pathophysiology of secondary injury following return of spontaneous circulation; and, 2) establish important physiologic relationships between the physiologic determinants of cerebral oxygen delivery and brain tissue oxygenation in hypoxic ischemic brain injury. Study 1 investigated the burden of brain hypoxia following return of spontaneous circulation and determined the relationships between physiologic determinants of cerebral oxygen delivery with brain tissue oxygenation. Episodes of brain hypoxia were prevalent following resuscitation. Study 2 sought to delineate the state of autoregulation in hypoxic ischemic brain injury patients and identify the optimal within- individual mean arterial pressure. Overall, autoregulation was dysfunctional during â¼50% of the monitoring but with significant heterogeneity. Study 3 investigated the temporal patterns of intracranial pressure and compliance in hypoxic ischemic brain injury patients after return of spontaneous circulation. Overall, hypoxic ischemic brain injury was characterized by low intracranial pressure but abnormal intracranial compliance. Study 4 examined the mechanisms of brain hypoxia after cardiac arrest and determined the presence of diffusion limitation of oxygen delivery physiology in hypoxic ischemic brain injury patients. The results identified distinct physiologic phenotypes in that diffusion limitation of oxygen delivery accounted for the predominant mechanism of brain hypoxia after resuscitation in half of the cohort; the remaining patients in the study exhibited physiologic patterns consistent with dependence upon augmentation of cerebral oxygen delivery. Collectively, the results of this thesis indicate that brain hypoxia is prevalent after return of spontaneous circulation and autoregulation seems to be dysfunctional; however, significant heterogeneity exists with respect to the vasomotor control of cerebral blood flow and optimal perfusion pressures. Finally, there appear to be distinct physiologic phenotypes with respect to oxygen transport in the cerebral microvasculature and the presence of diffusion limitation being a novel mechanism of brain hypoxia after cardiac arrest.
The Pathophysiology of Hypoxic Ischemic Brain Injury After Cardiac Arrest by Mypinder Myp Sekhon Doctor of Medicine, The University of British Columbia, 2008 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE COLLEGE OF GRADUATE STUDIES (Kinesiology) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) February 2021 © Mypinder Myp Sekhon, 2021 i The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis/dissertation entitled: THE PATHOPHYSIOLOGY OF HYPOXIC ISCHEMIC BRAIN INJURY AFTER CARDIAC ARREST submitted by Mypinder Myp Sekhon in partial fulfillment of the requirements of the degree of Doctor of Philosophy Philip N. Ainslie, School of Exercise and Health Sciences, UBC-Okanagan Supervisor Neil. Eves, School of Health and Exercise Sciences, UBC-Okanagan Supervisory Committee Member Donald E. Griesdale, Department of Anesthesiology, Therapeutics and Pharmacology, Faculty of Medicine, UBC Supervisory Committee Member Alexander Rauscher, Department of Pediatrics, Faculty of Medicine, UBC University Examiner Andrew Baker, Department of Anesthesiology and Interdepartmental Critical Care Medicine, Faculty of Medicine, University of Toronto External Examiner ii ABSTRACT The pathophysiology of hypoxic ischemic brain injury comprises of an initial primary injury during circulatory arrest followed by the secondary injury following return of spontaneous circulation. Management strategies are aimed at mitigating the negative consequences of secondary injury to improve long term neurological outcome. This thesis aimed to: 1) delineate the underlying cerebrovascular pathophysiology of secondary injury following return of spontaneous circulation; and, 2) establish important physiologic relationships between the physiologic determinants of cerebral oxygen delivery and brain tissue oxygenation in hypoxic ischemic brain injury. Study 1 investigated the burden of brain hypoxia following return of spontaneous circulation and determined the relationships between physiologic determinants of cerebral oxygen delivery with brain tissue oxygenation. Episodes of brain hypoxia were prevalent following resuscitation. Study 2 sought to delineate the state of autoregulation in hypoxic ischemic brain injury patients and identify the optimal within- individual mean arterial pressure. Overall, autoregulation was dysfunctional during ï¾50% of the monitoring but with significant heterogeneity. Study 3 investigated the temporal patterns of intracranial pressure and compliance in hypoxic ischemic brain injury patients after return of spontaneous circulation. Overall, hypoxic ischemic brain injury was characterized by low intracranial pressure but abnormal intracranial compliance. Study 4 examined the mechanisms of brain hypoxia after cardiac arrest and determined the presence of diffusion limitation of oxygen delivery physiology in hypoxic ischemic brain injury patients. The results identified distinct physiologic phenotypes in that diffusion limitation of oxygen delivery accounted for the predominant mechanism of brain hypoxia after resuscitation in half of the cohort; the remaining patients in the study exhibited physiologic patterns consistent with dependence upon augmentation of cerebral oxygen iii delivery. Collectively, the results of this thesis indicate that brain hypoxia is prevalent after return of spontaneous circulation and autoregulation seems to be dysfunctional; however, significant heterogeneity exists with respect to the vasomotor control of cerebral blood flow and optimal perfusion pressures. Finally, there appear to be distinct physiologic phenotypes with respect to oxygen transport in the cerebral microvasculature and the presence of diffusion limitation being a novel mechanism of brain hypoxia after cardiac arrest. iv LAY SUMMARY This thesis delineated the mechanisms of additional brain injury which occur following a cardiac arrest. The results demonstrate that episodes of low brain oxygen levels after cardiac arrest are prevalent and significant relationships exist between augmenting delivery of oxygen to the brain and improved brain oxygenation. The brainâs ability to regulate its own blood flow and hence, oxygen delivery, was impaired and the optimal blood pressure in individual patients was significantly higher than guidelines. Although the pressure within the skull was normal, the compliance of the injured brain was markedly abnormal. A novel mechanism of low brain oxygen levels was identified stemming from an inability of oxygen to diffuse into the brain tissue. Finally, red blood cell transfusion resulted in a differential response to improved brain oxygenation, likely related to heterogenous physiology of patient exhibiting normal and abnormal oxygen transport into the brain. v PREFACE The University of British Columbia Clinical Research Ethics Board approved the overall studies of which the experimental chapters comprise this dissertation (CRED ID: H16-04466 and H16-03114). Chapter 1. Chapter one was written by Mypinder Sekhon and edited by Professor Philip Ainslie. The background for section 1.2.1.1 and 1.2.1.2 formed as the introduction as part of the a published manuscript: Sekhon MS, Gooderham P, Menon DK, Brasher PMA, Foster D, Cardim D, Czosnyka M, Smielewski P, Gupta AK, Ainslie PN, Griesdale DEG. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med. 2019. Jul;47(7):960-969. The background for section 1.2.1.3 formed as the introduction as part of the a published manuscript: Sekhon MS, Griesdale DE, Ainslie PN, Gooderham P, Foster D, Czosnyka M, Robba C, Cardim D. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019 Aug;141:96-103. The background for section 1.2.1.4 formed as the introduction as part of the a published manuscript: Sekhon MS, Ainslie PN, Menon DK, Foster D, Cardim D, Thiara S, Hoiland RL, Gupta AK, Gooderham P, Griesdale DEG. Brain hypoxia secondary to diffusion limitation in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med. 2019. In Press. Chapter 2. Chapter two was written by Mypinder Sekhon and edited by Professor Philip Ainslie. Chapter 3. Chapter three was written and published in Critical Care as a narrative review: Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model. Crit Care. 2017 Apr 13;21(1):90. The manuscript, figures, tables and text were drafted by Dr. Sekhon and edited by Professor Ainslie and Dr. Griesdale. Chapter 4. Chapter four was published in a manuscript in Critical Care Medicine: Sekhon MS, Gooderham P, Menon DK, Brasher PMA, Foster D, Cardim D, Czosnyka M, Smielewski P, vi Gupta AK, Ainslie PN, Griesdale DEG. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med. 2019. Jul;47(7):960-969. Results of the study were also presented at Neurocritical Care, Boca Raton Florida, September 2018. Dr. Sekhon was responsible for data collection, conducting the study, analysis and manuscript preparation. The figures were created with substantial assistance and guidance from Dr. Griesdale. Professor Ainslie assisted with editing the manuscript. CREB H16-04466 Chapter 5. Chapter five was published in a manuscript in Critical Care Medicine: Sekhon MS, Gooderham P, Menon DK, Brasher PMA, Foster D, Cardim D, Czosnyka M, Smielewski P, Gupta AK, Ainslie PN, Griesdale DEG. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med. 2019. Jul;47(7):960-969. Results of the study were also presented at Neurocritical Care, Boca Raton Florida, September 2018. Dr. Sekhon was responsible for data collection, conducting the study, analysis and manuscript preparation. The figures were created with substantial assistance and guidance from Dr. Griesdale. Professor Ainslie assisted with editing the manuscript. CREB H16-04466 Chapter 6. Chapter six was published in a manuscript in Resuscitation: Sekhon MS, Griesdale DE, Ainslie PN, Gooderham P, Foster D, Czosnyka M, Robba C, Cardim D. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019 Aug;141:96-103. Results of the study were also presented at Neurocritical Care, Boca Raton Florida, September 2018. Dr. Sekhon was responsible for data collection, conducting the study, analysis and manuscript preparation. The figures were created with substantial assistance and guidance from Dr. Cardim. Professor Ainslie assisted with editing the manuscript. CREB H16-04466 Chapter 7. Chapter seven was published in a manuscript in Critical Care Medicine: Sekhon MS, Ainslie PN, Menon DK, Foster D, Cardim D, Thiara S, Hoiland RL, Gupta AK, Gooderham P, Griesdale DEG. Brain hypoxia secondary to diffusion limitation in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med. 2019. In Press. Results of the study vii were also presented at Neurocritical Care, Vancouver BC, Canada, October 2019. Dr. Sekhon was responsible for data collection, conducting the study, analysis and manuscript preparation. The figures were created with substantial assistance and guidance from Dr. Griesdale. Professor Ainslie assisted with editing the manuscript. CREB H16-04466. Chapter 8. This study has not been presented at a conference in an abstract form and has not been published in a peer review journal. Dr. Sekhon developed the study design, obtained ethical approval, conducted data collection and analysis. The figures were created with assistance from Dr. Danilo Cardim. CREB H16-03114. viii TABLE OF CONTENTS PAGE ABSTRACTâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦ii LAY SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.......iv PREFACEâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...v TABLE OF CONTENTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...viii LIST OF FIGURESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...xvi LIST OF TABLESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.xx LIST OF EQUATIONSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.xxi ACKNOWLEDGEMENTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..xxiii GLOSSARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...xxv 1. CHAPTER 1: INTRODUCTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..1 1.1 THESIS OBJECTIVESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦3 1.2 SPECIFIC AIMS AND HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦..4 1.2.1 STUDY 1 (CHAPTER 4)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...4 1.2.1.1 STUDY 1 â AIMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...4 1.2.1.2 STUDY 1 â HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦â¦.4 1.2.2 STUDY 2 (CHAPTER 5)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...4 1.2.2.1 STUDY 2 â AIMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...4 1.2.2.2 STUDY 2 â HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦â¦..4 1.2.3 STUDY 3 (CHAPTER 6)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....5 1.2.3.1 STUDY 3 â AIMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...5 1.2.3.2 STUDY 3 â HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦â¦..5 1.2.4 STUDY 4 (CHAPTER 7)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....5 1.2.4.1 STUDY 4 â AIMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....5 1.2.4.2 STUDY 4 â HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦â¦...6 1.2.5 STUDY 5 (CHAPTER 8)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...â¦..6 1.2.5.1 STUDY 5 â AIMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....6 1.2.5.2 STUDY 5 â HYPOTHESISâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦6 ix 2. CHAPTER 2: A REVIEW OF CEREBRAL OXYGEN DELIVERY 2.1 THE DETERMINANTS OF CEREBRAL OXYGEN DELIVERY 2.1.1 CEREBRAL BLOOD FLOWâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.8 2.1.1.1 CEREBRAL PERFUSION PRESSUREâ¦â¦â¦â¦â¦â¦â¦...11 2.1.1.2 MEAN ARTERIAL PRESSUREâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....13 2.1.1.3 INTRACRANIAL PRESSUREâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...14 2.1.1.4 CEREBRAL BLOOD FLOW REGULATIONâ¦â¦â¦â¦â¦...17 2.1.1.4.1 NEUROVASCULAR COUPLINGâ¦â¦â¦â¦..18 2.1.1.4.2 HYPOXEMIAâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...20 2.1.1.4.3 CARBON DIOXIDEâ¦â¦â¦â¦â¦â¦â¦â¦â¦....20 2.1.1.4.4 METABOLISMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....22 2.1.1.4.5 AUTONOMIC NERVOUS SYSTEMâ¦â¦â¦..22 2.1.1.4.6 AUTOREGULATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦..23 2.1.1.5 LEFT VENTRICULAR PHYSIOLOGYâ¦â¦â¦â¦â¦â¦â¦â¦.25 2.1.2 ARTERIAL OXYGEN CONTENTâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..29 2.1.2.1 HEMOGLOBIN CONCENTRATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦29 2.1.2.2 ARTERIAL OXYGEN TENSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦.......30 2.1.3 NEUROMONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...31 2.1.3.1 INVASIVE INTRACRANIAL PRESSURE MONITORâ¦....31 2.1.3.2 BRAIN OXYGEN MONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..33 2.1.3.2.1 BRAIN TISSUE OXYGEN MONITORâ¦â¦..33 2.1.3.2.2 JUGULAR VENOUS BULB OXIMETRYâ¦..34 2.1.3.2.3 NEAR INFRARED SPECTROSCOPYâ¦â¦...35 2.1.3.3 CEREBRAL MICRODIALYSIS MONITORINGâ¦â¦â¦â¦...37 2.1.3.4 INVASIVE CEREBRAL BLOOD FLOW MONITORâ¦â¦...38 2.1.3.5 AUTOREGULATION MONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦...38 3. CHAPTER 3: A REVIEW OF HYPOXIC ISCHEMIC BRAIN INJURY PATHOPHYSIOLOGY x 3.1 PRIMARY INJURYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.......45 3.2 SECONDARY INJURYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.49 3.2.1 MICROCIRCULATION AND REPERFUSION INJURYâ¦â¦â¦50 3.2.2 ANEMIAâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...55 3.2.3 CARBON DIOXIDEâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦56 3.2.4 CEREBRAL EDEMAâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..58 3.2.5 CEREBRAL AUTOREGULATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦59 3.2.6 TEMPERATUREâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.63 3.2.7 NORMOBARIC HYPEROXIAâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...65 3.2.8 GAPS IN HIBI PATHOPHYSIOLOGYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.68 4. CHAPTER 4: BRAIN HYPOXIA AND CEREBRAL OXYGEN DELIVERY IN HYPOXIC ISCHEMIC BRAIN INJURY 4.1 STUDY 1 â METHODSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦70 4.1.1 STUDY POPULATION AND SETTINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦...70 4.1.2 NEUROMONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..70 4.1.3 DATA COLLECTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.72 4.1.4 PATIENT MANAGEMENTâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...73 4.1.5 STATISTICAL ANALYSESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...73 4.2 STUDY 1 â RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..75 4.2.1 SUMMARY RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...75 4.2.2 BRAIN HYPOXIA AND MEAN ARTERIAL PRESSURE â¦â¦.77 4.2.3 BRAIN OXYGENATION AND CARBON DIOXIDE, TEMPERATURE AND INTRACRANIAL PRESSUREâ¦â¦â¦..78 4.2.4 CEREBRAL PERFUSION PRESSURE AND MEASURES OF CEREBRAL OXYGEN DELIVERYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..79 4.3 STUDY 1 â DISCUSSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.83 4.3.1 THE BURDEN OF BRAIN HYPOXIA DESPITE GOAL ORIENTED RESUSCITATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..83 xi 4.3.2 THE RELATIONSHIP BETWEEN BRAIN TISSUE OXYGENATION AND MEAN ARTERIAL PRESSUREâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.85 4.3.3 AGREEMENT BETWEEN BRAIN TISSUE OXYGENATION AND JUGULAR VENOUS OXIMETRY AND NEAR INFRARED SPECTROSCOPYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.87 4.4 STUDY 1 â SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..88 5. CHAPTER 5: AUTOREGULATION AND OPTIMAL MEAN ARTERIAL PRESSURE IN HYPOXIC ISCHEMIC BRAIN INJURY 5.1 STUDY 2 â METHODSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...90 5.1.1 STUDY POPULATION AND SETTINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦.....91 5.1.2 PRESSURE REACTIVITY INDEXâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.91 5.1.3 DATA COLLECTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...92 5.1.4 OPTIMAL MEAN ARTERIAL PRESSURE, LOWER AND UPPER LIMIT OF AUTOREGULATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....92 5.1.5 STATISTICAL ANALYSESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..93 5.2 STUDY 2 â RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.94 5.2.1 SUMMARY RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....94 5.2.2 PRESSURE REACTIVITY INDEX AND AUTOREGULATION â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..96 5.2.3 AUTOREGULATION OVER TIMEâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....97 5.2.4 OPTIMAL MEAN ARTERIAL PRESSURE, LOWER AND UPPER LIMIT OF AUTOREGULATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦.100 5.2.5 OPTIMAL MEAN ARTERIAL PRESSURE AND BRAIN TISSUE OXYGENATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....101 5.2.6 PRESSURE REACTIVITY INDEX RELATIONSHIP TO CARBON DIOXIDE TENSION AND TEMPERATUREâ¦â¦â¦..103 5.3 STUDY 1 â DISCUSSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..104 5.3.1 THE SIGNIFICANCE OF AUTOREGULATION IMPAIRMENTâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.104 5.3.2 THE RELATIONSHIP OPTIMAL MEAN ARTERIAL PRESSURE xii AND IMPROVED BRAIN TISSUE OXYGENATIONâ¦â¦â¦â¦.105 5.3.3 STRENGTHS AND LIMITATIONSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..106 5.4 STUDY 1 â SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦108 6 CHAPTER 6: INTRACRANIAL PRESSURE AND COMPLIANCE IN HYPOXIC ISCHEMIC BRAIN INJURY 6.1 STUDY 3 â METHODSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.110 6.1.1 STUDY POPULATION AND SETTINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.110 6.1.2 INTRACRANIAL PRESSURE AND COMPLIANCE MONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.111 6.1.3 DATA COLLECTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..112 6.1.4 INTRACRANIAL PRESSURE MANAGEMENTâ¦â¦â¦â¦â¦â¦..113 6.1.5 STATISTICAL ANALYSESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.113 6.2 STUDY 3 â RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦114 6.2.1 SUMMARY RESULTS â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...114 6.2.2 INTRACRANIAL PRESSURE AND COMPLIANCE OVER TIMEâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦116 6.2.3 BURDEN OF INTRACRANIAL HYPERTENSION AND LIMITED COMPLIANCEâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..117 6.2.4 RELATIONSHIP BETWEEN INTRACRANIAL PRESSURE AND TEMPERATURE AND CARBON DIOXIDEâ¦â¦â¦â¦â¦..118 6.2.5 INTRACRANIAL PRESSURE MANAGEMENTâ¦â¦â¦â¦â¦â¦.119 6.3 STUDY 3 â DISCUSSION 6.3.1 THE SIGNIFICANCE OF NORMAL INTRACRANIAL PRESSURE AFTER CARDIAC ARRESTâ¦â¦â¦â¦â¦â¦â¦â¦â¦121 6.3.2 THE SIGNIFICANCE OF LIMITED INTRACRANIAL COMPLIANCE AFTER CARDIAC ARRESTâ¦â¦â¦â¦â¦â¦â¦..123 6.3.3 LIMITATIONSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦125 6.4 STUDY 1 â SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦125 xiii 7 BRAIN HYPOXIA SECONDARY TO DIFFUSION LIMITATION IN HYPOXIC ISCHEMIC BRAIN INJURY 7.1 STUDY 4 â METHODSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...127 7.1.1 STUDY SUBJECTS AND MANAGEMENTâ¦â¦â¦â¦â¦â¦â¦â¦.127 7.1.2 DEFITION OF BRAIN NORMOXIA VERSUS HYPOXIAâ¦â¦.128 7.1.3 NEUROMONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..128 7.1.4 BLOOD GAS DATA COLLECTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.129 7.1.5 SECONDARY MEASURES AND CALCULATIONSâ¦â¦â¦â¦..130 7.1.6 COMPUTED TOMOGRAPHYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..130 7.1.7 STATISTICAL ANALYSESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..â¦.131 7.2 STUDY 4 â RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..131 7.2.1 SUMMARY RESULTS â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.131 7.2.2 DESCRIPTION OF DIFFUSION LIMITATIONâ¦â¦â¦â¦...â¦132 7.2.3 DETERMINANTS OF CEREBRAL OXYGEN DELIVERYâ¦..133 7.2.4 DIFFUSION LIMITATION OF OXYGEN DELIVERYâ¦â¦....134 7.2.5 SECONDARY DERIVATIVES OF METABOLISMâ¦â¦â¦â¦..135 7.2.6 COMPUTED TOMOGRAPHYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦136 7.3 STUDY 4 â DISCUSSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..â¦.136 7.3.1 THE SIGNIFICANCE OF DIFFUSION LIMITATION OF OXYGEN DELIVERYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..137 7.3.2 CLINICAL IMPLICATIONS OF DIFFERENTIAL PATHOPHYSIOLOGYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦139 7.3.3 LIMITATIONS AND FUTURE STEPSâ¦â¦â¦â¦â¦â¦â¦â¦â¦.140 7.4 STUDY 4 â SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...141 8 RED BLOOD CELL TRANSFUSION IN HYPOXIC ISCHEMIC BRAIN INJURY AFTER CARDIAC ARREST 8.1 STUDY 5 METHODSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦143 8.1.1 STUDY SUBJECTS AND STUDY SITEâ¦â¦â¦â¦â¦â¦â¦â¦â¦...143 8.1.2 PATIENT MANAGEMENTâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...144 xiv 8.1.3 NEUROMONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦144 8.1.4 BLOOD GAS DATA COLLECTIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦145 8.1.5 SECONDARY MEASURES AND CALCULATIONSâ¦â¦â¦â¦.145 8.1.6 RED BLOOD CELL TRANSFUSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.146 8.1.7 STATISTICAL ANALYSESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..146 8.2 STUDY 5 RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.147 8.2.1 SUMMARY RESULTSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..147 8.2.2 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFISION RESULTS â OVERALL COHORTâ¦â¦â¦â¦150 8.2.3 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFUSION AND JUGULAR VENOUS BULB OXYGEN SATURATION IN PATIENTS WITH < 75%.........156 8.2.4 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFUSION AND SECONDARY DERIVATIVES OF METABOLISMâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦162 8.3 STUDY 5 DISCUSSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..163 8.3.1 RED BLOOD CELL TRANSFUSION AND BRAIN OXYGENATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦163 8.3.2 DIFFERENTIAL EFFECTS OF RED BLOOD CELL TRANSFUSIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.164 8.3.3 LIMITATIONS AND FUTURE STEPSâ¦â¦â¦â¦â¦â¦â¦â¦â¦..165 8.4 STUDY 5 SUMMARYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..166 9 CONCLUSION 9.1 REVIEW OF OBJECTIVES AND CONCLUSIONSâ¦â¦â¦â¦.167 9.1.1 THE BURDEN OF BRAIN HYPOXIAâ¦â¦â¦â¦â¦...168 9.1.2 RELATIONSHIPS BETWEEN DETERMINANTS OF CEREBRAL OXYGEN DELIVERY AND BRAIN TISSUE OXYGENATIONâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..169 9.1.3 AUTOREGULATION AND OPTIMAL MEAN ARTERIAL PRESSUREâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..170 xv 9.1.4 INTRACRANIAL PRESSURE AND COMPLIANCEâ¦.170 9.1.5 DIFFUSION LIMITATION OF OXYGEN DELIVERYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.171 9.2 CLINICAL IMPLICATIONSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.172 9.2.1 OPTIMAL MEAN ARTERIAL PRESSUREâ¦â¦â¦â¦â¦172 9.2.2 ABNORMAL INTRACRANIAL COMPLIANCEâ¦â¦â¦.173 9.2.3 DIFFUSION LIMITATION OF OXYGEN DELIVERYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.173 9.3 FUTURE DIRECTIONSâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.174 9.3.1 GAPS IN THE PATHOPHYSIOLOGY OF HYPOXIC ISCHEMIC BRAIN INJURYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦174 9.3.2 INCORPORATING CEREBRAL BLOOD FLOW MONITORINGâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...175 9.3.3 INCORPORATING BRAIN BIOMARKERS IN FUTURE STUDIESâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.176 9.3.4 INTERVENTIONAL STUDY DESIGN IN HYPOXIC ISCHEMIC BRAIN INJURYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....176 BIBLIOGRAPHYâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....178 xvi LIST OF FIGURES Figure 2.1 The determinants of cerebral oxygen deliveryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.7 Figure 2.2 The anatomy of the cerebrovasculatureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦11 Figure 2.3 Cerebral perfusion pressure as a determinant of cerebral oxygen deliveryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.12 Figure 2.4 The intracranial pressure volume relationship and compliance curveâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..16 Figure 2.5 The intracranial pressure waveforms of compliance and non-complianceâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..16 Figure 2.6 The autoregulation curve in normal healthâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..24 Figure 2.7 The pressure volume relationship of the left ventricle and afterloadâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦27 Figure 2.8 Computed tomography demonstrating bolt and intracranial pressure catheter placementâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.31 Figure 2.9 Methods of neuromonitoringâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..32 Figure 2.10 Brain tissue oxygen monitoringâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦34 Figure 2.11 Lateral cervical spine x-ray confirming jugular venous bulb catheter placementâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦35 Figure 2.12 Regional oxygen saturation using near infrared spectroscopyâ¦â¦â¦â¦â¦..36 Figure 2.13 A U-shaped curve denoting the optimal mean arterial pressureâ¦â¦â¦â¦...40 Figure 2.14 A real time U-shaped curve optimal cerebral perfusion pressure identification and intact zone of autoregulationâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.41 Figure 3.1 Diffusion weighted imaging of focal hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...43 xvii Figure 3.2 Computed tomography and diffusion weighted imaging of diffuse hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.44 Figure 3.3 Approach to the management of hypoxic ischemic brain injuryâ¦â¦â¦...50 Figure 3.4 The pathophysiology of hypoxic ischemic brain injury at the neurovascular unitâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.51 Figure 3.5 The effect of carbon dioxide tension on intracranial pressureâ¦â¦â¦â¦...57 Figure 3.6 Right shifted and narrowed intact zone of autoregulation in hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.â¦61 Figure 3.7 Optimal mean arterial pressure identification using cerebral oxygen indexâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.62 Figure 4.1 Study design and data collection of neurophysiology variablesâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..71 Figure 4.2 Bedside placement of the invasive neuromonitoring via a cranial boltâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..72 Figure 4.3 Scatterplots of brain tissue oxygenation and mean arterial pressure in individual patientsâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....77 Figure 4.4 The relationship between brain tissue oxygenation and carbon dioxideâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦....78 Figure 4.5 The relationship between brain tissue oxygenation and temperatureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....79 Figure 4.6 The relationship between brain tissue oxygenation and cerebral perfusion pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....80 Figure 4.7 The relationship between regional oxygen saturation and cerebral perfusion pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.....80 Figure 4.8 The relationship between jugular venous bulb oxygen saturation and cerebral perfusion pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.81 xviii Figure 4.9 The relationships between brain tissue oxygenation versus regional oxygen saturation and jugular venous bulb oxygen saturationâ¦â¦â¦â¦...82 Figure 4.10 Bland-Altman between brain tissue oxygenation and jugular venous bulb oxygen saturationâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.â¦.82 Figure 4.11 Bland-Altman between brain tissue oxygenation and regional oxygen saturationâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..83 Figure 4.12 ICM+ screenshot with brain tissue oxygenation and regional oxygen saturationâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..86 Figure 4.13 ICM+ screenshot with brain tissue oxygenation and cerebral perfusion pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.........86 Figure 4.14 ICM+ screenshot with brain tissue oxygenation and cerebral perfusion pressure and intracranial pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.88 Figure 5.1 Individual scatterplots of pressure reactivity index over timeâ¦â¦.........96 Figure 5.2 Patterns of autoregulation using pressure reactivity index in hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...97 Figure 5.3 Optimal mean arterial pressure, lower and upper limit of autoregulation over timeâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...98 Figure 5.4 The relationship between norepinephrine dose and pressure reactivity indexâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.99 Figure 5.5 The relationship between propofol dose and pressure reactivity indexâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.99 Figure 5.6 Optimal mean arterial pressure, lower and upper limit of autoregulation in the cohortâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.100 Figure 5.7 Time density plot of actual mean arterial pressure within optimal mean arterial pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.101 Figure 5.8 The relationship between brain tissue oxygenation and difference between actual mean arterial pressure and optimal mean xix arterial pressureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..102 Figure 5.9 The relationship between pressure reactivity index and temperatureâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..103 Figure 5.10 The relationship between pressure reactivity index and end tidal carbon dioxideâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.103 Figure 6.1 The intracranial compliance curve and compensator reserve index (RAP)â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...112 Figure 6.2 Individual scatterplots of intracranial pressure over timeâ¦â¦â¦â¦â¦116 Figure 6.3 Individual scatterplots of RAP over timeâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.117 Figure 6.4 The relationships between intracranial pressure versus brain tissue oxygenation, temperature and end tidal carbon dioxide tensionâ¦â¦â¦â¦.118 Figure 6.5 Patterns of intracranial pressure and compliance in hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.124 Figure 7.1 Study design of diffusion hypoxia in hypoxic ischemic brain Injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.130 Figure 7.2 Individual scatterplots of the PvO2 â PbtO2 gradients in patients with nomoxia and hypoxiaâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...133 Figure 7.3 The relationship between cerebral perfusion pressure and the PvO2 â PbtO2 gradients in patients with nomoxia and hypoxiaâ¦â¦â¦â¦â¦â¦....135 Figure 8.1 Pre and post red blood cell transfusion change in hemoglobin concentration, arterial and venous oxygen contentâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...154 Figure 8.2 Pre and post red blood cell transfusion change in hemoglobin concentration, arterial oxygen tension, arterial and venous oxygen content in patients with a pre transfusion saturation < 75%..............................................160 Figure 8.3 Pre and post red blood cell transfusion change in jugular venous bulb oxygen saturation in patients with a pre transfusion saturation < 75%........161 xx LIST OF TABLES Table 3.1. Summary of mechanisms of secondary brain injury after hypoxic ischemic brain injuryâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦.48 Table 3.2. Pathophysiology summary of cerebral reperfusion injury after cardiac arrestâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...54 Table 4.1. Patient demographics and clinical outcome of study cohortâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..76 Table 5.1. Patient demographics and clinical outcome of study cohortâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..95 Table 6.1. Patient demographics and clinical outcome of study cohortâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..115 Table 6.2. Intracranial pressure management interventions in the cohortâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..120 Table 7.1 Patient demographics in study subjects with brain normoxia versus hypoxiaâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦132 Table 7.2 Physiology of study subjects with brain normoxia versus hypoxiaâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...134 Table 7.3 Cerebral oxygenation and metabolism data in patients with brain normoxia versus hypoxiaâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦..136 Table 8.1 Patient demographics of the red blood transfusion cohortâ¦â¦â¦â¦.149 Table 8.2 Pre and Post red blood transfusion data in the cohortâ¦â¦â¦â¦â¦â¦150 Table 8.3 Pre and Post red blood transfusion data in patients with jugular venous bulb oxygen saturation < 75%...............................................................156 Table 8.4 Pre and Post RBC Transfusion of secondary measures of ischemia and metabolismâ¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦â¦...162 xxi LIST OF EQUATIONS 1. CaO2 = 1.36 x [SaO2 / 100] x [Hb] + 0.003 x PaO2 2. CvO2 = 1.36 x [SvO2 / 100] x [Hb] + 0.003 x PvO2 3. O2EF = [(CaO2 â CvO2) / CaO2)] x 100% 4. ÎPCO2 = PvCO2 â PaCO2 5. AJDO2 = ([SaO2 â SjvO2] x [Hb] x 1.34) + ([PaO2 â PvO2] x 0.003) 6. Ratio = ÎPCO2 / AJDO2 7. VADL = Jugular venous bulb lactate â arterial lactate 8. Lactate oxygen index = VADL / AJDO2 9. Cerebral blood flow = cerebral perfusion pressure / cerebrovascular resistance 10. Cerebral oxygen delivery = CBF x CaO2 11. CMRO2 = CBF x (CaO2 â CvO2) 12. Oxygen diffusion barrier gradient = PvO2 â PbtO2 13. Cerebral perfusion pressure = mean arterial pressure â intracranial pressure 14. Mean arterial pressure = DBP + (1/3) (SBP â DBP) xxii 15. Blood pressure = Cardiac output x Systemic vascular resistance 16. Cardiac output = Stroke volume x heart rate 17. Oxygen delivery = Cardiac output x CaO2 18. MAPDIFF = Optimal mean arterial pressure â actual mean arterial pressure xxiii ACKNOWLEDGEMENTS The body of work which encompasses this thesis is the culmination of tremendous teamwork stemming from mentorship, collaboration and guidance from numerous individuals locally and internationally. I have been fortunate to benefit from many of the brightest and most intuitive scientific minds in the field of neurocritical care, critical care and cerebrovascular research. Firstly, I would like to thank my supervisor, Professor Philip Ainslie for his guidance, mentorship and support. It has been a true pleasure and honor to learn from you and be part of the Ainslie Lab. In the same breath, I would like to thank my mentor, colleague and best friend, Donald Griesdale. When I met you as a first-year medical resident and began working with you, I found myself wanting to emulate you professionally and personally. Most of what I have and have accomplished thus far in my career is directly attributable to you. Thank you. Thank you to Denise Foster, our ICU research coordinator. You have incredible patience for me and you are the foundation of our research program. Thank you to my ICU clinical colleagues for your support of our program of research and your collaboration. Thank you to Dr. Peter Gooderham, our neurosurgery colleague and collaborator. Thank you also to my colleague, friend and collaborator, Dr. Danilo Cardim. Thank you for all your help and I have learned greatly from you. To Professors David Menon and Arun Gupta, my mentors from the University of Cambridge. Not only did you teach me the fundamentals of neurocritical care but you taught me numerous xxiv lessons on how to conduct quality research, to push the boundaries of science and strive for excellence. Thank you to Dr. Neil Eves and my committee members for their support and guidance. To my wife, Becca, you inspire me and push me to the best person I can be. It is no coincidence that since I have met you, I have grown tremendously as a doctor, scientist but most importantly, as a person and husband. You are absolutely incredible and I am so fortunate to have you (and Lily â our dog) in my life. Thank you. To my parents, Satnam and Harman. I am beyond fortunate to have you as parents. Your support, guidance and love have paved the way for me in life. I am forever indebted and appreciative. You provided me with every opportunity and incredible upbringing, while making personal sacrifices, working multiple simultaneous jobs and enduring a long distance marriage to provide us with the optimal childhood. To my brother, Indy, you are actually a pretty cool guy and a tremendous little brother. I appreciate you more and more as we have grown and I am so lucky to have you as my sibling. To my grandparents (Gurmit and the late Avtar, Manjit and Gulzara), you raised me and brought our family to Canada. Your perseverance, hard work and dedication is something that I will never forget. Thank you. xxv GLOSSARY AJDO2 Arterio-jugular venous difference in oxygen content AQP4 Aquaporin 4 ATP Adenosine triphosphate BBB Blood brain barrier CA Cardiac arrest Ca2+ Calcium CaO2 Arterial oxygen content CBF Cerebral blood flow CDO2 Cerebral oxygen delivery CMRO2 Cerebral metabolic rate of oxygen COx Cerebral oxygen index CPP Cerebral perfusion pressure CT Computed tomography CvO2 Venous oxygen content DBP Diastolic blood pressure EEG Electroencephalography ETCO2 End tidal carbon dioxide GCS Glasgow coma scale GOS Glasgow outcome scale Hb Hemoglobin HIBI Hypoxic ischemic brain injury xxvi ICP Intracranial pressure ICU Intensive care unit JVB Jugular venous bulb LOI Lactate oxygen index LLA Lower limit of autoregulation MAP Mean arterial pressure MAPDIFF Difference between optimal MAP and actual MAP MAPOPT Optimal mean arterial pressure NH Normobaric hyperoxia NIRS Near infrared spectroscopy O2EF Oxygen extraction fraction ONSD Optic nerve sheath diameter ÎPCO2 Partial pressure of arterial carbon dioxide PaCO2 Arterial carbon dioxide tension PaO2 Partial pressure of arterial oxygen PbtO2 Brain tissue oxygenation PET Positron emission tomography PRx Pressure reactivity index PvCO2 Venous carbon dioxide tension PvO2 Venous oxygen tension PvO2 â PbtO2 Venous to brain tissue oxygen gradient RAP Compensatory reserve index ROSC Return of spontaneous circulation xxvii rSO2 Regional saturation of oxygen SaO2 Arterial oxygen saturation of hemoglobin SBP Systolic blood pressure SjvO2 SvO2 Jugular venous bulb hemoglobin oxygen saturation Venous oxygen saturation of hemoglobin TBI Traumatic brain injury TH Therapeutic hypothermia ULA Upper limit of autoregulation VADL Veno-arterial difference of lactate VF Ventricular fibrillation 1 1 CHAPTER 1: INTRODUCTION All cellular function depends upon the delivery of oxygen to end capillary beds to facilitate aerobic metabolism. The respiratory system inhales oxygen from the surrounding environment, allows its transfer into the pulmonary capillary bed and subsequent binding to hemoglobin before being transported to the capillary beds of the bodyâs various organs by the cardiovascular system. The intimate dependence of the central nervous system upon the heart and the cardiovascular system to provide continuous supply of blood flow and hence, oxygen and nutrient delivery, underpins the pathophysiology of hypoxic ischemic brain injury during and after cardiac arrest1. The brain and central nervous system, consumes upwards of 10 times of the cardiac output, relative to its mass, to maintain adequate neuron homeostasis and essential functioning2,3. This, in part secondary to the lack of significant inherent energy stores, is essential to meet the high metabolic demands of the brain in health and also in diseased states2,4. During cardiac arrest, whether the etiology originates from a primary cardiac etiology or secondary to systemic causes (hypoxia, hemorrhage, electrolyte disturbances etc.), immediate cessation of cerebral blood flow results and then the brain is placed at significant risk of irreversible damage1,5â7. In fact, animal studies have demonstrated a near immediate loss of electroencephalography signals within 20 to 30 seconds after experimental cessation of cerebral blood flow and hence, oxygen delivery8. Furthermore, human studies have also shown a clinical loss of consciousness during a similar timeline following either cardiac arrest or cessation of cerebral blood flow8. This unique sensitivity to ischemia was highlighted during an unethical series of human experiments known as the Red Wing studies in the 1940âs. Entitled âAcute arrest of circulation in the human brainâ, the investigators took advantage of nonâconsenting 2 psychiatric patients to gain a better understanding of why pilots were blacking out and to assess âanoxic shock therapyâ as an alternative treatment for schizophrenia9. After application of a specialized cervical pressure cuff that could be inflated to 600 mmHg within â th of a second, unconsciousness was consistently observed within 4â10 s of ischemia. Partly based on these early observations, conventional teaching has suggested that within 3 to 4 minutes of absence of cerebral blood flow, irreversible neuron and cell death occurs. Recently, this long held belief is being increasingly challenged in recognizing that a significant portion of the cerebrovascular pathophysiology following cardiac arrest may occur after successful return of spontaneous circulation after successful resuscitation1. The secondary injury following cardiac arrest, emanating following resuscitation, results from many underlying pathophysiologic mechanisms which will be discussed in chapter 3. The bulk of literature aimed at identifying therapeutic strategies geared towards mitigating secondary injury has focused on the use of therapeutic hypothermia. In recent years, it has also been demonstrated that an imbalance or perturbations in physiologic variables that affect cerebral oxygen delivery, are associated with adverse clinical outcome10â13. As such, increasing attention is being targeted towards identifying optimal hemodynamic resuscitation strategies for patients after cardiac arrest14,15. Although epidemiologic studies provide tantalizing justification, the in-depth evaluation of the cerebrovascular pathophysiology and foundational relationships between the determinants of cerebral oxygen delivery and brain oxygenation in cardiac arrest patients with hypoxic ischemic brain injury has not been identified. This thesis is aimed at clarifying these underlying relationships and providing insights into the post-resuscitation pathophysiology of hypoxic ischemic brain injury. Chapter 1 provides 3 a general introduction and objectives as well as hypotheses of the experimental chapters. Chapter 2 focuses on providing a narrative review of the determinants of cerebral oxygen delivery, cerebral blood flow regulation and the neuromonitoring techniques used in the forthcoming experimental chapters. Chapter 3 reviews the main pathophysiologic mechanisms of hypoxic ischemic brain injury during circulatory arrest and following successful resuscitation. Chapters 4 to 7 form the experimental chapters of this thesis, each of which aims to delineate underlying pathophysiologic mechanisms of post-cardiac arrest patients that incorporate important clinical considerations for the design and implementation of future therapeutic interventions. Chapter 8 aims to investigate the effect of red blood transfusion - an intervention aimed at increasing cerebral oxygen delivery on brain oxygenation - in patients with hypoxic ischemic brain injury. This chapter builds upon the concepts outlined in chapters 4 to 7 and examines whether a therapeutic intervention can alter the pathophysiology of hypoxic ischemic brain injury. The final chapter provides the conclusions from this thesis and highlights the next steps in post-resuscitation brain injury management. 1.1 THESIS OBJECTIVES: The main theme and central objectives of this thesis focus on investigating the pathophysiology of hypoxic ischemic brain injury after resuscitation from cardiac arrest as it pertains to secondary injury, cerebral autoregulation disturbances, intracranial pressure, burden of brain hypoxia and identification of distinct physiologic phenotypes. Furthermore, this thesis aims to understand the relationships between physiologic determinants of cerebral oxygen delivery and their relationships with brain oxygenation following resuscitation. The following sections outline an introduction, specific aims and hypotheses for each experimental chapter. 4 1.2 SPECIFIC AIMS AND HYPOTHESES: 1.2.1 STUDY 1 (CHAPTER 4) 1.2.1.1 STUDY 1 â AIM The aims of this study were to a) investigate the burden of brain hypoxia after HIBI using parenchymal brain tissue oxygen (PbtO2) monitoring and, b) determine the relationships between cerebral perfusion pressure (CPP) and PbtO2, regional oxygen saturation (rSO2) and jugular venous bulb oxygen saturation (SjvO2) in hypoxic ischemic brain injury (HIBI) after cardiac arrest. 1.2.1.2 STUDY 1 - HYPOTHESES 1) During normoxemia (PaO2 80 - 100mmHg), post resuscitation brain hypoxia (PbtO2 < 20mmHg) will be prevalent (>25% of the time) during the study monitoring period despite goal-oriented management; 2) There will be a significant linear relationship between CPP with PbtO2 and SjvO2 but not rSO2. 1.2.2 STUDY 2 (CHAPTER 5) 1.2.2.1 STUDY 2 â AIM The aims of the study were to (1) describe autoregulation longitudinally using pressure reactivity index (PRx), (2) determine the optimal mean arterial pressure (MAPOPT), (3) determine the lower (LLA) and upper limit of autoregulation (ULA), and (4) characterize the relationship between deviance from MAPOPT and PbtO2. 1.2.2.2 STUDY 2 - HYPOTHESIS 1) Monitoring autoregulation using PRx after resuscitation will yield significant changes over time following resuscitation; 2) Using PRx, MAPOPT will be identified at a higher value 5 than is currently advocated in international guideline recommendations (MAP > 65mmHg); 3) The LLA and ULA will be identified using PRx following resuscitation and will be higher values than is currently advocated in international guideline recommendations for MAP targets; 4) There will be a significant relationship between perfusion within proximity to MAPOPT and improved PbtO2. 1.2.3 STUDY 3 (CHAPTER 6) 1.2.3.1 STUDY 3 â AIM The specific aims of this study were to a) characterize the burden of intracranial hypertension (ICP > 20 mmHg), b) evaluate the changes in ICP and intracranial compliance over time; and c) examine the relationships between core body temperature and carbon dioxide tension with ICP in patients with HIBI after cardiac arrest. 1.2.3.2 STUDY 3 - HYPOTHESIS 1) Despite goal-oriented management, there will be a significant burden (>25% of the time) of intracranial hypertension (ICP > 20mmHg) during the study monitoring period; 2) There will be limited intracranial compliance using the compensatory reserve index (RAP) during the study monitoring period; 3) There will be significant relationships between increased core body temperature and carbon dioxide with increased intracranial pressure following resuscitation. 1.2.4 STUDY 4 (CHAPTER 7) 1.2.4.1 STUDY 4 â AIM The aim of this study was to a) determine the difference between jugular venous bulb oxygen tension to brain tissue oxygen tension (PvO2 â PbtO2) in HIBI patients with brain 6 hypoxia versus normoxia as a surrogate for the diffusion barrier of oxygen delivery at the neurovascular unit and to b) determine the presence of diffusion limitation of oxygen delivery by assessing the relationship between the PvO2 â PbtO2 gradient and CPP in patients with brain hypoxia vs. normoxia. 1.2.4.2 STUDY 4 - HYPOTHESIS 1)There will be a significant absolute difference between the PvO2 â PbtO2 gradient in patients with brain normoxia versus hypoxia; 2) There will be an inverse relationship between CPP and the PvO2 â PbtO2 gradient in patients with brain normoxia but no relationship between CPP and the PvO2 â PbtO2 gradient in patients with brain hypoxia. 1.2.5 STUDY 5 (CHAPTER 8) 1.2.5.1 STUDY 5 â AIM The aims of this study were to investigate whether red blood cell transfusion would result in an increase in the jugular venous bulb oxygen saturation. 1.2.5.2 STUDY 5 - HYPOTHESIS 1)There will be a significant absolute increase in the jugular venous bulb oxygen saturation after red blood cell transfusion. 7 2 CHAPTER 2: A REVIEW OF CEREBRAL OXYGEN DELIVERY 2.1 THE DETERMINANTS OF CEREBRAL OXYGEN DELIVERY Although the brain parenchyma constitutes 2% of the body weight, it receives 20-25% of the cardiac output to maintain normal cellular function2. The highly metabolically active nature of the brain parenchyma demands continuous oxygen and nutrient delivery to prevent neuron ischemia or metabolic crisis2. Therefore, maintaining adequate cerebral oxygen delivery (CDO2) is of paramount importance after acute brain injury. CDO2 is directly dependent upon cerebral blood flow, the volume of blood which flows through the cerebral vasculature per minute, and arterial oxygen content4. Cerebral blood flow can vary depending on the type of cerebral tissue Figure 2.1. Cerebral oxygen delivery is equivalent and dependent upon cerebral blood flow and arterial oxygen content. Cerebral blood flow is proportional to the cerebral perfusion pressure, which in turn is equivalent to mean arterial pressure subtracted by intracranial pressure. Cerebral blood flow is inversely proportional to cerebrovascular resistance. Arterial oxygen content is predominantly dependent upon hemoglobin concentration and to a lesser extent, dissolved oxygen tension. CDO2 = Cerebral oxygen delivery; CBF = Cerebral blood flow; O2 = oxygen. This figure is original for this manuscript. 8 and ranges from 35ml/100g/min in subcortical white matter to upwards of 100ml/100g/min in highly metabolic regions of the cerebrum in normal health2,16,17. The arterial oxygen content is principally determined hemoglobin concentration and saturation3. A much smaller component of arterial oxygen content is determined by the dissolved portion of arterial oxygen gas tension. 2.1.1 CEREBRAL BLOOD FLOW Cerebral blood flow, the main determinant of oxygen delivery to the brain and central nervous system is tightly controlled and dependent upon numerous intrinsic feedback and forward mechanisms to maintain constant oxygen and nutrient delivery to the brain2,16,18. The physics of flow are encapsulated by Ohmâs law which states: Q = Î P / R Q = Flow Î P = Pressure differential across a hollow tube R = Resistance to flow in a hollow tube Whereby: R = (8 * µ * L) / (Ï * r4) µ = viscosity constant of the fluid L = length of a hollow tube Ï = pi r = radius of a hollow tube Given this application of Ohmâs law for cerebral blood flow, ÎP can be substituted by cerebral perfusion pressure, the driving pressure of flow into the intracranial space and R can be assumed to represent cerebrovascular resistance2. In the setting of the cerebrovasculature, µ 9 assumes the viscosity of blood, which is proportional to the hematocrit in healthy states19. The length of continuum of the cerebrovasculature is fixed in the absence of surgical interventions such as bypass grafting. The radius of the cerebrovasculature can be modified by physiological and therapeutic interventions which will be discussed in the upcoming sections. The cerebrovascular anatomy is also imperative to understand as alterations in cerebral blood flow can occur at various locations through its path. In health, the aorta originates from the left ventricle and through the great vessels, supplies blood flow to the central nervous system. Specifically, the brachiocephalic artery is the first great vessel to splinter off the aortic arch and branches into the right common carotid and subclavian arteries, respectively. Thereafter, the left common carotid and left subclavian arteries emerge. The cerebrovascular anatomy can be divided into the anterior and posterior circulation, of which contribute 80% and 20% of the cerebral blood flow to the brain, respectively2,20. At the level of the thyroid cartilage, both common carotid arteries splinter into the right and left internal and external carotid arteries. The internal carotid arteries traverse through the internal carotid canal, cavernous sinus and enter the intracranial space while the external carotid arteries supply blood flow to the facial tissues and muscles20. Upon entering the intracranial space, the internal carotid arteries bifurcate into the middle and anterior cerebral arteries20. The anterior cerebral arteries are joined by the anterior communicating artery and supply blood flow to the medial aspect of the frontal and parietal lobes including the pre-frontal sensory and motor cortex for the lower extremities20. The middle cerebral arteries supply blood flow to the lateral aspect of the frontal lobes, temporal lobe and parietal lobes20. Particularly, critical structures pertaining to the perception of speech (Wernickeâs area) and production of speech (Brocaâs area) are supplied by the terminal 10 projections of middle cerebral artery blood flow in the dominant hemisphere as well as lateral aspects of the pre-frontal sensory and motor cortex pertaining to contralateral upper limb and facial innervation20. Furthermore, the deep projections of the middle cerebral arteries, the lenticulostriate arteries and deep perforators from the anterior cerebral arteries supply blood flow to the basal ganglia, internal capsules and thalami20. The posterior circulation us supplied by the vertebral arteries which originate from the ipsilateral subclavian arteries and subsequently traverse through intervertebral foramen. The vertebral arteries enter the spinal canal and merge at the level of the caudal pons to form the basilar artery. The basilar artery supplies blood flow to the pons and midbrain through small perforators and bifurcates into the posterior cerebral arteries upon entering the foramen of monro2,20. The posterior cerebral arteries subsequently project posteriorly and supply the ipsilateral occipital cortex while joining the middle cerebral arteries via the posterior communicating arteries. The joining of the anterior and posterior circulation forms the Circle of Willis, which serves as an anatomical backup mechanism to provide collateral flow in the setting of an acute compromise of vascular supply in one of the major branches of the major intracranial arteries20. Given the complexity of vascular supply, the arterial cerebrovasculature can be divided into four distinct regions which can be uniquely responsive to physiologic stressors. Specifically, these regions are the a) extra-cranial portion of the vertebral and internal carotid arteries; b) major intracranial arteries (anterior, middle and posterior cerebral arteries), pial arteries and parenchymal arteriole vasculature2. 11 Figure 2.2. A depiction of the cerebral vascular anatomy. The anterior and posterior circulations join at the Circle of Willis which is located at the level of the foramen magnum. Re-printed with permission from Cambridge University Press: Neurocritical care Essentials: A Practical Guide 2.1.1.1 CEREBRAL PERFUSION PRESSURE As stated, cerebral blood flow is directly proportional to the cerebral perfusion pressure, which represents the driving cardiovascular pressure to the brain parenchyma inside the intracranial space21. Cerebral perfusion pressure is equivalent to the mean arterial pressure minus the intracranial pressure and is the principal determinant of cerebral blood flow in health and after acute brain injury22. In fact, physiological studies have demonstrated that CPP augmentation is improved with improved cerebral blood flow on positron emission scanning23. Furthermore, CPP augmentation has also shown to increase parenchymal tissue oxygenation, an invasive monitoring technique which serves as an indirect monitor of cerebral blood flow24. 12 International guidelines have advocated for maintenance of CPP 50 â 70mmHg after acute traumatic brain injury and routine monitoring of CPP has been identified as a quality metric of acute brain injury intensive care25. CPP guided perfusion therapy and resuscitation is an established strategy for acute traumatic brain injury26â28; however, this dogma has not been systematically evaluated or advocated for in HIBI patients. High quality studies incorporating invasive intracranial pressure monitoring in HIBI have not been conducted previously and, as such, key physiological relationships between CPP and cerebral oxygen delivery or clinical outcome are unknown. Figure 2.3. Cerebral perfusion pressure is the primary determinant of cerebral blood and as such, cerebral oxygen delivery. Cerebral perfusion pressure is equivalent to mean arterial pressure subtracted by intracranial pressure. CDO2 = Cerebral oxygen delivery; CBF = Cerebral blood flow; O2 = Oxygen. This figure is original for this manuscript. 13 2.1.1.2 MEAN ARTERIAL PRESSURE The mean arterial pressure is the driving pressure of flow generated by the cardiovascular system in the systemic arterial vasculature29. It is calculated as follows: Mean arterial pressure = DBP + (1/3) (SBP â DBP) DBP = Diastolic blood pressure SBP = Systolic blood pressure Importantly, it should be recognized that MAP is ultimately a derivative of blood pressure which is proportional to the cardiac output and systemic vascular resistance. As such, the generation of MAP is reflected by its dependence upon diastolic and systolic blood pressure, whereby diastolic blood pressure is dependent upon the vascular tone and elastance in the large and small systemic arterial tree29. In critically ill states, perfusion guided resuscitation has predominantly focused on the assumption that MAP is equivalent to tissue perfusion. This assumption is, of course, an imperfect link30. The systemic delivery of oxygen to the vital organs is directly dependent upon cardiac output and absolute blood pressure is only partially related to systemic oxygen delivery via cardiac output30. Therefore, it is plausible and often manifested in critically ill states where the cardiac output may be reduced (i.e. acute cardiogenic failure, obstructive or hypovolemic shock) and compensatory systemic vasoconstriction occurs with an increased systemic vascular resistance29,30. As such, absolute blood pressure and hence, MAP, may be preserved while overall oxygen delivery being severely compromised30. Notwithstanding, the ability to easily and relatively non-invasively continuously monitor MAP, as opposed to cardiac output and systemic vascular resistance, has spurned troves of physiologic studies equating MAP perturbations to clinical outcomes of tissue ischemic, hypoxia and organ failure in critically ill states31â35. Given these assumptions, it is important that a 14 thorough discussion of the importance and limitations of MAP be provided in this thesis. As stated above, MAP is the primary driver of CPP and hence, CBF, particularly in the setting of normal or low intracranial pressure. Its importance also must be taken into context with concomitant contractile function of the left ventricle, which will be discussed in an upcoming section (2.1.1.5). 2.1.1.3 INTRACRANIAL PRESSURE Intracranial pressure (ICP), the sum of pressures exerted by the intracranial compartments within the rigid skull, is a key physiologic variable in assessing the dynamic pathophysiological states of acute brain injuries36. The intracranial space is composed of distinct volume compartments pertaining to brain parenchyma, cerebrospinal fluid and vascular volumes. Due to the rigid nature of the skull, the overall sum of these compartmentâs volumes cannot exceed the available space in the intracranial vault without herniation syndromes taking place37. As such, the Monro-Kellie doctrine states: âThe skull is a rigid bowl that offers little flexibility for changes in the size of the three intracranial components. To maintain normal pressure in the skull, any increase in the size of one component initially will lead to a compensatory decrease in one or both of the other twoâ In a typical adult human, the intracranial space holds approximately 1500ml of total volume, of which, 1200ml (80%) is encompassed by parenchymal tissue, 150ml (10%) by the ventricular system and 150ml (4-10%) with the cerebrovasculature37. In the setting of a mass expanding lesion, the compensatory mechanisms consist of collapse and shunting of cerebrospinal fluid out of the ventricular system or shunting of venous blood flow out of the intracranial space36,37. At the level of the arachnoid villa in the superior sagittal sinus, 15 cerebrospinal fluid is reabsorbed into the venous sinus and then exits the intracranial space via the venous vasculature. As important as is the concept of the absolute value of intracranial pressure, its interpretation in the context of intracranial compliance encompasses the importance of ICP. In figure 2.4, the intracranial compliance curve depicted with ICP (y axis) plotted versus the volume of a mass expanding lesion (x axis). In otherwise healthy humans, the ICP remains low, in the absence of a pathologic mass expanding lesion. As the volume of a mass continues to expand, the compensatory mechanisms become limited the ICP rises precipitously given small increases in the volume of the mass37. At the top portion of the curve, the ICP plateaus as the mass continues to grow, indicating herniation through the foramen magnum. Estimating the intracranial compliance can also be estimated by interrogating the ICP waveform. In the normal setting, the ICP waveform has three distinct peaks: P1, P2 and P338,39. P1 is largely accepted to represent the transmission of the arterial pulse from the cerebrovasculature during systole36. P2 represents the bulk of cerebral parenchymal tissue and is denoted as the venous rebound wave36. P3 is thought to represent the transmission of the recoil in the arterial vasculature from the closure of the aortic valve36. In health, the amplitude of P1 is greater than P2 and P339. As the intracranial compliance worsens, prominence of P2 predominates over P1 and P339. In the setting of pre-herniation, the waveform becomes rounded as all three components merge into one peak39. 16 Figure 2.4. The intracranial compliance curve refers to the pressure volume relationship within the cranial cavity. As the volume of a mass expanding lesion increases, initially the intracranial pressure stays stable because of excellent compensatory reserve. As the volume increases, the intracranial pressure rises precipitously because of limited compensatory reserve. At the top of the curve, the intracranial pressure plateaus because compensatory reserve is exhausted. The figure is original for this manuscript. Figure 2.5. The intracranial pressure waveform has three distinct peaks, P1, P2 and P3. As the cranial vault enters a non-compliant state, P2 becomes accentuated as compared to P1 and P3. Re-printed with permission from Cambridge University Press: Neurocritical care Essentials: A Practical Guide 17 2.1.1.4 CEREBRAL BLOOD FLOW REGULATION Given the importance of continual delivery of oxygen and nutrients to the brain parenchymal, cerebral blood flow regulation in lieu of various physiological variables is necessary. Cerebral blood flow is regulated by both intrinsic and extrinsic physiological , variables2. Intrinsically, cerebral blood flow is regulated by mean arterial pressure, a process termed âautoregulationâ, which will be discussed below as well as the underlying state of cerebral metabolic activity2. Extrinsically, cerebral blood flow is regulated by body temperature, arterial carbon dioxide tension, arterial oxygen tension and blood viscosity. The brain has a unique ability to match its blood flow requirements to the underlying metabolic activity, a phenomenon referred to as âflow-metabolic couplingâ. In normal health, when exposed to central nervous system depressant anesthetic agents such as propofol or benzodiazepines, the cerebral vasculature undergoes appropriate vasoconstriction to match the blood flow requirements of the parenchyma and avoid the harmful effects of excess cerebral blood flow40. Importantly, halogenated volatile anesthetics do not maintain this relationship and may lead to excess cerebral blood flow in lieu of reduced metabolic activity. Similarly, core body temperature can influence cerebral blood flow through âflow-metabolicâ coupling41. For every degree (Celsius) decrease in core body temperature, the cerebral blood flow also appropriately decreases by ~7% as cerebral metabolic activity is reduced by hypothermia2. Arterial oxygen tension can also influence cerebral blood flow. When exposed to arterial hypoxemia (PaO2 < 50mmHg), the cerebral vasculature dilates to maintain adequate cerebral oxygen delivery3. The mechanisms underlying this physiologic phenomenon will be discussed in the upcoming sections. Conversely, arterial normobaric hyperoxia may cause cerebral vasoconstriction and decrease cerebral blood flow42. Finally, blood viscosity, principally 18 determined by red blood cell mass, may also affect blood flow in the cerebrovasculature2. Optimal cerebral blood flow is thought to occur between a hematocrit of 30 to 35%. 2.1.1.4.1 NEUROVASCULAR COUPLING The neurovascular unit comprises of the anatomical functional unit in the microvascular beds of the cerebrovasculature where critical interplay occurs between the vasculature and surrounding cells that control microvascular cerebral blood flow18. At this anatomical level, the cerebral vasculature is surrounded by astrocyte end-feet processes which help form the tight blood brain barrier. The physical proximity of these structures also facilitates control mechanisms on the regulation of blood flow from astrocytes43. In the surrounding tissue, glial cells, neuron cell bodies, end synapses and pericytes are also located, all of which play a role in the regulation of blood flow at this level18. The notion of neurovascular coupling describes the underlying cellular mechanisms and signaling pathways which underlie this intricate network of blood flow regulation. The necessity of neurovascular coupling in the microvasculature is required because of the lack of inherent neuronal energy stores, the requirement of continual nutrient and oxygen delivery to meet the high metabolic demands of the brain and the recognition of heterogenous metabolic profiles of distinct structures of the brain which require local control of blood flow and metabolism16. Neurovascular coupling allows each of the brainâs critical structures to alter their own blood flow and metabolism and function as distinct microclimates within the overall structure of the cerebrum. Conceptually, these control mechanisms can be summarized into distinct pathways but the reality is that there are multiple links between them and further unrecognized cross-over 19 effects that are yet to be determined. However, for simplicity, the various mechanisms that are currently known to play a role in neurovascular coupling will be discussed. First, nitric oxide signaling has been identified as major controller of microvascular blood flow at the neurovascular unit18. Mediators such as glutamate, adenosine triphosphate, gamma aminobutyric acid (GABA) and acetylcholine activate surface receptors including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and GABA, respectively, on neuron cell bodies which subsequently cause in the intracellular influx of calcium ion16,18. The increase in intracellular calcium ion concentration then stimulates the production of nitric oxide, which is then shuttled into the vascular smooth muscle of cerebral arterioles18. Nitric oxide, through the production of cyclic guanosine monophosphate (GMP) then facilitates vasodilation and augmentation of microvascular blood flow18. A relatively depletion of nitric oxide and hence, cyclic GMP, would conversely lead to net vasoconstriction and reduction of cerebral blood flow. Second, prostaglandin mediated vascular control has also emerged as an identified control mechanism of blood flow at the neurovascular unit. Activation of purine receptors on the cell surface of astrocytes leads to intracellular calcium influx, which then activates cyclo-oxygenase to convert arachidonic acid into prostaglandins18. Arachidonic acid can also be converted into epoxyeicosatrienoic acids (EET) which is then shuttled into the vascular smooth muscle from the astrocytes and facilitates vasodilation and CBF augmentation18. Finally, end synapse release of extracellular potassium accumulates in the vascular smooth muscle and facilitates vasodilation18. This release of potassium is stimulated by various metabolites and physiologic stressors which will be discussed below. 20 2.1.1.4.2 HYPOXEMIA The exposure to acute hypoxemia (PaO2 < 50mmHg) with preserved overall bulk blood flow elicits a profound response that stimulates various structures of the brain to elicit vasodilatory responses to increased CBF. Specifically, the nitric oxide and prostaglandin pathways appear to play an intricate role in the regulation of blood flow in the microvasculature when exposed to hypoxemia3,44. For example, hypoxemia is known to result in the activation of intrinsic nitric oxide synthase (iNOS) in the neuron cell bodies and then leads to production of increased nitric oxide, cyclic GMP and vasodilation45. The aforementioned prostaglandin pathway emanating from the astrocytes also appears to be augmented by acute hypoxemia. It is important to note that hypoxemia should be distinguished from tissue ischemia, in which anaerobic cellular metabolism ensues from reduced cerebral oxygen delivery from a reduction in cerebral blood flow or arterial oxygen content. In this setting, tissue ischemia is known to elicit the production of adenosine, increased extracellular potassium concentration and lactate production, all of which lead to vasodilation and hence increases in cerebral blood flow16,18. Finally, it is imperative to appreciate the regional differences in the effect of acute hypoxemia on cerebral blood flow. In particular, the cerebral cortex and brainstem are especially sensitive to hypoxemia induced increases in CBF, thereby highlighting the heterogenous nature of the regional pathways within the brain2. 2.1.1.4.3 CARBON DIOXIDE Arterial carbon dioxide tension is a key modulator of cerebral blood flow. Specifically, hypocapnia (PaCO2 < 35mmHg) results in cerebral vasoconstriction whereby, cerebral blood 21 flow decreases by 2 to 3% for every decrease of 1 mmHg in the arterial carbon dioxide tension2,17. Conversely, hypercapnia (PaCO2 > 45mmHg) leads to cerebral vasodilation and can augment cerebral blood flow. Importantly, prolonged elevations in arterial carbon dioxide can cause cerebral vascular engorgement and lead to increased intracranial pressure. In health the arterial carbon dioxide tension mediates CBF and its effects on cerebrovascular reactivity occur throughout a wide range of arterial carbon dioxide tension (15 to 60 mmHg)2. The mechanism underlying the effect of PaCO2 on CBF involves its direct effect within the smooth muscle of the cerebrovasculature2. PaCO2 freely diffuses across the cerebral endothelium and within the smooth muscle, it combines with water to form carbonic acid (H2CO3). Thereafter, H2CO3 dissociates into hydrogen and bicarbonate (HCO3-) ions. The hydrogen ion and the development of an acidotic environment within the smooth muscle results in vasodilation. The converse is true when exposed the hypocapnia. The effect of arterial carbon dioxide tension is mitigated over time whereby vascular smooth muscle buffering with bicarbonate ions renders its effect on cerebral vascular tone ineffective. Quantitatively, CBF increases by 3 â 6% for every mmHg increase in PaCO2 and conversely, CBF decreases by 1 to 3% per mmHg decrease of PaCO2 in otherwise healthy humans2. The effect of PaCO2 on the cerebrovasculature occurs anatomically from the extracranial vasculature (internal carotid and bilateral vertebral arteries), large intracranial arteries, pial arterioles and parenchymal vessels2. Historically, the pial vessels were thought to dilate up to 40% and represent the major site of decrease in cerebrovascular resistance in the setting of hypercapnia. Importantly, the effect of PaCO2 does not occur homogenously throughout the cerebral parenchyma and remainder of the central nervous system. Magnetic resonance imaging indicates 22 that the effect of PaCO2 mediated changes in CBF occur to a greater extent in the grey matter than in the sub-cortical white matter2. 2.1.1.4.4 METABOLISM With the mechanisms of neurovascular coupling in mind, cerebral metabolism is a potent regulator of blood flow in the cerebrovascular beds. Overall, the brain exhibits a unique ability to undergo flow-metabolic coupling, in that when exposed to changes in regional or diffuse changes in metabolism, the cerebrovasculature is able to alter blood flow to meet with metabolic demands of the neuronal tissues2,16. Clinically, this concept is manifested by activation of the visual cortex leading to an increase of upwards of 20% of blood flow in the posterior cerebral arteries selectively2,46. The heterogenous nature of this finding highlights the local regulation of blood flow within the cerebrovasculature. In a pathologic state such as refractory status epilepticus, widespread seizures can increase the basal metabolic rate of the cerebral parenchyma and the net effect of increased metabolism is matched with a proportional rise in cerebral blood flow and oxygen delivery47. Conversely, depressing metabolism, with the use of select intravenous sedatives or therapeutic hypothermia can result in a matched reduction of cerebral blood flow. Importantly, it must be stated that halogenated volatile anesthetics can uncouple flow-metabolic coupling as can concomitant disease states. 2.1.1.4.5 AUTONOMIC NERVOUS SYSTEM The autonomic nervous system, which is encompassed by the balance between the sympathetic and parasympathetic balance, is a critical modulator of systemic hemodynamics and also has effects on the cerebrovasculature2,48. Anatomically, sympathetic nerve fibers are located 23 in the distinct layers of the cerebrovasculature: a) a para-vascular layer on the surface of the adventitia; b) a perivascular layer within the adventitia; and c) a perivascular layer between the adventitia and tunica media of the vasculature2. Traditionally, the cerebrovasculature was thought to be relatively devoid of adrenergic receptors compared with the peripheral or splanchnic vascular beds and hence, immune to the vascular effects of sympathetic output or circulating catecholamines. This historical dogma has been challenged and recent studies in healthy humans suggest the contrary. For example, it has been demonstrated that cerebral blood flow is increased following cervical sympathetic ganglionectomies49. Furthermore, studies involving trimethaphan induced sympathetic ganglion blockade or alpha receptor blockade using phentolamine with subsequent Valsalva maneuvers in healthy humans demonstrate a greater change in CBF than in control patients2. It should be noted that the density of sympathetic fiber innervation is greater in the internal carotid arteries than the vertebral arteries, thereby allow the autonomic nervous system to act as a buffer against exposing the cerebrovasculature to extreme hypertension2,50. It should be stated that the role of the parasympathetic nervous system in regulating CBF is much less clear at the present time. 2.1.1.4.6 AUTOREGULATION Cerebral autoregulation is a unique property of the cerebrovasculature which enables the cerebral parenchyma to receive stable cerebral blood flow over a range of systemic perfusion pressures. Specifically, the cerebrovasculature undergoes cyclical vasodilation and vasoconstriction in the setting of hypotension and hypertension, respectively, to maintain uniform cerebral blood flow to ensure adequate cerebral oxygen delivery while preventing against the harmful risks of cerebral ischemia and hyperemia2,51,52. Mechanistically, endogenous 24 release of cerebral vasodilators and vasoconstrictors is partly responsible for the compensatory vasoreactivity which takes place to ensure stable cerebral blood flow. Furthermore, activation of L â type calcium channel receptors in the cereobrovasculature with concomitant signaling from adjoining astrocyte end foot processes contributes to overall vascular tone in the cerebrovasculature and maintains autoregulation2,18. Figure 2.6. The autoregulation curve depicts the intact zone of autoregulation is narrowed and forms a less steep slope than the ischemic or hyperemic zones. Because of compensatory vasoconstriction in the preserved zone of autoregulation, cerebral blood volume decreases and as such, intracranial pressure decreases. CBF = Cerebral blood flow; MAP = Mean arterial pressure; ICP = Intracranial pressure; CBV = Cerebral blood volume. This figure is original for this manuscript. Historically, autoregulation has been assumed to occur over a wide range of systemic perfusion pressures, typically 50mmHg to 150mmHg. In the 1957, Lassen published a human description of the regulation of cerebral blood flow and graphically depicted it as CBF being static from a MAP range of 50mmHg to 150mmHg53. This conventional teaching has been propagated throughout innumerable reviews and clinical studies. Since Lassenâs initial 25 description, it has become clear that in fact there is tremendous heterogeneity of cerebral blood flow regulation via a myogenic autoregulation mechanism in a healthy population2. This heterogeneity is reflected by the zone of âintactâ autoregulation within individuals and also in the slope over a perfusion range. In fact, the slope within the âintactâ zone of autoregulation is likely less steep than in the ischemic or hyperemic zone. Furthermore, there appears to be differences in the slopes of the autoregulation curves between the ischemic versus hyperemic zone. Across multiple studies in healthy humans, the CBF appears to increase 0.8% / mmHg in the ischemic zone versus 0.2% / mmHg in the hyperemic zone, meaning the cerebrovasculature appears to protect itself to a greater extent against systemic hypertension than hypotension2. Historically, autoregulation after acute brain injury has been thought to be completely disrupted, thereby resulting in a pure pressure passive relationship between cerebral blood flow and systemic perfusion pressures. However, recently, emerging physiological animal and human studies suggest that the zone of intact autoregulation is intact, albeit severely narrowed and in some cases, significantly right shifted54,55. This narrowed zone of intact autoregulation is likely disease and patient specific and represents an attractive therapeutic target in critical care settings for optimizing and personalizing perfusion targets for individual patients. 2.1.1.5 LEFT CARDIAC VENTRICULAR PHYSIOLOGY To purely equate MAP to be the primary determinant of CBF without appreciating the importance of myocardial function and specifically, the left ventricle (LV), would provide an incomplete description of the determinants of CBF. The left ventricle, receives richly oxygenated blood and ejects its stroke volume into the aorta in a pulsatile fashion. The precise 26 stroke volume depends on the loading conditions of the ventricle and also inherent contractility of the myocardium29. Understanding left ventricular physiology requires an appreciation of the left ventricular pressure volume loop and its components. Diastole has four phases56. The first phase, isovolumetric relaxation, occurs immediately following systole and closure of the aortic valve during which ventricular volume is static and pressure decreases rapidly due to the relaxation of the myocardium. This is followed by early passive diastolic filling and then late passive diastolic filling is characterized by a slight increase in the left ventricular pressure owing to a near completely filled ventricle. Finally, atrial depolarization and contraction takes place and an acute increase left ventricular pressure occurs which overcomes the left atrial pressure and facilitates mitral valve closure. Systole is characterized by ventricular electrical depolarization which is followed by an actively contracting myocardium which then results in a sharp increase in pressure with a static volume owing to the simultaneous closure of the mitral and aortic valves30,57. Once the left ventricular pressure exceeds the aortic pressure, the aortic valve opens and stroke volume ensues. Critical to this phase is the left ventricleâs strength of contractility. On the pressure-volume curve of the left ventricle, contractility is depicted as dP/dT and represents the pressure that the given ventricle can generate at any given ventricular volume. The steeper the curve, the greater the contractility and the greater the stroke volume in the setting of stable afterload29. Due to its spherical structure, the loading conditions of the left ventricle can be depicted by LaPlaceâs Law: Tension = [(ÎP)*(r)] / 2*T ÎP = pressure differential between the intraventricular pressure and 27 External ventricular pressure (pericardial pressure) r = left ventricle chamber radius T = thickness of ventricular wall Preload is defined as the tension across the left ventricular wall at the end of diastole56. The Starling curve states that the force of myocardial contraction and hence, stroke volume, increases proportionally with increases in end diastolic volume until a breaking point, at which the myocardial stretch exceeds the ability of the myocardium to continue to increase its force of contraction56. Beyond this point, a reduction in contractility ensues with reduced stroke volume and cardiac output. Afterload is represented by the tension across the ventricular wall during systole30. There is an inverse relationship between afterload and stroke volume in that the greater the afterload which opposes any given left ventricle, the lower the stroke volume which is resulted. Given the relatively constant state of the left ventricleâs wall thickness and radius in the acute setting, left ventricular afterload is predominantly determined by the changes in ÎP30,58. As stated, ÎP is the Figure 2.7. The pressure volume loop of the left ventricle depicts that with reduction of the afterload, stroke volume is increased by magnitudes, particularly with a decompensated left ventricle. SV = Stroke volume. This figure is original for this manuscript. 28 difference between the left ventricular systolic pressure, which is influenced by systemic vascular resistance, and the external ventricular pressure (intra-pericardial pressure). In the absence of pericardial pathology, this pressure is assumed by the intra-pleural pressure. As such, reducing ÎP by lowering systemic vascular resistance with peripheral vasodilators or increasing the intra-pleural pressure with positive pressure ventilation will lower the tension and afterload and thereby increase stroke volume30. This effect is greatly magnified in the setting of a decompensated left ventricular with reduced contractility as opposed to a normally functioning left ventricular30. Therefore, reducing afterload in cardiogenic failure states, such as post-cardiac arrest, may have an important effect on stroke volume and thus, cardiac output. With respect to the role of LV function and its importance in the regulation of cerebral blood flow, contractility and afterload become of paramount importance. As mentioned in previous sections, the predominant cardiovascular determinant of cerebral blood flow is MAP, which is derived from systolic and diastolic blood pressure. As such, MAP is dependent upon cardiac output and systemic vascular resistance. In settings of decreased cardiac output stemming from reduced LV contractility, compensatory mechanisms take place which augment systemic vascular resistance to maintain overall blood pressure. Therefore, MAP may be preserved, however, the overall cardiac output would be reduced and also cerebral blood flow. Therefore, the contribution of the LV to the regulation of cerebral blood flow becomes especially important in states of decreased LV function and the augmentation of cerebral blood flow in these instances should focus on augmenting LV contractility instead of purely administering vasopressors to increase MAP59. 29 2.1.2 ARTERIAL OXYGEN CONTENT The arterial oxygen content is a major determinant of systemic and cerebral oxygen delivery. Arterial oxygen content is in turn dependent upon hemoglobin concentration and a smaller dissolved portion of arterial oxygen gas tension. The equation of arterial oxygen content is displayed below: Arterial oxygen content = (1.34 x [Hb] x SaO2) + (PaO2 x 0.003) [Hb] = hemoglobin concentration SaO2 = hemoglobin saturation PaO2 = arterial oxygen tension 2.1.2.1 HEMOGLOBIN CONCENTRATION As the major determinant of arterial oxygen content, optimal hemoglobin (Hb) concentration in critically ill patients has been a significant area of research. Rheological studies suggest that the optimal hematocrit for blood flow in the capillary bed is 30 to 35%60. As the principal determinant of viscosity, red blood cell mass can influence microcirculatory significantly. In states of severe polycythemia, increased red blood cell mass can impede microcirculatory flow, cause spontaneous thrombosis and vital organ ischemia3. Clinically, in the non-bleeding critically ill patient, a red blood cell transfusion trigger of Hb < 70g/dL has been shown to be associated with improved outcomes61,62. In states of concomitant brain injury, anemia has been shown to be associated with episodes of brain hypoxia and secondary ischemic neurological injury63,64. Furthermore, adverse neurological outcome is associated with concomitant anemia in the setting of traumatic and hypoxic ischemic brain injury after cardiac arrest63,65. Data pertaining to the association of post-cardiac arrest 30 anemia with reduced cerebral oxygen delivery is limited to an association between reduced regional oxygen saturation using near infrared spectroscopy and hemoglobin levels66. As of yet, the benefits of therapeutically increasing arterial oxygen content through red blood cell transfusion is unknown in hypoxic ischemic brain injury. Studies from TBI suggest an increase in brain tissue oxygenation following transfusion but no change in the overall balance in aerobic versus anerobic metabolism67â69. 2.1.2.2 ARTERIAL OXYGEN TENSION As stated, the dissolved portion of arterial oxygen content is overall, a small contributor but can become critically important in states of acute brain injury. Epidemiological data suggest that pre-hospital hypoxia is a significant and independent variable in its association with adverse neurological outcome after traumatic brain injury70. After cardiac arrest, episodes of arterial hypoxemia are also associated with worse long term neurological outcome12. Physiologically, episodes of arterial hypoxemia are associated with reduced parenchymal tissue oxygenation in traumatic brain injury. If sustained, these episodes of brain hypoxia are also associated with adverse neurological outcome71. At the cellular level, perivascular and cerebral interstitial edema can lead to an increased diffusion barrier for oxygen delivery from the intravascular to the intracellular compartment72,73. In such cases, normobaric hyperoxia has been suggested as a potential therapeutic intervention to facilitate aerobic metabolism. Furthermore, arterial oxygen tension augmentation has been shown to reduce the rim of cytotoxic edema surrounding intracerebral contusions by overcoming the enlarged diffusion barrier74. 31 2.1.3 NEUROMONITORING 2.1.3.1 INVASIVE INTRACRANIAL PRESSURE MONITORING Due to the skullâs rigid nature, the intracranial space is a confined space with three distinct compartments: 1) Brain parenchyma; 2) Cerebrospinal fluid; 3) Cerebrovascular blood volume. As such, following brain injury and stemming from the consequences of mass effect Figure 2.8. Invasive neuromonitoring is undertaken by drilling a 0.5cm diameter hole into the skull. A screw bolt is then placed into the hole and a series of catheters are passed into the parenchyma through the dura mater. This figure is original for this manuscript. produced by cerebral edema or space occupying lesions, there is limited capacity for compensatory decreases in the intracranial compartmentâs respective volumes. As the intracranial compliance becomes exhausted, the intracranial pressure continually rises which places the brain at risk of herniation syndromes and secondary cerebral ischemia. Therefore, intracranial pressure monitoring is a cornerstone in the management of acutely brain injured patients to 1) detect expansion of a space occupying lesion or cerebral edema; 2) prevent 32 secondary neuronal injury, and; 3) facilitate titration of therapies that decreased ICP and prevent herniation syndromes38,39. Various methods of ICP monitoring have been used in the management of patients with Figure 2.9. Parenchymal intracranial pressure monitoring. The intraparenchymal catheter is placed through a cranial bolt. Additional neuromonitoring catheters are placed into the cerebral parenchyma which can measure brain oxygenation (PbtO2), markers of metabolism (Microdialysis) and CBF (Bowman). The neuromonitoring variables are recorded into a software program (ICM+) and pressure reactivity index, a measure of autoregulation, is recorded in real time. This figure is original for this manuscript. acute brain injuries. The gold standard of monitoring ICP is achieved by invasive methods. Specifically, insertion of an external ventricular drain, a pliable hollow catheter, which is placed into the lateral or 3rd ventricle of the cerebrospinal fluid system is widely regarded as the most robust clinical measure of ICP75. Once placed, this catheter is transduced and leveled at the interventricular foramina (or foramen of Monro), thereby providing a continual estimation of ICP with the added benefit of serving the therapeutic benefit of cerebrospinal fluid diversion36,75. 33 Alternatively, intra-parenchymal ICP monitoring can be undertaken as well. Using this technique, the intracranial space is accessed through a drill in the skull bone that penetrates the inner table of the skull. Subsequently, a single or multi-lumen bolt is placed into the access port and a fiberoptic wire is passed which sits directly within the brain parenchyma. Using this technique, the ICP measurements are equivalent to those achieved from external ventricular drain monitoring; however, intra-parenchymal ICP monitor does not come with the added therapeutic benefit of cerebrospinal fluid diversion21. 2.1.3.2 BRAIN OXYGEN MONITORING 2.1.3.2.1 BRAIN TISSUE OXYGEN MONITORING Preventing secondary ischemic injury after acute brain injury is of paramount importance and the cornerstone of critical care management. Therefore, a real time assessment of cerebral oxygen delivery is a logical clinical assessment tool. Parenchymal brain oxygen monitoring, a technique which utilizes a Clarke electrode placed within the brain parenchyma that monitors that partial pressure of tissue oxygen, is the gold standard monitoring technique to measure cerebral oxygen delivery76. 34 Figure 2.10. Parenchymal brain oxygen monitoring is conducted by placing a Clarke electrode catheter into the parenchyma of the brain. The tip of this catheter is placed into sub-cortical white matter. Clinical studies demonstrate that prolonged brain hypoxia episodes (brain tissue oxygen < 10mmHg) are consistently associated with adverse outcome77. Interestingly, episodes of brain hypoxia are modifiable with physiological interventions aimed at augmenting cerebral oxygen delivery including increasing cerebral perfusion pressure, decreasing intracranial pressure, normocapnic ventilation, red blood cell transfusion and normobaric hyperoxia71,78. 2.1.3.2.2 JUGULAR VENOUS BULB OXIMETRY Jugular venous bulb oximetry, a technique by which an intravenous catheter is inserted retrograde into the dominant jugular vein and positioned within the jugular venous bulb. By sampling the venous blood from the jugular bulb, a venous oxygen saturation is obtained which provides valuable physiological delineation of the state of cerebral oxygen delivery and uptake79. In states of decreased jugular venous bulb saturation (SjvO2 < 55%), clinical interventions aimed at augmenting cerebral oxygen delivery (increasing cerebral perfusion pressure, decreasing 35 intracranial pressure, red blood cell transfusion or normocapnic ventilation) or reducing cerebral oxygen utilization (intravenous sedation or reducing core body temperature)70. States of increased jugular venous bulb saturation (SjvO2 > 80%) indicate that there is limitation of cerebral oxygen uptake (mitochondrial dysfunction, cerebral infarct) or cerebral hyperemia79. Clinical evidence pertaining to the use of jugular venous bulb oximetry is limited to traumatic brain injury patients. Observational studies suggest worse neurological outcomes in patients who sustain episodes of either SjvO2 < 55% or > 80%79â81. Figure 2.11. The tip of the jugular venous bulb catheter is confirmed in its position at the level of the ipsilateral mastoid process on lateral c-spine x-ray. Re-printed with permission from Cambridge University Press: Neurocritical care Essentials: A Practical Guide 2.1.3.2.3 NEAR INFRARED SPECTROSCOPY Near infrared spectroscopy, a non-invasive monitoring technique, utilizes adhesive cerebral oximetry pads which are affixed to the forehead. NIRS emits an afferent 900nm infrared light which penetrates the scalp tissue and skull to enter the superficial 1 to 2cm of 36 frontal lobe82. This afferent infrared light is then either absorbed or refracted by oxygenated and deoxygenated hemoglobin molecules in the microcirculation. The ratio of deoxygenated versus oxygenated hemoglobin is then calculated into a ratio of the regional oxygenation saturation (rSO2) depicted by the following equation: (deoxygenated hemoglobin / oxygenated hemoglobin) x 100%82. Physiologically, NIRS serves as a real time monitor for the balance of cerebral oxygen delivery and utilization. In fact, studies suggest that rSO2 approximates cerebral blood flow and Figure 2.12. Near infrared spectroscopy uses infrared light sources to estimate the ratio of deoxygenated versus oxygenated hemoglobin in the venules and arterioles. Panel A demonstrates the typical location of the light sensor on the forehead and Panel B displays bilateral readings from both sensors shown. This figure is original for this manuscript. changes with perturbations of other variables that can affect cerebral oxygen delivery (hemoglobin concentration, arterial carbon dioxide tension and arterial oxygen tension)82. Observational studies that decreased rSO2 are associated with adverse neurological outcome in hypoxic ischemic brain injury after cardiac arrest83,84. Unfortunately, the relevance of the 37 absolute numerical value of rSO2 in an acutely injured brain is unclear82. Significant limitations of NIRS including being affected by skin moisture, ambient light and contamination of the signal from scalp blood flow remain significant problems with current monitoring devices82. 2.1.3.3 CEREBRAL MICRODIALYSIS MONITORING Cerebral microdialysis, a monitoring technique which facilitates monitoring of parenchymal tissue metabolites, provides crucial physiological information of the underlying metabolic activity of the brain21. A dual lumen microcatheter is inserted into the cerebral parenchyma through a multi-lumen cranial access bolt. Typically, this catheter is placed in the non-dominant frontal lobe white matter. An external pump moves isotonic fluid into the outer lumen of the catheter at an adjustable rate. The outer lumen, which has a semi-permeable membrane, allows diffusion of cerebral metabolites down their concentration gradient (cerebral tissue to microcatheter). The dialysate is then recovered through a central lumen of the catheter and exits the cranial space in the efferent limb of the tubing. Finally, an external collection tube is then used to analyze the contents of the dialysate. Specifically, metabolites such as lactate, pyruvate, glucose, glycerol and glutamate are routinely measured85. Measurement of cerebral glucose can detect dangerous drops < 0.8mmol/L which are associated with adverse neurologic outcome and indicate periods of severe neuroglycopenia86. Glycerol and glutamate both represent markers of neuronal degeneration and indicate ongoing neuron losses or excitotoxicity. Finally, measurement of lactate and pyruvate provide crucial information pertaining to the underlying balance between aerobic and anaerobic metabolism. In states of anaerobic metabolism, the lactate / pyruvate ratio is elevated > 25 and predicts a worse clinical neurological outcome85. Conversely, in the setting of an optimal balance between 38 cerebral oxygen / nutrient delivery and metabolism, the lactate / pyruvate ratio is maintained < 25 and is associated with an improved long term neurological outcome87. 2.1.3.4 INVASIVE CEREBRAL BLOOD FLOW MONITORING As stated previously, cerebral blood flow is the principal determinant of cerebral oxygen delivery. As such, monitoring cerebral blood flow in real time presents an attractive and crucial step in the management of acutely brain injured patients at risk of secondary cerebral ischemia. The gold standard of CBF measurement is achieved with positron emission scanning or xenon computed tomography, both modalities which are limited by single time point measurements23,88. Hence, a continuous monitor has been the target of significant research. Parenchymal laser Doppler blood flow monitoring has emerged as a robust measure of real time and continuous CBF monitoring in acutely brain injured patients. This probe, 2mm in diameter, is placed into the non-dominant hemisphereâs frontal lobe white matter through a multi-lumen cranial access bolt. It provides real time physiologic data of CBF reported in mls/100g/min is able to detect critical episodes of oligemia with < 20mls/100g/min of blood flow89. This technique is increasingly being used in traumatic brain injury and aneurysmal subarachnoid hemorrhage patients with evidence of vasospasm who are at risk of delayed cerebral ischemia89. 2.1.3.5 AUTOREGULATION MONITORING As stated, cerebral autoregulation is the innate ability of the cerebrovasculature to regulate its own compensatory vascular tone to ensure stable CBF over a wide range of mean arterial pressure. Traditionally, autoregulation had been thought to be lost after acute brain 39 injury. More recently, however, it is recognized that the intact zone of autoregulation is highly individualized and narrowed. Maintaining perfusion within this narrowed zone is associated with improved clinical outcomes in traumatic brain injuries28. Monitoring autoregulation and identifying the narrowed intact zone has garnered significant interest in recent years. Historically, transcranial Doppler has been used to identify this narrowed zone by analyzing variations between mean arterial pressure and middle cerebral artery blood flow velocity as a marker of cerebral blood flow90,91. Recently, additional methods of real time autoregulation assessment have emerged with clinical implications. Following brain injury, the narrowed intact zone of autoregulation maintains uniform cerebral blood flow while mitigating the negative effects of cerebral ischemia (below the lower inflection point of autoregulation) and hyperemia (above the inflection point of autoregulation)55. Autoregulation can be monitored in real time by establishing a correlational coefficient between mean arterial pressure and intracranial pressure, termed pressure reactivity index (PRx)21,92,93. Below the lower limit of autoregulation (ischemic zone), there is a linear relationship between MAP and blood flow owing to a pressure passive relationship in the cerebrovasculature as the MAP gradually increases and approaches the lower limit of autoregulation93. Similarly, this same linear relationship exists between MAP and blood flow in the hyperemic zone. Outside the preserved range of autoregulation, as blood flow increases, the cerebral blood volume also increases. Because of the rigid nature of the skull, the increase in cerebrovascular blood volume in both the ischemic and hyperemic zones, the intracranial pressure also proportionally rises. Therefore, the correlational coefficient (PRx) in these zones between MAP and ICP is positive. Conversely, in the narrowed intact zone of autoregulation, as the MAP continues to rise, the cerebrovasculature compensates by undergoing vasoconstriction to maintain stable CBF23,93,94. 40 As such, in this narrowed zone, the cerebrovascular blood volume decreases and therefore, ICP decreases. Hence, there is a negative relationship between MAP and ICP and a below zero PRx is yielded93. Figure 2.13. A schematic depiction of a U-shaped curve with the nadir being designated as the optimal mean arterial pressure, the pressure reactivity index is positive in the ischemic and hyperemic zones. The pressure reactivity index becomes negative in the preserved zone of autoregulation. CBF = Cerebral blood flow; MAP = Mean arterial pressure; ICP = Intracranial pressure; PRx = Pressure reactivity index. This figure is original for this manuscript. Alternative correlational coefficients between MAP and other physiological variables have also been proposed as real time measures of autoregulation. For example, a correlational coefficient between MAP and mean flow velocity of the middle cerebral artery via transcranial Doppler, termed Mx can also be used to identify the lower limit of autoregulation and optimal MAP after acute brain injury91. Furthermore, the correlational coefficient between the regional saturation of oxygen from NIRS and MAP, termed cerebral oxygen index (COx), has been used to identify the lower limit of autoregulation, optimal MAP and intact zone of autoregulation in 41 acutely brain injured patients95. Regrettably, there is insufficient data in human HIBI patients comparing invasive versus non-invasive methods of autoregulation monitoring at this time. The notion of personalized perfusion targets in individual patients after acute brain injuries has increasingly emerged as a viable therapeutic strategy to limit secondary ischemic injury. By plotting individual PRx or COx data points along the entire perfusion range of MAP, a U shaped curve can be produced with the nadir of the curve being denoted as the optimal MAP96,97. Observationally, perfusion of the actual CPP within +/- 5mmHg of the identified optimal CPP as identified by PRx, has been associated with improved neurological outcomes in traumatic brain injury28. Thus far, it has been unclear whether this association holds true in other disease states, namely hypoxic ischemic brain injury. Figure 2.14. Above, a U-shaped curve is shown with PRx on the Y-axis and CPP range in 5mmHg bins on the x â axis. The nadir of the U-shaped curve demonstrates that the intact zone of autoregulation reveals a cerebral perfusion pressure range of 80 to 100mmHg. CBF = Cerebral blood flow; CPP = Cerebral perfusion pressure; PRx = Pressure reactivity index. This figure is original for this manuscript. 42 3 CHAPTER 3: A REVIEW OF HYPOXIC ISCHEMIC BRAIN INJURY PATHOPHYSIOLOGY Cardiac arrest (CA) is a major cause of mortality worldwide and is associated with significant long-term morbidity in survivors. In both Europe and North America, the incidence of out-of-hospital CA is approximately 80 patients per 100,000 persons annually98 and 1-5 patients per 1000 hospital admissions for in-hospital CA7,98,99. Of these, nearly 50 patients per 100,000 persons annually receive emergency medical resuscitation efforts prior to hospitalization99. Unfortunately, despite advances in pre-hospital resuscitation systems and expertise, clinical outcomes remain dismal with only 10% of CA patients surviving until discharge98 and 5% returning to their pre-morbid level of functioning100,101. The predominant determinant of these catastrophic long-term outcomes is the neurological dysfunction associated post CA, termed hypoxic ischemic brain injury (HIBI). In fact, HIBI has been established as the primary cause of death in 68% and 23% of out-of-hospital and in-hospital CA survivors, respectively102. Furthermore, HIBI has been cited as the principal determinant of long term neurological dysfunction which has considerable societal costs7,102,103. The spectrum of neurological dysfunction attributable to HIBI post CA ranges from mild cognitive deficits and protracted delirium to minimally conscious and vegetative states100. Consequently, there are also considerable alterations on quality of life metrics and incidence of psychiatric co-morbidities such as depression, anxiety and post-traumatic stress disorder in HIBI patients after CA103â107. 43 Figure 3.1. The top row shows axial slices and images of a non-contrast computed tomography head scan. The second row reveals the corresponding diffusion weighted image apparent diffusion coefficient image revealing extensive diffuse restricted diffusion. The bottom row shows abnormal diffusion weighted imaging. This figure is printed with permission from Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: A âtwo-hitâ model. Crit Care 2017;21(1). Given these devastating outcomes in HIBI patients after CA, considerable research has been directed at clarifying the pathophysiology of HIBI after CA and investigating the effects of therapeutic interventions after CA on clinical outcomes. Historically, the critical care management and associated research has focused on limiting additional cerebral injury in patients with HIBI after CA108,109. Unfortunately, despite large scale studies and detailed physiological research, outcomes in CA patients have not appreciably changed over the past 20 years110,111. This disappointing trend is contrasted with improving outcomes in other critical care diseases such as sepsis112 and acute respiratory distress syndrome113 over the same period. 44 Figure 3.2. Magnetic resonance imaging sequences are presented to demonstrate focal hypoxic ischemic brain injury (HIBI) within the hippocampi and basal ganglia bilaterally. The images are shown represent the acute changes after HIBI within the first week after resuscitation. In the first row, T2 sequences are shown revealing abnormal signaling in the hippocampi and basal ganglia. In the bottom row, restricted diffusion on diffusion weighted imaging confirms HIBI in the affected regions. This figure is printed with permission from Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: A âtwo-hitâ model. Crit Care 2017;21(1). This stagnation in HIBI outcomes suggests that there remains considerable opportunity to further study this devastating disease and improve clinical outcomes. To do so, a deep understanding of the pathophysiology of HIBI is required before developing therapeutic strategies which could affect clinical outcomes. Increasingly, the pathophysiology of HIBI is being recognized as a âtwo hitâ model, being determined by both the primary brain injury from cessation cerebral oxygen delivery and the secondary neuronal injury which occurs from modifiable physiological variables in the hours and days after CA. Therefore, in this manuscript, we aim to present a comprehensive narrative review of a âtwo hitâ model for the underlying 45 pathophysiology of HIBI and highlight recent advances which may serve as potential future targets of clinical studies in HIBI. 3.1 PRIMARY INJURY Upon the initiation of cardiovascular collapse, cessation of cerebral blood flow (CBF) and therefore, cerebral oxygen delivery results in neurological dysfunction and ultimately, neuronal cell death. It is well recognized that the cerebrum, diencephalon, mesencephalon and cerebellum are highly metabolically active tissues which consume 20-25% of the cardiac output for necessary oxygen and nutrient delivery to maintain normal neurological function7,100. These structures are devoid of nutrient stores and hence, are exquisitely susceptible to cellular metabolic crisis and ischemia in the setting of inadequate cerebral oxygen delivery114â116. In fact, neuroglycopenia and depletion of neuronal cellular energy production dissipates with ten minutes of the onset of CA115, giving rise to a cascade of pathophysiological phenomenon resulting in irreversible tissue damage after on the onset of global ischemia117,118. The onset of CA has been shown to result in an immediate decrease in brain oxygenation as demonstrated with invasive parenchymal neuromonitoring119. At a cellular level, the sudden decrease in the delivery of oxygen and nutrients results in numerous pathophysiological alterations which are deleterious to normal cellular functioning and integrity instantaneously120,121. Firstly, the production of adenosine triphosphate (ATP) through aerobic metabolism diminishes and energy dependent ion channels such as the Na+ / K+ ATPase cease their functional abilities122. The subsequent result is an accumulation of intracellular Na+ and extracellular K+ which is associated transit of water out of the intravascular space and resultant cytotoxic cerebral edema. The depletion of ATP also gives rise to the cellular 46 anaerobic metabolism and cerebral lactate production. Thereafter, the cellular milieu continues to become acidotic which leads to further neuronal damage123. Secondly, cellular ischemia results in intracellular Ca2+ influx through NMDA channels and entrapment of intracellular Ca2+stores, which in turn activate numerous cell lytic enzymes including nucleases, proteases and caspases124, ultimately resulting in cell death from apoptosis125â127. The accumulation of intracellular Ca2+ has also been suggested to initiate mitochondrial damage, thereby depleting ATP production even further after the onset of global ischemia100. Finally, excitatory neurotransmitters such as glutamate release markedly increases after global ischemia which is known to activate destructive enzymes such as lipases, proteases and heat shock proteins which promote the induction of apoptosis128. Although programmed cell death from apoptosis is a significant contributor to neuronal damage, the predominant for of cell death post HIBI is cellular necrosis which is induced by profound cellular hypoxia6,127. A third form of cellular death, termed autophagocytosis also occurs but plays a minor role in the neuronal loss after HIBI127. Clinically, the loss of neurological functioning manifested by altered level of consciousness has long been well established after the onset of global neuronal ischemia following CA129. Historically, this clinical finding was first described by Rossen et al. in a physiological study in humans which demonstrated that cessation of carotid arterial blood flow by cuff insufflation of a neck cuff to 600mmHg129. Decreased level of consciousness was demonstrated with 4 to 10 seconds after the onset of neck constriction129. The onset of decreased level of consciousness in CA after ventricular fibrillation (VF) has been documented to occur within 20 seconds after on the onset of VF130,131. 47 The loss of neurological functioning, as determined by isoelectric electro-encephalography (EEG) has also been demonstrated in observational studies129. In a systematic review investigating the time from loss of CBF to neurological functioning, Pana et al. identified numerous observational human studies demonstrating isoelectric EEG rhythms within 30 seconds of aystole129,132,133. Time to loss of EEG rhythms have been documented to occur in approximately 10 to 15 seconds after the onset of VF130,134. Unfortunately, many of these human studies have been confounded by concomitant anesthetic agents known to inherently blunt EEG rhythms. However, these findings have been corroborated in animal studies establishing a similar time profile of 10 to 30 seconds from the onset of established cerebral ischemia and isoelectric EEG signalling135,136 without the confounding effect of general anesthesia. 48 Table 3.1. Summary of mechanisms of secondary brain injury after hypoxic ischemic brain injury. Pathophysiology Mechanisms Consequences Microvascular Dysfunction Microthrombi Cerebral vasoconstriction Blood brain barrier disruption Increased cerebrovascular resistance Decreased CBF, decreased cerebral O2 delivery Vasogenic cerebral edema Cerebral Edema Vasogenic cerebral edema Cytotoxic cerebral edema Increased ICP and decreased CPP, decreased CBF Herniation, brain death Anemia Decreased arterial oxygen content Cerebral ischemia Impaired Autoregulation Narrowed and right shifted autoregulation Pressure passive cerebral hemodynamics Cerebral ischemia and hyperemia Carbon Dioxide Hypocapnia induced vasoconstriction Hypercapnia induced vasodilation Decreased CBF, cerebral ischemia Increased ICP, decreased CPP, decreased CBF Hyperoxia Increased O2 free radicals Neuronal cell dysfunction and cell death Hyperthermia Increased CMRO2 Decreased seizure threshold Induction of apoptosis Neuronal cell metabolic crisis, cell death Non-convulsive seizures, increased CMRO2 Neuronal cell death 49 3.2 SECONDARY INJURY Secondary brain injury refers to the additional neuronal damage which occurs after the inciting pathophysiological consequences of the cessation of CBF during and immediately after CA. Multiple pathophysiological mechanisms have been implicated in contributing to secondary injury after in HIBI and have been correlated to adverse long neurological outcomes. Specific tissues of the central nervous system are especially susceptible to secondary injury, particularly neurons located in the hippocampi, thalami, cerebral cortex, corpus striatum and purkinje cells of the cerebellar vermi137â139. The cornerstone of critical care management of HIBI after CA focusses on optimizing the delicate balance between cerebral oxygen delivery and utilization to minimize secondary ischemic injury108,140. Excluding therapeutic hypothermia, limited prospective studies have aimed at the optimization of physiological variables known to exacerbate secondary brain injury after HIBI7,111,141. Therefore, we will review the principal mechanisms implicated in secondary brain injury in HIBI which may serve as potential future therapeutic targets. 50 Figure 3.3. The figure represents interventions aimed at managing and mitigating secondary injury of hypoxic ischemic brain injury in the critical care setting by balancing improving cerebral oxygen delivery and limiting cerebral oxygen utilization. CBF = Cerebral blood flow; CDO2 = Cerebral oxygen delivery; O2 = Oxygen; CMRO2 = Cerebral metabolic rate of oxygen utilization; CaO2 = Arterial oxygen content; CvO2 = Venous oxygen content; ICP = intracranial pressure; CPP = Cerebral perfusion pressure; PaCO2 = Arterial carbon dioxide tension. Re-printed with permission from Cambridge University Press: Neurocritical care Essentials: A Practical Guide 3.2.1 MICROCIRCULATION AND REPERFUSION INJURY Upon return of spontaneous circulation (ROSC), multiple microcirculatory changes occur which lead to further neuronal damage. The endothelium of the cerebrovasculature plays a critical role in maintaining the integrity of the blood brain barrier, regulating vasomotor tone and microcirculatory blood flow and releasing mediators which act as auto-anticoagulants142. After HIBI, there is established neuronal dysfunction but also widespread damage to the cerebrovascular endothelium which results in dysfunction in the aforementioned physiological roles of the endothelium. In fact, systemic biomarkers of diffuse endothelial injury have been associated with adverse outcome in HIBI after CA143. 51 Immediately after ROSC, reperfusion injury leads to significant neuronal damage despite restoration of the innate cardiovascular hemodynamics144. There is a brief period of global Figure 3.4. A schematic demonstrating the various microvascular and cellular pathophysiological consequences which occur during the primary and secondary injury in HIBI. Decreased cerebral oxygen delivery manifests as reduced neuronal aerobic metabolism, causing reduced cellular adenosine triphosphate (ATP) production. Intracellular calcium accumulation leads to mitochondrial toxicity and further reduced ATP production. Inability to sustain cellular respiration results in cell death and apoptosis. This figure is printed with permission from Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: A âtwo-hitâ model. Crit Care 2017;21(1). 52 hyperemia followed by prolonged hypo-perfusion which results in a phenomenon known as âno reflowâ post CA145,146. No reflow after CA results in prolonged global hypo-perfusion which puts the injured brain at risk of reduced cerebral oxygen delivery and additional ischemic secondary injury. Multiple mechanisms have been implicated including impaired regulation of vasomotor tone in the microvasculature is impaired and resultant vasoconstriction occurs with reduced microcirculatory flow7,142,143. Reduction of endothelial production of nitric oxide and therefore, vascular smooth muscle mediated vasodilation has been suggested a possible mechanism142. Furthermore, during reperfusion injury, extravasation of intravascular water through a porous blood brain barrier with concomitant perivascular edema leads to both increased intravascular viscosity and cerebrovascular resistance45,46,48. Other mechanisms associated with reperfusion injury include increased release of oxygen free radicals, glutamate production, accumulation of intracellular Ca2+, all of which induce neurodegeneration and neuronal apoptosis148,149. As mentioned, the endothelium also plays a sentinel role in maintaining vascular tone and acting as an auto-anticoagulant in the microcirculation. There is established literature which suggests that both of these functions are also impaired in HIBI, leading to the formation of diffuse microthrombi in the cerebrovasculature and impaired vasodilation, both of which increase cerebrovascular resistance and reduce CBF121,150,151. Interventional studies have demonstrated that both heparin and tissue plasminogen activator administration separately improve flow in the cerebral microcirculation after CA152. Unfortunately, these findings have not translated into consistent improved clinical outcomes in HIBI when evaluated prospectively153,154. Finally, the use of intravenous prostacyclin after CA has been suggested a 53 possible therapeutic target in promoting endothelial function through its vasodilatory and anti-platelet effects142 but large scale clinical outcome studies are not yet available. 54 Table 3.2. Pathophysiology summary of cerebral reperfusion injury after cardiac arrest. Pathophysiology Mechanisms Consequences Endothelial Dysfunction Impaired vasomotor control of blood flow Microthrombi formation Blood brain barrier disruption Impaired blood flow in microcirculation and limited oxygen delivery Cerebral edema Free radical formation Activation of lytic cellular enzymes Neuronal apoptosis and cell death Ca2+ Accumulation Mitochondrial toxicity Activation of cellular lytic enzymes Reduced adenosine triphosphate production Cell death, apoptosis 55 3.2.2 ANEMIA Hemoglobin concentration is the major determinant of arterial oxygen content and therefore, for systemic oxygen delivery. Concomitant anemia has been demonstrated to exacerbate ischemic brain injury in animal models of traumatic brain injury (TBI)19. The balance between the optimization of arterial oxygen carrying capacity through red blood cell transfusion and limiting transfusion associated risks has posed a significant challenge to intensivists. As such, multiple studies have attempted to answer this question with a transfusion threshold of hemoglobin <70g/L as being the accepted cutoff in a general critical care patient population62,155. Unfortunately, this liberal transfusion threshold may not be generalizable in brain injured patients who are exquisitely susceptible to secondary ischemic brain injury from concomitant anemia60. In TBI, a disease stateâs management paradigm which also focusses on optimizing cerebral oxygen delivery to minimize secondary injury, considerable work has been devoted to answering this question. Retrospective studies have established a link between concomitant anemia and adverse outcome following TBI63,156,157. Physiological studies have also demonstrated a direct link between red blood cell transfusion and improvement in cerebral oxygen delivery as measured with invasive parenchymal brain oxygenation monitoring67â69. Transfusion thresholds and the role of anemia in contributing to secondary brain injury in HIBI is much less well established. Wang et al. conducted a single center observational study and did demonstrate an association with adverse outcome in HIBI after CA and the initial hemoglobin level upon admission to the emergency department158. Unfortunately, a pre-morbid anemic hemoglobin level may be an indicator of chronic illness, instead of a direct contributor to secondary ischemic neurological injury after HIBI. Subsequently, Wormsbecker et al. have 56 completed a single center observational study linking the mean 7-day hemoglobin level to worse neurological outcome at discharge as determined by the cerebral performance score. Finally, Ameloot et al. reported on an observational study established a link between concomitant anemia and desaturation of regional brain oxygen saturation using near infrared spectroscopy in HIBI patients after CA and adverse outcome159. Although intriguing, this field of study requires significant further work to clarify the role of anemia in exacerbating secondary ischemic injury in HIBI. 3.2.3 CARBON DIOXIDE Arterial carbon dioxide (PaCO2) is a known modulator of cerebrovascular resistance, vascular tone and blood flow through its effects of vascular smooth muscle12. Specifically, hypocapnia (PaCO2 < 35mmHg) induces cerebrovascular vasoconstriction and results in a 3% decrease in CBF for every mmHg PaCO2 decrease160. Reductions in PaCO2 have also been shown to decrease global CBF161â163 and increase cerebral oxygen extraction with positron emission tomography scanning164. Therapeutically, hypocapnia has been suggested a target for the reduction of the intracranial pressure after brain injury through its effect on reduction of CBF and therefore, the cerebrovascular volume12,165. Although effective in treating intracranial hypertension through decreasing CBF166,167, sustained hypocapnia has been shown to induce cerebral ischemia in brain injured patients as measured by parenchymal brain tissue oxygenation, jugular venous oximetry and near infrared spectsoscopy162,164,168â171. The negative effects of sustained hyperventilation and hypocapnia have been corroborated by establishing a link between adverse outcome in TBI patients172. Conversely, hypercapnia (PaCO2 > 45mmHg), a potent mediator of cerebrovascular vasodilation, promotes cerebral hyperemia and may 57 exacerbate cerebral edema with dangerous increases in intracranial pressure7,165,173. Ultimately, sustained hypercapnia can cause increased intracranial pressure with subsequent reductions in cerebral perfusion pressure, CBF and cerebral oxygen delivery165. Finally, hypercapnia has also been associated with neuronal excitotoxicity and increased cerebral oxygen demand as mechanisms of secondary injury in HIBI174,175. Figure 3.5. The top panel reveals real time recording of end tidal carbon dioxide tension (in KiloPascals). The second panel shows mean arterial blood pressure and cerebral perfusion pressure. The bottom panel shows intracranial pressure. As the ventilation of this patient was increased, the end tidal carbon dioxide decreased and intracranial pressure proportionally decreased. This figure is original for this manuscript. Clinically, perturbations in PaCO2 have been studied in various disease states. Specifically, with respect to HIBI, observational pediatric studies have demonstrated conflicting results for association between adverse outcomes and both hypocapnia and hypercapnia176,177. In adults with HIBI, Schenider et al. demonstrated an association between hypocapnia and increased hospital mortality after HIBI178. Furthermore, Lee et al, established an association between favorable neurological outcome after HIBI and maintenance of normocapnia after 58 CA179. Importantly, exposure of hypocapnia and hypercapnia has been demonstrated to occur 36% and 42% of the time during critical care admission in a prospective single center observational study12. Additionally, preserved PaCO2 reactivity has been established after HIBI, thereby supporting the biological plausibility of fluctuations in PaCO2 having a significant effect on secondary brain injury163,180. Interestingly, animal models of HIBI management bundles incorporating normocapnia with induced hypertension and therapeutic hypothermia have established improved neurological outcomes181,182. 3.2.4 CEREBRAL EDEMA After cerebral ischemia, the onset of tissue edema is a recognized complication which can lead to secondary brain injury. The intracranial space has a limited compliance due to the skullâs rigid nature and increases in the volume of one of the intracranial compartments can lead to dangerous elevations in intracranial pressure (ICP)183. In HIBI, cerebral edema may lead to increased ICP184 with subsequent decreases in cerebral perfusion pressure, CBF and oxygen delivery, culminating in further cerebral ischemia7. This phenomenon initiates the vicious cycle of increased cerebral edema and ischemia with eventual herniation and neurological brain death. Multiple cellular mechanisms have been implicated in the origin of cerebral edema after global ischemia. Firstly, aquaporin-4 (AQP4) is transporter of water in the central nervous system and is located in perivascular astrocytic end-feet, processes and in the ependyma185. The perivascular pool of AQP4 has been identified as the predominant cluster involved in the origin of cerebral edema after global ischemia with increased expression of AQP4 within 24 to 48 hours after the onset of cerebral ischemia185. Furthermore, the perivascular pool of AQP4 has also been suggested as possible therapeutic target. Recently, Nakayama et al demonstrated that 7.5% 59 hypertonic saline (HS) attenuates cerebral edema via the perivascular pool of AQP4 and also that HS had no effect on cerebral edema in a mice knockout model of AQP4185. Previous studies have also confirmed that the perivascular AQP4 pool is involved in the attenuation of cerebral edema post ischemia after HS administration186,187. HS administration has also been suggested to restore blood brain barrier disruption mediated by AQP4 in tissues from the hippocampi, cerebellum, cortex and basal ganglia185. Finally, an additional study by Nakayama et al also established the achieving a serum osmolality > 350mOsm/L with a continuous infusion of conivaptan, a V1 and V2 antagonist, attenuated cerebral edema188. Although AQP4 is an attractive target for future therapeutic targets, other mechanisms of cerebral edema also exist. Sulfonylurea receptors are located within the central nervous system and have recently been implicated in the pathophysiology of ischemia induced cerebral edema. Interestingly, glyburide, an inhibitor sulfonylurea receptor activation through the ATP sensitive potassium channel has recently been suggested to attenuate malignant cerebral edema after acute middle cerebral infarction127. Furthermore, these findings have been corroborated with animal studies that suggest sulfonylurea receptor antagonism decreases cerebral edema after neuronal ischemia189. Finally, Rungta et al. have recently established that the Na+Cl- receptor SLC26A11, is involved in the intracellular transport of chloride and subsequent cerebral edema after ischemia190. In fact, blockade of this receptor results in attenuation of cytotoxic cerebral edema190. 3.2.5 CEREBRAL AUTOREGULATION The brain has the unique ability to regulate its blood flow to match metabolic demands. This phenomenon, termed cerebral autoregulation, is the innate ability of the cerebrovasculature 60 to undergo cyclical vasoconstriction and vasodilation over a wide range of mean arterial pressure (MAP) to maintain stable CBF191. This protective mechanism prevents against the harmful effects of both ischemia and hyperemia with resultant increased ICP and cerebral edema191. The determination of the state of intact CA has been the target of previous research with the aim of identifying optimal blood pressures in HIBI. Nishizawa et al. initially suggested that autoregulation was dysfunctional in HIBI and a pure linear relationship existed between MAP and CBF192. This was determined by a linear relationship demonstrated between increasing MAP with intravenous norepinephrine infusion and jugular venous oximetry at 72 hours post autoregulation192. More recently, Nemoto and Hossman et al. have demonstrated that autoregulation is intact in animal models of autoregulation123,193. Furthermore, Christopherson et al. demonstrated that autoregulation was intact in a dog model of 12 and 18 minutes of global ischemia after autoregulation194. Thereafter, Sundgreen et al. conducted a prospective physiological study in humans after autoregulation using transcranial Doppler for measurement of mean flow velocity of the middle cerebral artery and a stepwise increase of MAP with intravenous norepinephrine195. Although autoregulation was dysfunctional, the zone of autoregulation was identified to be narrowed and right shifted in their subjects195. The importance of this finding has enormous implications as it may explain why autoregulation has thought to be impaired after autoregulation due to the inability to identify the lower limit of intact autoregulation because of it being severely right shifted. Also, the narrowed nature of the intact autoregulation zone suggests that perfusion outside of that range may expose HIBI patients to the deleterious effects of ischemia and hyperemia. 61 Figure 3.6. The narrowed zone of intact autoregulation in hypoxic ischemic brain injury is often righted shifted. ICP = intracranial pressure, HIBI = Hypoxic ischemic brain injury; CBF = Cerebral blood flow; MAP = Mean arterial pressure. This figure is original for this manuscript. Recently, observational studies have demonstrated intact autoregulation in HIBI using near infrared spectroscopy (NIRS). NIRS provides a measure of the regional saturation of oxygen (rSO2) in the outermost 1 to 2 centimeters of the frontal lobe. The rSO2 represents the state of oxygenated hemoglobin within the microvasculature in the frontal lobe but also correlates with CBF196. Therefore, continually integrating the fluctuations between rSO2 and MAP, a pearsonâs correlation coefficient varying between +1 and -1 can be generated. This correlation coefficient, termed COx, has garnered interest as a measure of CA post HIBI197. Near zero and negative COx values indicate intact autoregulation, whereas positive COx values indicate a dysfunctional state of autoregulation197. Lee et al. have demonstrated the use of COx to identify the lower limit of autoregulation in a swine model of pediatric autoregulation197 and have also shown feasibility of autoregulation monitoring in pediatric autoregulation human 62 subjects198. Recently, Ameloot et al. retrospectively calculated COx from MAP and rSO2 to show that autoregulation was intact 33 out of 51 total adult autoregulation subjects. Pham et al. have also investigated autoregulation after CA and demonstrated an association between dysfunctional autoregulation and adverse outcome at 3 months after CA199. Figure 3.7. The zone of preserved autoregulation after hypoxic ischemic brain injury appears to be narrowed and right shifted after cardiac arrest. Within the zone of autoregulation, regional saturation of oxygen (rSO2) is stable due to the innate vasoconstriction and vasodilation of the cerebral vasculature to maintain stable cerebral blood flow. Outside of the zone of autoregulation, a linear relationship exists between rSO2 and mean arterial pressure (MAP). By continually integrating the fluctuations of MAP and rSO2 with one another, a correlation coefficient, termed COx can be generated. The COx approaches negative values or near zero within the preserved zone of autoregulation, resulting in a U-shaped curve. The nadir of the U-shaped curve represents the optimal MAP for each individual patient. This figure is original for this manuscript. This figure is original for this manuscript. The concept of individualized perfusion pressures for patients has emerged as an attractive therapeutic target in brain injured patients200. In TBI, autoregulation monitoring using a similar correlational coefficient called pressure reactivity index (PRx), identification of the optimal cerebral perfusion pressure has been demonstrated93,201. By plotting PRx on the y axis and cerebral perfusion pressure on the x â axis, a U shaped curve can be identified with the 63 optimal cerebral perfusion pressure being identified as the range associated at the nadir of the curve202. Furthermore, adverse clinical outcome has been shown in patients who are perfused at greater than +/- 5mmHg from the optimal range for the majority of time28 . Similarly, in CA, COx can be used to generate U shaped autoregulation curves by plotting COx on the y axis and MAP on the x axis, with the optimal MAP being identified as the 5mmHg perfusion associated with the most negative COx203. Recently, we have demonstrated the feasibility of monitoring COx in real time and identification of optimal MAP prospective observational study of 20 CA subjects203. Considerable work remains to be done in this field but autoregulation monitoring in CA for the identification of optimal individualized MAP targets is an attractive therapeutic target. 3.2.6 TEMPERATURE Therapeutic hypothermia (TH) has been the target of considerable HIBI research over the past two decades. Controlling core body temperature is a mainstay in the prevention of secondary brain injury in the hours and days after the primary injury of CA has taken place204. At the cellular level and in animal studies, the beneficial effects of TH have been well documented. Specifically, TH reduces cerebral metabolism, global carbon dioxide production and systemic oxygen consumption proportionally to decreases in core body temperature205. Cerebral metabolism decreases by 5 to 10% per 1oC decrease in core body temperature, thereby allotting available cellular energy stores to be used for necessary neuronal functioning and survival204. By decreasing cerebral metabolism, TH avoids excessive intracellular anaerobic metabolism associated with increased lactate production and also improves global cerebral glucose utilization204,206,207. Additional benefits of TH include the prevention of apoptosis by 64 decreasing pro-apoptotic mediators such as p53, tumor necrosis factor alpha and caspase enzymes while increasing anti-apoptotic proteins such as Bcl-2208â213. Improved cellular functioning with TH has also been shown to prevent mitochondrial dysfunction, a key pathway involved in the promotion of apoptosis by release of cytochrome c into the cellular cytoplasm204. Another key pathophysiological phenomenon post HIBI is the detrimental effects on the blood brain barrier and cerebrovascular endothelium, leading to extravasation of water and generation of cerebral edema. Interestingly, TH has been associated with decreased extravasation of heme moieties in a TBI model and has been suggested to reverse blood brain barrier breakdown after ischemia214,215. Finally, TH has also been associated with decreasing inflammatory mediators such as interleukin-1216, decreased chemotaxis of leukocytes into the brain interstitium204, reduced release of excitotoxic neurotransmitters (glutamate and glycine)217,218 and decreased free radical production after HIBI205. Conversely, hyperthermia has been associated with numerous pathophysiological sequelae which are deleterious after HIBI. Specifically, hyperthermia increases glutamate production which in turn causes intracellular Ca2+ influx and leads to neuronal cell death7. Additionally, glutamate accumulation has also been associated with post CA seizures. Furthermore, hyperthermia has been suggested to increase the likelihood of at risk neurons undergoing apoptosis205. Increased cerebral metabolism, hyperemic blood flow and increased ICP are also downstream consequences of uncontrolled hyperthermia in HIBI after CA7. Recently, we have also shown that progressive hyperthermia during rewarming is associated with dysfunctional autoregulation in HIBI patients, as measured by COx203. Ultimately, increased systemic core body temperature has been associated with increased neuronal damage in numerous animal models219â221. 65 Clinical studies investigating have historically established a firm link between efficacy for TH and improved outcome after CA. In 2002, two randomized control trials demonstrated marked improvement in clinical outcomes in CA patients after ventricular fibrillation or ventricular tachycardia who were treated with TH compared to standard of care222,223. A persistent criticism of both of these trials were that the standard of care groups maintained core body temperatures > 37oC, thereby exposing patients to the harmful effects of hyperthermia. This prompted a third recent randomized control trial comparing core body temperature control of 36oC (normothermia) versus 33oC (hypothermia) in HIBI after CA 141. This pragmatic trial included HIBI patients with all initial cardiac rhythms and ultimately did not demonstrate an appreciable benefit of TH versus normothermia141. Importantly, it must be stated that the maintenance of normothermia at 36oC after CA does in fact, require active cooling of HIBI patients. The negative effects of sustained hyperthermia and adverse outcomes after CA have been repeatedly demonstrated224â226, thereby reinforcing the importance of aggressive core body temperature control after CA. 3.2.7 NORMOBARIC HYPEROXIA Maintaining optimal cerebral oxygen delivery to the injured brain in HIBI is a cornerstone in the critical care management. Augmenting arterial oxygen content has been touted as a crucial modifiable factor in achieving this goal. As discussed, red blood cell transfusion for optimization of hemoglobin concentration is a mainstay in this management paradigm; however, normobaric hyperoxia (NH) has also been suggested as a potential therapeutic maneuver to augment arterial oxygen content and cerebral oxygen delivery227. 66 Upon ROSC after CA, reperfusion injury in HIBI occurs through multiple cellular mechanisms. Among these mechanisms, the generation of oxygen free radicals takes place, specifically superoxide (O2-), hydrogen peroxide (H2O2), hydroxyl anions (OH-) and oxynirite (NO2-), all of which play a sentinel role in oxidizing critical neuronal structures and promoting neuronal cell death228. Endogenous antioxidants play a critical role by balancing the generation of free radicals and stabilizing cellular function. Administration of NH has been suggested to tip the pendulum in favor of further generation of oxygen free radicals and promote cellular dysfunction228. Specifically, animal studies have demonstrated that NH is associated with increased neuronal damage after CA229,230 and impaired oxidative cellular metabolism in susceptible neuronal tissues in HIBI such as the hippocampi42,231. A systematic review conducted by Pilcher et al. confirmed that the balance of animal studies of HIBI suggests that increased neuronal dysfunction occurs after NH administration, however, significant heterogeneity exists between studies with respect to ventilation strategies, timing of NH administration, dose of NH, concomitant use of TH and primary outcomes assessed227. Adverse effects such as increased cerebrovascular resistance from cerebral vasoconstriction, myocardial vasoconstriction, increased systemic vascular resistance, decreased CBF, seizures and increased release neuronal degeneration biomarkers such as neuron specific enolase have also been suggested after NH administration post CA205,228,232,233. Although there appears to significant side effects of NH, beneficial physiologic effects of NH such as increased arterial oxygen content, improved parenchymal brain oxygenation and overcoming diffusion barriers in brain injury have been touted as biological rationale for NH administration74,234. Numerous clinical studies have evaluated NH administration in HIBI after CA with conflicting results. Kuisma et al. conducted a small prospective randomized study of 28 patients 67 who were either given 21% or 100% inspired oxygen after ROSC for one hour235. The group who received 21% inspired oxygen exhibited lower serum levels of neuron specific enolase and NH was associated with increase serum NSE but only if TH was not concomitantly used after ROSC. Kilgannon et al conducted large database evaluation investigating the effects of NH and systemic hypoxemia (defined by PaO2 > 300mmHg or < 60mmHg on a single arterial blood gas in the 1st 24 hours after ROSC) in HIBI after CA and demonstrated that both NH and hypoxemia were associated with increased hospital mortality236. In a single center retrospective study by Spindelboeck et al., NH and hypoxemia during cardiopulmonary resuscitation were associated with increased hospital mortality237, suggesting that the deleterious effects of NH may take place in the early stages of HIBI. Finally, Bellomo et al. conducted a large retrospective analysis of CA patients in Australia and New Zealand and demonstrated that NH and hypoxemia were associated with increased mortality, however, after adjusting for confounders, this relationship was no longer significant238. Importantly, significant limitations in methodology should be noted, particularly the retrospective nature of these studies, the limitation of using mortality as a primary outcome in a brain injured population and the definition of NH with a single PaO2 > 300mmHg does not capture the true biological exposure of NH to patients after CA. Furthermore, TH was not routinely used in all patients. An additional series of retrospective analyses investigating the use of NH after HIBI with concomitant TH have attempted to addressed prior shortcomings. Janz et al. demonstrated an association between adverse neurological outcome and NH administration after CA239. These results are contrasted with retrospective analyses by Ihle et al and Lee et al which failed to establish an association between NH and adverse neurological outcome in HIBI in patients who also were managed with TH240,241. These findings have been supported by a prospective study in 68 HIBI patients treated with TH which demonstrated that patients who had a favorable neurological outcome after CA had higher mean PaO2 levels than those who experienced adverse outcomes242. Thus, it seems that the concomitant use of TH may play a critical role in modifying the deleterious effects of NH in HIBI after CA and further studies are required to clarify the precise role of NH in HIBI. 3.2.8 GAPS IN HIBI PATHOPHYSIOLOGY HIBI remains a significant cause of adverse clinical outcomes after CA despite rigorous experimental and clinical investigation. The pathophysiology of HIBI is complex with a significant contribution to overall outcome attributable to the primary injury and ensuing secondary brain injury which occurs in the hours and days following CA. Significant animal and clinical studies have been devoted to studying the effects of interventions aimed at preventing additional secondary brain injury in HIBI, most notably TH. Future possible targets of further study to clarify the roles of modifiable variables for the prevention secondary brain injury include individualized perfusion targets, NH, red blood cell transfusion, and PaCO2 titration in HIBI. 69 4 CHAPTER 4: BRAIN HYPOXIA AND CEREBRAL OXYGEN DELIVERY IN HYPOXIC ISCHEMIC BRAIN INJURY In the pathophysiology of hypoxic ischemic brain injury after cardiac, the primary injury during the cardiac arrest is followed immediately by numerous physiologic mechanisms that contribute to a secondary ischemic injury1,6,7. Increasingly, this secondary injury is being recognized as a major contributor to long term neurological outcome and may be reversible. As such, the cornerstone of critical care management in HIBI is to optimize the balance between adequate oxygen delivery and utilization243. Therefore, accurate real time monitoring of cerebral oxygen delivery remains a vital target of HIBI research to provide clinicians with a real time monitor to facilitate adequacy of cerebral resuscitation. In traumatic brain injury, parenchymal brain tissue oxygenation has emerged as the gold standard for monitoring cerebral oxygen delivery and to facilitate titration of therapies to prevent secondary ischemic injury76. In fact, observational data suggests improved neurological outcomes in patients managed with a PbtO2 monitoring after TBI78,244. Previously, jugular venous bulb oximetry has also been used in TBI patients and carries a more favorable risk profile than invasive intra-parenchymal PbtO2 monitoring25. Although jugular venous bulb oximetry has been studied in HIBI after cardiac arrest79â81,245, PbtO2 monitoring has not. After HIBI, monitoring cerebral oxygen delivery and utilization using NIRS and rSO2 has been touted as a viable non-invasive alternative to invasive monitoring246â250. Although widely used in the peri-operative setting, NIRS requires a baseline rSO2 measurement (when the patient is awake) from which a trend can be monitored. Individual variation of the absolute rSO2 number is sporadic and the inability to achieve an accurate baseline limits its utility in HIBI thus far. Furthermore, NIRS currently has considerable concerns with respect to the degree of 70 ambient light interference and scalp blood flow contamination, limiting its utility as an accurate marker of CBF and clinical outcomes196,251. 4.1 STUDY 1 â METHODS 4.1.1 STUDY POPULATION AND SETTING The Vancouver General Hospital intensive care unit (ICU) is a quaternary closed 34 bed mixed medical-surgical unit affiliated with the University of British Columbia. The ICU provides quaternary neurotrauma care for the province of British Columbia and conducts invasive multimodal neuromonitoring in approximately 40 neurologically injured patients annually. Patients were included if they sustained a cardiac arrest and fulfilled the following criteria: 1) time to ROSC of greater than 10 minutes with greater than 20 minutes of sustained circulation, 2) post ROSC un-confounded Glasgow coma score of less than 9, and 3) inclusion within 72 hours of cardiac arrest. We excluded patients who had any of the following criteria: 1) concurrent coagulopathy (INR > 1.5, prothrombin time > 40 seconds, platelet count < 100 x 109/L), 2) likely cardiac catheterization within 7 days, 3) current or anticipated anticoagulant or antiplatelet therapy during the study period, 4) therapeutic hypothermia targeting a temperature under 35oC, 5) prior history of severe TBI, intracranial hemorrhage or stroke, 6) anticipated withdrawal of life-sustaining therapy within 72 hours. 4.1.2 NEUROMONITORING ICP (Camino®, Integra Lifesciences, New Jersey, USA) and PbtO2 (Licox®, Integra Lifesciences, New Jersey, USA) catheters were inserted through a dual lumen bolt in the non- 71 dominant frontal lobe by the attending neurosurgeon or designate. We also inserted a continuous oximetric jugular venous bulb (SjvO2) catheter (Pediasat®, Edwards Lifesciences, USA). The SjvO2 catheter was placed in the dominant internal jugular vein identified by ultrasonography, and positioned at the level of the mastoid process on skull base x-ray. Near-infrared spectroscopy (NIRS) pads (INVOS®, Medtronic, Minneapolis, MN, USA) were affixed to the forehead bilaterally. The following data were recorded at 300 Hz using ICM+® brain monitoring software (Cambridge Enterprise, United Kingdom): ICP, MAP, PbtO2, rSO2, SjvO2, temperature, and ETCO2). Figure 4.1. A depiction of the data collection. Individual neurophysiologic variables are collected at 300Hz into ICM+ and PRx is generated in real time from intracranial pressure and mean arterial pressure. This figure is original for this manuscript. 72 Figure 4.2. The monitoring was placed at the bedside by our neurosurgical colleagues through a single cranial burr hole in the non-dominant hemisphere with the catheters sitting in the sub-cortical white matter. This figure is original for this manuscript. 4.1.3 DATA COLLECTION We also collected information relating to the cardiac arrest: etiology of the cardiac arrest, initial rhythm, whether the arrest was witnessed or unwitnessed, administration of bystander cardiopulmonary resuscitation, duration until ROSC, doses of epinephrine administered, and number of defibrillation attempts. We also collected multiple daily arterial blood gas samples. We defined brain tissue hypoxia as a PbtO2 below 20 mmHg, as extrapolated from patients with traumatic brain injury 200,252. Neurologic outcomes were recorded at 6 months by telephone interview using the Glasgow Outcome Scale: (1) death, (2) persistent vegetative state, (3) severe disability - conscious but disabled, (4) moderate disability â independent for daily activities but with disabilities, and (5) good recovery â normal activities although may have minor deficits. 73 An independent intensive care physician reviewed each subject to assess for any complications related to the invasive monitoring. 4.1.4 PATIENT MANAGEMENT Our ICU uses targeted temperature management guideline for post cardiac arrest care of patients with HIBI targeting a goal temperature of 36oC using external surface cooling techniques and anti-pyrexial medications. Core body temperature is monitored using a continuous esophageal, rectal or urinary bladder temperature probe. Patients are sedated with intravenous propofol infusions during targeted temperature management and hemodynamic targets are set in accordance with international guidelines at the attending physicianâs discretion253. All patient care decisions were left to the discretion of the attending physician and they were allowed to use the neuromonitoring data for clinical decisions as per usual practice. Our ICU uses a tier based algorithm in patients with multimodal neuromonitoring in situ which utilizes increasing intensity of therapy aimed at keeping ICP < 25 mmHg and with titration of MAP / CPP to target PbtO2 > 20 mmHg 254 using intravenous norepinephrine as the primary vasopressor. Strict adherence to arterial normoxemia (PaO2 80 to 100mmHg) was maintained for the duration of the monitoring period in each study subject to allow delineations of the physiologic relationships with PbtO2. 4.1.5 STATISTICAL ANALYSES A sample of 10 was chosen as the number of patients we could enroll within the time available for the study. Data collected by ICM+® brain monitoring software were exported at 10-sec averaged values into Microsoft Excel (Redmond, WA, USA). The data were then 74 subsequently imported into Stata 15.0 (StataCorp, Texas, USA), which was used for all analyses. ICM+® software calculates PRx in real-time as a moving Pearson correlation coefficient between 30 consecutive, 10 s averaged values of MAP and ICP signals51. MAPOPT is determined as a secondary derivative by plotting PRx (y-axis) against the MAP range (x-axis) in 5 mmHg bins. An automatic multi-window curve-fitting methodology was used to estimate MAPOPT (OptimalValueFlex function in ICM+). The LLA and ULA were also determined using this methodology 27, adopting a PRx optimal threshold of 0.25. We calculated the difference between actual MAP and MAPOPT for each time point MAPDIFF. We then collapsed the 10-second data over 10-minutes using mean values. All analyses were two-sided and we considered p<0.05 to be statistically significant. Characterization of brain oxygenation and hypoxia over time and its relationship to MAP. PbtO2 and MAP were first assessed visually by plotting both over time for each individual. To characterize the degree of brain tissue hypoxia, we calculated the number of 10-minute periods where PbtO2 was below 20 mmHg for each individual. In order to estimate the average profiles of PbtO2 and MAP over time, we fitted a linear mixed model specifying âpatientâ as a random-effect (STATA command xtreg) to account for the within-subject correlation of the data structure. We then visually assessed the relationship of each variable of brain hypoxia (PbtO2, rSO2 and SjvO2) by plotting each against MAP. We overlaid the scatterplot with ten locally weighted scatterplot smooths, one for each individual. For each measure of brain hypoxia (PbtO2, rSO2 and SjvO2) we fit a linear mixed model that included MAP as a fixed effect and âpatientâ as a random effect (STATA command xtreg). For modelling, we calculated the marginal and conditional R2 as a measure of the variance explained. 75 Characterize the relationship between both PbtO2 and PRx with temperature and end-tidal carbon dioxide (ETCO2). We plotted PbtO2 and PRx against temperature and ETCO2 and overlaid the scatterplot with ten locally weighted scatterplot smooths for each individual. As part of an exploratory analysis, we compared PRx in survivors and non-survivors and how this changed over time. This latter analysis was performed by fitting a linear mixed model specifying âpatientâ as a random-effect (STATA command xtreg) and included an interaction variable of time (hours) and favourable neurologic outcome (modeled as a dichotomous variable). 4.2 STUDY 1 â RESULTS 4.2.1 SUMMARY RESULTS Twenty-two consecutive patients were screened between November 2016 and January 2018, of which 10 met inclusion criteria and were enrolled. Individual demographics of the patients are shown in Table 4.1. The median age of the cohort was 47 and seven were male. The initial rhythm was pulseless electrical activity in 9 patients and 1 patient had ventricular fibrillation. The median duration from time of cardiac arrest to insertion of multimodal neuromonitoring was 15 hours and the median duration of multimodal monitoring was 47 hours. Over the entire cohort and duration of monitoring the mean (SD) of MAP, ICP and CPP were 88 (15) mmHg, 14 (15) mmHg and 75 (7) mmHg, respectively. The mean ETCO2 was 32 (6) mmHg and mean core body temperature was 35.7 oC (0.8). There were no serious adverse events related to the monitoring (intracranial hemorrhage or infection) during or after the study period. 76 Table 4.1. Patient demographics and clinical outcome of study cohort. Study ID Age Sex Arrest Etiology Initial Rhythm Witnessed Time to ROSC (mins) Post ROSC GCS Arrest to MMM (h) Admission to MMM (h) Duration of MMM (h) 6 month GOS 1 20 Male Hypoxia PEA No 12 5 26 16 24 4 2 47 Male Hypoxia PEA No 15 3 14 6 39 1 3 23 Male Hemorrhage PEA Yes 22 3 18 14 51 5 4 71 Female Hypoxia PEA No 14 4 21 8 37 1 5 31 Female VF VF Yes 25 4 106 43 94 5 6 57 Male Anaphylaxis PEA No 24 6 9 7 42 1 7 37 Male Drowning PEA Yes 36 3 10 6 18 1 8 67 Female Hypoxia PEA Yes 17 3 8 8 8 1 9 48 Male Opioid overdose PEA No 27 3 10 10 62 5 10 49 Male Asthma PEA Yes 18 4 8 9 47 1 Abbreviations: PEA â Pulseless electrical activity; VF â Ventricular fibrillation; ROSC â Return of spontaneous circulation; GCS â Glasgow coma scale; MMM â Multimodal monitoring; GOS â Glasgow outcome score 77 4.2.2 BRAIN HYPOXIA AND MEAN ARTERIAL PRESSURE Characterization of brain oxygenation and hypoxia over time and relationship to MAP. The mean PbtO2 in the entire cohort was 23 (8) mmHg. Of the 1944 10-minute averaged periods, 743 (38%) had a PbtO2 under 20 mmHg. On an individual patient level, the mean percentage of time that patients in the cohort experienced a PbtO2 under 20 mmHg was 38% (range 6 â 100). During the study period, the mean rSO2 was 67 (14) % and mean SjvO2 was 74% (11). Relationships between PbtO2 and MAP in individual patients over time during the monitoring period are presented in Figure 4.3. Both PbtO2 (0.20 mmHg, 95% CI: 0.18 â 0.22) and MAP (0.16 mmHg, 95% CI: 0.12 â 0.19) increased per hour during the monitoring period. Figure 4.3. Scatter plots and locally weighted scatterplot smoothing function of PbtO2 (mmHg, black) and MAP (mmHg, blue) versus time (hours, x-axis) for each patient. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 78 4.2.3 BRAIN OXYGENATION AND CARBON DIOXIDE, TEMPERATURE AND INTRACRANIAL PRESSURE There did appear to be a significant inversely parabolic non-linear relationship between PbtO2 with ETCO2, p<0.001 (figure 4.4). Furthermore, there was an inverse linear relationship between PbtO2 and temperature, R2 = 0.42, p = 0.045 (figure 4.5). There did not appear to be a significant relationship between PbtO2 versus ICP. Figure 4.4. Scatter plots between PbtO2 and ETCO2. The light grey dots are corresponding values of PbtO2 and the variable of interest. The light grey solid lines are a locally weighted scatterplot smooth for each patient. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 79 Figure 4.5. Scatter plots between PbtO2 and temperature. The light grey dots are corresponding values of PbtO2 and the variable of interest. The light grey solid lines are a locally weighted scatterplot smooth for each patient. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 4.2.4 CEREBRAL PERFUSION PRESSURE AND MEASURES OF CEREBRAL OXYGEN DELIVERY Figure 4.6 â 4.8 demonstrates the relationship between MAP and indices of brain oxygenation. MAP was linearly related to both PbtO2 (figure 4.6) and SjvO2 (figure 4.7) but not rSO2 (figure 4.8). The large difference between the conditional and marginal R2 values observed indicates marked between-patient variability in the effects of MAP on the indices of oxygenation. 80 Figure 4.6 Brain tissue oxygen (PbtO2) on the y-axis vs. mean arterial pressure (MAP) in mmHg (x axis). The dots are scatterplots between the two variables. Light grey lines are locally weighted scatterplot smoothing function for each individual patient. Black line is the overall regression line. R2m is the marginal R2. R2c is the conditional R2. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. Figure 4.7. Jugular venous bulb oxygenation saturation (JvSaO2) on the y-axis vs. mean arterial pressure (MAP) in mmHg (x axis). The dots are scatterplots between the two variables. Light grey lines are locally weighted scatterplot smoothing function for each individual patient. Black line is the overall regression line. R2m is the marginal R2. R2c is the conditional R2. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 81 Figure 4.8. Regional saturation of oxygen (rSO2) on the y-axis vs. mean arterial pressure (MAP) in mmHg (x axis). The dots are scatterplots between the two variables. Light grey lines are locally weighted scatterplot smoothing function for each individual patient. Black line is the overall regression line. R2m is the marginal R2. R2c is the conditional R2. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. Agreement between measures of brain oxygenation By plotting PbtO2 versus SjvO2 and rSO2, there did not appear to be significant relationships between PbtO2 and SjvO2, R2 p=0.23 or between PbtO2 and rSO2, R2 p=0.38. Bland-Altman analysis revealed wide limits of agreement between PbtO2 and SjvO2 (figure 4.10). Similarly, wide limits of agreement were also observed between PbtO2 and rSO2 (figure 4.11). 82 Figure 4.9. Brain tissue oxygenation (PbtO2) on the y-axis vs. regional oxygen saturation (rSO2) in % (x axis) (left panel) and PbtO2 on the y-axis vs. jugular venous bulb oxygen saturation (JvSaO2) in % (x axis). The dots are scatterplots between the two variables. Light grey lines are locally weighted scatterplot smoothing function for each individual patient. Black line is the overall regression line. R2m is the marginal R2. R2c is the conditional R2. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. Figure 4.10. Bland Altman agreement analysis between brain tissue oxygenation (PbtO2) on the y-axis vs. jugular venous bulb oxygen saturation (JvSaO2) in % (x axis). The dotted lines represent the limits of agreement. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 83 Figure 4.11. Bland Altman agreement analysis between brain tissue oxygenation (PbtO2) on the y-axis vs. regional oxygen saturation (rSO2) in % (x axis). The dotted lines represent the limits of agreement. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 4.3 STUDY 1 â DISCUSSION We present the first prospective study using invasive multimodal neuromonitoring to evaluate brain hypoxia and cerebral autoregulation using PRx in patients with HIBI. Overall, there was a significant burden of brain hypoxia demonstrated in our cohort. Although there was a linear relationship between PbtO2 and SjvO2 with MAP, there was marked between-patient variability. 4.3.1 THE BURDEN OF BRAIN HYPOXIA DESPITE GOAL ORIENTED RESUSCITATION It is increasingly evident that secondary injury leads to adverse neurologic outcome and identification of ongoing brain hypoxia after ROSC is imperative. Human studies have principally focused on establishing links between decreased rSO2 as a surrogate marker of brain 84 oxygenation and neurological outcome, but have yielded conflicting results in its predictive utility 83,84,196,251. These conflicting results, along with technical limitations of NIRS have hindered its routine use in evaluating brain hypoxia post cardiac arrest. We present the first prospective study evaluating the burden of brain hypoxia using a direct invasive measure of cerebral oxygenation in post cardiac arrest patients with HIBI. Our results demonstrating a significant burden of brain hypoxia in our cohort during the âno reflowâ period are in keeping with prior physiologic and animal studies confirming the presence of oligemic CBF, brain hypoxia and neuronal ischemia after ROSC. Eight of ten subjects in our study exhibited an initial PbtO2 < 20mmHg (figure 1) indicating that we may have captured the cerebrovascular physiologic profile in these subjects during âno reflowâ. Importantly, the median duration from time of cardiac arrest to data collection was 15 hours in our study, a timeline that is relatively late in the âno reflowâ period when the resolution of reduced CBF and CDO2 would be expected. As such, it is possible that the burden of brain hypoxia may be underestimated in our study. Delineating the significance of brain tissue hypoxia as a modifiable factor, as opposed to an expected epiphenomenon in the natural history of HIBI, is essential. In animal models, MAP augmentation using exogenous vasopressors has demonstrated improved PbtO2 in thalamic and cortical tissue, structures which are exquisitely susceptible to secondary injury 256,257. We also observed a relationship between MAP and PbtO2 in individual patients over time. Although significant, the variation of this relationship within patients could be explained by numerous factors including simultaneous fluctuations in other physiologic variables such as ETCO2, temperature and hemoglobin. As part of the study protocol, attending physicians were able to manipulate multiple physiologic variables to achieve PbtO2 > 20mmHg and hence, we are unable to imply causality to augmented MAP and increased PbtO2. Despite goal-oriented therapy, 85 patients continued to experience a considerable burden of brain hypoxia, thereby raising possibilities of missing pathophysiologic mechanisms of brain hypoxia or opportunities for optimizing CDO2 after ROSC from cardiac arrest. Our results are consistent with epidemiologic data which suggests that post-ROSC hypotension may contribute to worse neurologic outcomes 31. A systematic review of studies examining MAP thresholds in patients following cardiac arrest demonstrated that increased MAP targets were associated with improved neurologic outcomes 258. Although generalized increased MAP targets post cardiac arrest may be a viable therapeutic intervention, the âone size fits allâ approach fails to account for physiological differences between patients. Furthermore, uniform MAP augmentation using vasopressors carries significant risks, including increased afterload on decompensated left ventricular function, arrhythmias, and mesenteric or limb ischemia. Therefore, an individualized approach to MAP targets in HIBI patients has emerged as an attractive area of research 55. 4.3.2 THE RELATIONSHIP BETWEEN BRAIN TISSUE OXYGENATION AND CEREBRAL PERFUSION PRESSURE We demonstrated a significant relationship between CPP and PbtO2. This is remarkable as PbtO2 monitoring currently represents the closest estimator that is available with respect to neuromonitoring that can approximate CDO2 in real time76. Previous animal studies of post cardiac arrest management have demonstrated improved PbtO2 with MAP augmentation259. In human traumatic brain injury patients, this physiologic observation has been consistently demonstrated in humans but such observations have not been previously demonstrated in adult HIBI patients. Both figures 4.13 and 4.14 demonstrate the real time relationship between CPP 86 and PbtO2 in individual HIBI patients. Remarkably, fluctuations in PbtO2 appear to mirror changes in CPP over minutes, thereby highlighting the importance of studying these variables temporally with one another over short periods of time. Future studies must focus on whether the association between improved CPP and PbtO2 translates to improved aerobic metabolism and reduced secondary ischemic injury after ROSC. Figure 4.13. An ICM+ screenshot with date and time on the x axis. On the top panel, Cerebral perfusion pressure (CPP) in mmHg is on the y axis. The bottom panel represents the PbtO2 is on the y axis. With fluctuations in the CPP, the PbtO2 mirrors the fluctuations in the CPP. This figure is original for this manuscript. Figure 4.14. An ICM+ screenshot with date and time on the x axis. On the top panel, Cerebral perfusion pressure (CPP) in mmHg is on the y axis. The bottom panel represents the PbtO2 is on the y axis. With fluctuations in the CPP, the PbtO2 mirrors the fluctuations in the CPP. The middle panel shows intracranial pressure and pressure reactivity index. This figure is original for this manuscript. 87 4.3.3 AGREEMENT BETWEEN BRAIN TISSUE OXYGENATION AND JUGULAR VENOUS OXIMETRY AND NEAR INFRARED SPECTROSCOPY We also sought to delineate the relationships between CPP and non-invasive measures of CDO2, namely rSO2 and SjvO2. As in the case with PbtO2, we did observe a significant association between increasing CPP and SjvO2, but this relationship was less robust than the relationship between CPP and PbtO2. As opposed to PbtO2, which is principally determined by CBF in the setting of stable PaO2, SjvO2 is additionally dependent cerebral metabolic rate and arterial oxygen content 89. These were not held constant in our study. We did not find a relationship between CPP and rSO2, raising doubts as to the validity of rSO2 by itself to monitor cerebral perfusion in HIBI. NIRS has been advocated as a surrogate measure of CBF and CDO2 during cardiopulmonary resuscitation and in identifying early ROSC 260, however, data is lacking in establishing rSO2 as a reliable estimator of CBF beyond the immediate post ROSC period. Consistent methodologic shortcomings associated with NIRS including scalp blood flow contamination, non-adherence of cutaneous NIRS pads and ambient light interference persist82. Figure 4.12 demonstrates a period of simultaneous PbtO2 and rSO2 monitoring in a subject who underwent neurological brain death. The moment of cessation of cerebral blood flow is indicated by the absence of further PbtO2 readings whereas, rSO2 monitoring continued to reveal approximately 60% throughout the monitoring period. Plausible explanations of such an observation necessitate that scalp blood flow contamination continues to plague NIRS as reliable monitoring technique82,196. 88 Figure 4.12. An ICM+ screenshot with date and time on the x axis. On the top panel, PbtO2 is on the y axis. In the middle of the recording, the PbtO2 approaches zero and stops reading at the time of cessation of cerebral blood flow. The bottom panel represents the right and left regional oxygen saturation. Both the right and left rSO2 continues reading approximately 60% at the time of cessation of cerebral blood flow. This figure is original for this manuscript. 4.4.1 STUDY 1 - SUMMARY Episodes of brain hypoxia are prevalent and there appears to be a linear relationship between increased MAP / CPP and PbtO2 in adult human HIBI patients. To a lesser extent, there appears to be a linear relationship between CPP and SjvO2 but not rSO2. There does not appear to be a relationship or agreement between PbtO2 and SjvO2 or rSO2. Further physiologic research is warranted to delineate the significance of these observations. 89 5 CHAPTER 5: AUTOREGULATION AND OPTIMAL MEAN ARTERIAL PRESSURE IN HYPOXIC ISCHEMIC BRAIN INJURY Management hypoxic-ischemic brain injury (HIBI) after cardiac arrest focusses on balancing cerebral oxygen delivery (CDO2) and demand to minimize secondary injury4. Research efforts have targeted strategies to decrease cerebral oxygen demand, principally with hypothermia204,205. However, emerging literature has targeted the importance of optimizing CDO2 in HIBI4,14. CDO2 is dependent upon cerebral blood flow (CBF), which in turn is maintained over a wide range of mean arterial pressure (MAP) by autoregulation, the inherent capacity of the cerebrovasculature4 to undergo cyclical cerebral vasoconstriction and vasodilation to protect the brain from ischemia and hyperemia191. Recent studies have characterized the underlying state of intact versus dysfunctional autoregulation and identified a preserved zone of autoregulation243. Transcranial Doppler and near infrared spectroscopy studies have demonstrated marked between-patient heterogeneity in the degree of preserved versus dysfunctional autoregulation96,195,261. Definitive characterizations of autoregulation using positron emission scanning (PET) or invasive neuromonitoring have not been conducted. In traumatic brain injury (TBI), autoregulation monitoring is assessed using a moving Pearsonâs correlation coefficient between MAP and intracranial pressure (ICP), termed the pressure reactivity index (PRx)93. Dysfunctional autoregulation is characterized by a positive correlation between MAP and CBF, owing to pressure passive vasodilation of the cerebrovasculature262. Increased CBF results in increased cerebrovascular volume which itself leads to elevated ICP39. With intact autoregulation, increasing MAP is countered by vasoconstriction, which reduces cerebrovascular blood volume and ICP, thereby producing a 90 negative or near zero PRx262. By plotting the various PRx against MAP, a U-shaped curve is formed with the nadir denoted as the optimal MAP (MAPOPT)28. In TBI, perfusion within 5mmHg of the optimal cerebral perfusion pressure results in improved brain tissue oxygenation (PbtO2)24 and improved neurological outcome28. In HIBI, these crucial observations have not been elucidated. Therefore, the aims of this study were to a) characterize autoregulation over time as assessed by PRx in HIBI patients; b) characterize the MAPOPT, lower and upper limits of autoregulation over time; c) determine the relationship between perfusion within proximity to MAPOPT and PbtO2; and characterize the relationships between PRx and temperature and end tidal carbon dioxide tension (ETCO2). 5.1 STUDY 2 â METHODS We performed a prospective study in 10 HIBI patients using multimodal neuromonitoring. The study was approved by the University of British Columbia Clinical Research Ethics Board (H16-00466). 5.1.1 STUDY POPULATION AND SETTING The study was conducted at the Vancouver General Hospital intensive care unit (ICU), a quaternary, closed 34-bed mixed medical-surgical unit affiliated with the University of British Columbia. We included patients post-cardiac arrest under the following criteria: 1) time to return of spontaneous circulation (ROSC) > 10 minutes, 2) post-ROSC un-confounded Glasgow coma score < 9, and 3) inclusion within 72 hours of arrest. Patients were excluded for: 1) concurrent coagulopathy (INR > 1.5, prothrombin time > 40 seconds, platelets < 100 x 109/L), 2) anticipated 91 cardiac catheterization within 7 days, 3) concurrent or anticipated anticoagulants or antiplatelets, 4) hypothermia < 35oC, 5) history of TBI, intracranial hemorrhage or stroke, 6) anticipated withdrawal of care within 72 hours. Written informed consent was obtained from the legal authorized representative. An independent intensive care physician conducted independent safety reviews for each case. 5.1.2 PRESSURE REACTIVITY INDEX A sample of 10 was chosen as the number of patients we could enroll within the time available for the study. Data collected by ICM+® brain monitoring software were exported at 10-sec averaged values into Microsoft Excel (Redmond, WA, USA). The data were then subsequently imported into Stata 15.0 (StataCorp, Texas, USA), which was used for all analyses. ICM+® software calculates PRx in real-time as a moving Pearson correlation coefficient between 30 consecutive, 10 s averaged values of MAP and ICP signals51. MAPOPT is determined as a secondary derivative by plotting PRx (y-axis) against the MAP range (x-axis) in 5 mmHg bins. An automatic multi-window curve-fitting methodology was used to estimate MAPOPT (OptimalValueFlex function in ICM+). The LLA and ULA were also determined using this methodology 27, adopting a PRx optimal threshold of 0.25. We calculated the difference between actual MAP and MAPOPT for each time point MAPDIFF. We then collapsed the 10-second data over 10-minutes using mean values. All analyses were two-sided and we considered p<0.05 to be statistically significant. 92 5.1.3 DATA COLLECTION We collected the following cardiac arrest data: etiology, witnessed or unwitnessed arrest, bystander cardiopulmonary resuscitation, duration until ROSC, initial rhythm, epinephrine doses, and defibrillation attempts, post-ROSC Glasgow coma scores, time from arrest to neuromonitoring, and hypoxia (SpO2 < 92%) or hypotension (systolic blood pressure < 90mmHg) following ROSC. The following neurophysiologic data were collected into ICM+®: MAP, ICP, CPP, PbtO2, ETCO2, and temperature. Hourly doses of propofol (micrograms/kg/minute) and norepinephrine (micrograms/minute) were also recorded. Documentation of invasive neuromonitoring complications (hemorrhage and infection) were noted. Neurologic outcomes were recorded with the Glasgow Outcome Scale (GOS) and were determined at 6 months by telephone interview. 5.1.4 OPTIMAL MEAN ARTERIAL PRESSURE, LOWER AND UPPER LIMIT OF AUTOREGULATION Data were incorporated in real time into the ICM+® software at 300 Hz (Cambridge Enterprise, https://icmplus.neurosurg.cam.ac.uk/). PRx is calculated in real-time as a moving Pearson correlation coefficient between 30 consecutive, 10 s averaged values of MAP and ICP signals51. MAPOPT is determined as a secondary derivative by plotting PRx (y-axis) against the MAP range (x-axis) in 5 mmHg bins. An automatic multi-window curve-fitting methodology27 was used to estimate MAPOPT (OptimalValueFlex function in ICM+). MAPOPT was calculated using an 8-hour calculation window with an update every minute. The LLA and ULA were also determined using this methodology27, adopting a PRx optimal threshold of 0.25 with a minimum 93 calculation period for the flexible window of 7200 seconds with 600 second steps for both lower and upper limits. 5.1.5 STATISTICAL ANALYSES Characterization of cerebral autoregulation (PRx) over time. We plotted PRx over time for each individual. We determined average PRx by 10-minute periods to determine the percentage of time each patient demonstrated dysfunctional autoregulation, i.e. average PRx > 0.3. Characterization of MAPOPT, LLA and ULA over time and the relationship between MAPDIFF and PbtO2. We first plotted MAPOPT, LLA and ULA over time. In order to link brain tissue oxygenation to cerebral autoregulation, we sought to assess the relationship between PbtO2 and MAPDIFF, which is a measurement of how far away the patients actual MAP is from their MAPOPT. One would expect that PbtO2 would be low when MAPDIFF is below zero. We plotted PbtO2 vs. MAPDIFF for each patient and overlaid the scatterplot with ten locally weighted scatterplot smooths, one for each individual. Because of the non-linear relationship between PbtO2 and MAPDIFF, we modelled this relationship using fractional polynomial regression specifying âpatientâ as a random-effect. To numerically describe this relationship, we calculated the mean (SD) of PbtO2 stratified by quartiles of MAPDIFF. Characterize the relationship between both PRx with temperature and end-tidal carbon dioxide (ETCO2). We plotted PRx against temperature and ETCO2 and overlaid the scatterplot with ten locally weighted scatterplot smooths for each individual. As part of an exploratory analysis, we compared PRx in survivors and non-survivors and how this changed over time. This latter analysis was performed by fitting a linear mixed model 94 specifying âpatientâ as a random-effect (STATA command xtreg) and included an interaction variable of time (hours) and favourable neurologic outcome (modeled as a dichotomous variable). 5.2 STUDY 2 â RESULTS 5.2.1 SUMMARY RESULTS Between November 2016 and January 2018, 22 patients were screened. Twelve patients were ineligible for the following reasons: a) 6 - anticipated withdrawal of care within 72 hours, b) 4 â concurrent or anticipated anticoagulants or anti-platelets, c) 2 - history of TBI, stroke or intracranial hemorrhage, d) 1 â concurrent coagulopathy. 10 patients were included in the final analysis and demographics are presented in Table 5.1. There were no adverse events during or after the study. The median age of the cohort was 47 years (range 20 â 71) and 7 of 10 were male. The median time to ROSC was 22 minutes (range 12 â 36) and time from ROSC to neuromonitoring was 15 hours (range 6 â 44). The median duration of neuromonitoring was 47 hours (range 15 â 88). 95 Table 5.1. Patient demographics and clinical outcome of study cohort. Study ID Age Sex Arrest Etiology Initial Rhythm Witnessed Time to ROSC (mins) Post ROSC GCS Arrest to MMM (h) Admission to MMM (h) Duration of MMM (h) 6 month GOS 1 20 Male Hypoxia PEA No 12 5 26 16 24 4 2 47 Male Hypoxia PEA No 15 3 14 6 39 1 3 23 Male Hemorrhage PEA Yes 22 3 18 14 51 5 4 71 Female Hypoxia PEA No 14 4 21 8 37 1 5 31 Female VF VF Yes 25 4 106 43 94 5 6 57 Male Anaphylaxis PEA No 24 6 9 7 42 1 7 37 Male Drowning PEA Yes 36 3 10 6 18 1 8 67 Female Hypoxia PEA Yes 17 3 8 8 8 1 9 48 Male Opioid overdose PEA No 27 3 10 10 62 5 10 49 Male Asthma PEA Yes 18 4 8 9 47 1 Abbreviations: PEA â Pulseless electrical activity; VF â Ventricular fibrillation; ROSC â Return of spontaneous circulation; GCS â Glasgow coma scale; MMM â Multimodal monitoring; GOS â Glasgow outcome score 96 The mean MAP, CPP and ICP were 87 mmHg (SD 12), 75 mmHg (SD 7) and 12 mmHg (SD 15), respectively. The mean ETCO2 and temperature were 32 mmHg (SD 7) and 35.7oC (SD 0.7), respectively. 5.2.2 PRESSURE REACTIVITY INDEX AND AUTOREGULATION As part of an exploratory analysis, we compared PRx over time in survivors and non-survivors. The mean PRx was 0.31 (SD 0.19) in survivors and 0.16 (SD 0.32) in non-survivors. Figure 5.1. Scatter plots of PRx over time for all patients. The solid lines are a locally weighted scatterplot smooth for each patient. Values above the dashed line at a PRx of 0.3 represents a threshold of dysfunctional autoregulation. Patients denoted by the color cyan were survivors. Patients in black were non-survivors. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 97 There were several patterns that emerged when visually inspecting PRx over time. Survivors appeared to either have improving (Figure 5.1, patients 3 & 5) or preserved (Figure 5.1, patients 1 & 9) autoregulation. Non-survivors appeared to have dysfunctional (Figure 5.2, patient C & D) or worsening (Figure 5.1, patient 4 & 10) autoregulation. In non-survivors, the PRx increased each hour by 0.0052 (95%CI: 0.0032 to 0.0071) whereas in survivors, PRx decreased over each hour by -0.0078 (95%CI: -0.0090 to -0.0065) (p-interaction <0.001). Figure 5.2. Scatter plots of PRx over time for 4 patients with distinct patterns of PRx over time. The solid lines are a locally weighted scatterplot smooth for each patient. Values above the dashed line at a PRx of 0.3 represents a threshold of dysfunctional autoregulation. Panel A shows a patient who had dysfunctional autoregulation initially followed by intact autoregulation. Panel B shows a patient with intact autoregulation. Panel C shows a patient who had dysfunctional autoregulation. Panel D shows a patient who had intact autoregulation followed by dysfunctional autoregulation. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 5.2.3 AUTOREGULATION OVER TIME There were several patterns that emerged when visually inspecting PRx over time (Figure 5.1). Survivors tended to either have improving (Figure 5.2-patients A & B) or preserved 98 (Figure 5.1 â patients 1 & 9) autoregulation. Non-survivors tended to have dysfunction or worsening (Figure 5.2 â patients C & D) autoregulation. Mixed effects linear regression confirmed a difference in PRx over time comparing survivors and non-survivors (p-interaction <0.001). In non-survivors, the PRx increased each hour by 0.0052 (95%CI: 0.0032 to 0.0071) whereas in survivors, PRx decreased over each hour by -0.0078 (95%CI: -0.0090 to -0.0065). By plotting MAPOPT, LLA and ULA over time for each individual patient, there appeared to be considerable heterogeneity in between patients with respect to the fluctuation of the aforementioned variables longitudinally. Figure 5.3 demonstrates the MAPOPT, LLA and ULA and reveals variation over time from the initiation of neuromonitoring to completion of the study period. Figure 5.3. Optimal MAP (MAPOPT), Lower Limit of Autoregulation (LLA) and Upper Limit of Autoregulation (ULA) over time for each patient. The solid black line is MAPOPT. The grey dashed lines represent the LLA and ULA. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 99 Visually, there did not appear to be relationships between PRx versus propofol doses (p=0.42) (figure 5.5). Although a statistically significant p value was demonstrated between PRx and norepinephrine dose (p<0.001) (figure 5.4), visually, there did not appear to be discernable relationship. Figure 5.4. Scatter plots of PRx (y axis) versus norepinephrine dose (mcg/min) on the x axis. The grey lines are a locally weighted scatterplot smooth for each patient. Values above the dashed line at a PRx of 0.3 represents a threshold of dysfunctional autoregulation. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. Figure 5.5. Scatter plots of PRx (y axis) versus propofol dose (mcg/kg/min) on the x axis. The grey lines are a locally weighted scatterplot smooth for each patient. Values above the dashed line at a PRx of 0.3 represents a threshold of dysfunctional autoregulation. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 100 5.2.4 OPTIMAL MEAN ARTERIAL PRESSURE, LOWER AND UPPER LIMIT OF AUTOREGULATION Characterization of MAPOPT, LLA and ULA over time and determine the relationship between MAPDIFF and PbtO2. The mean (SD) MAPOPT, LLA and ULA were 89 (11) mmHg, 82 (8) mmHg and 96 (9) mmHg, respectively (figure 5.6). The median time spent of actual MAP Figure 5.6. Summary statistics across the entire cohort for the optimal mean arterial pressure, lower and upper limits of autoregulation. This figure is original for this manuscript. within 5 mmHg of MAPOPT was 42% (range 10 â 78). The percentage of time spent below -5 mmHg was 32% (range 12 â 74) and above +5 mmHg from the MAPOPT was 27% (range 4 â 54) (figure 5.7). 101 Figure 5.7. Time density plot of the time during which the actual mean arterial pressure was maintained within +/- 10mmHg of the optimal mean arterial pressure. Each grey bar represents the amount of time maintained within optimal mean arterial pressure in 5mmHg bins. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 5.2.5 OPTIMAL MEAN ARTERIAL PRESSURE AND BRAIN TISSUE OXYGENATION In order to link brain tissue oxygenation and cerebral autoregulation, we assessed the relationship between relationship between PbtO2 and MAPDIFF (Figure 5.8). Fractional polynomial regression demonstrated a non-linear relationship between PbtO2 and MAPDIFF (p<0.001). PbtO2 increased as the difference between MAP and MAPOPT approached zero. 102 Figure 5.8. Scatter plot between PbtO2 and the difference between MAP and MAPOPT (MAPDIFF). The light grey dots are corresponding PbtO2 and MAPDIFF. The light grey solid lines are a locally weighted scatterplot smooth for each patient. The solid black line is a predicted curve generated using a restricted cubic splines model. Fractional polynomial (fp) regression confirmed there was a non-linear relationship between PbtO2 and MAPDIFF. The best parameterization of MAPDIFF was using X0.5 (fp 0.5). This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. PbtO2 leveled off as MAPDIFF went above zero. To numerically describe this relationship, we divided MAPDIFF into quartiles and calculated the associated PbtO2. Quartile 1 (MAPDIFF â¤ -5mmHg) had a mean PbtO2 of 19 (9) mmHg; quartile 2 (MAPDIFF -4 to 2 mmHg) had a mean PbtO2 of 25 (9) mmHg; quartile 3 (MAPDIFF 2 to 9 mmHg) had a mean PbtO2 of 23 (10) mmHg; and quartile 4 (MAPDIFF > 9 mmHg) had a mean PbtO2 of 26 (9) mmHg. 103 5.2.6 PRESSURE REACTIVITY INDEX RELATIONSHIP TO CARBON DIOXIDE TENSION AND TEMPERATURE There did appear to be non-linear relationships between PRx and temperature (Figure 5.9) or ETCO2 (figure 5.10). Figure 5.9. Scatter plots between PRx and temperature (left panel) or ETCO2 (right panel). The light grey dots are corresponding values of PbtO2 and the variable of interest. The light grey solid lines are a locally weighted scatterplot smooth for each patient. Values above the dashed grey line at a PRx of 0.3 represent dysfunctional autoregulation. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. Figure 5.10. Scatter plots between PRx and temperature (left panel) or ETCO2 (right panel). The light grey dots are corresponding values of PbtO2 and the variable of interest. The light grey solid lines are a locally weighted scatterplot smooth for each patient. Values above the dashed grey line at a PRx of 0.3 represent dysfunctional autoregulation. This figure is printed with permission from Sekhon MS, Gooderham P, Menon DK, et al. The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest. Crit Care Med 2019. 104 5.3 STUDY 2 â DISCUSSION We were also able to characterize cerebral autoregulation using PRx and identify MAPOPT, LLA and ULA. Interestingly, the overall mean MAPOPT was 89 mmHg which is markedly higher than recommended by international guidelines 263. Finally, we found an association between perfusion within proximity of PRx derived MAPOPT and PbtO2. PbtO2 improved when the actual MAP approached within 10 mmHg of MAPOPT, suggesting improved CDO2 within proximity to MAPOPT. 5.3.1 THE SIGNIFICANCE OF AUTOREGULATION IMPAIRMENT The mean MAPOPT observed in our study (89 mmHg) is higher than international post cardiac arrest guidelines which recommend MAP > 65 mmHg 263. Importantly, there was considerable between and within-patient MAPOPT variability which further highlights the heterogeneous nature of HIBI. This marked heterogeneity may serve as an opportunity to therapeutically target individual MAP thresholds in patients with HIBI 55, rather than the current uniform approach. In particular, we found that cerebral autoregulation, as assessed by PRx, changes over time. Our data also suggests that the change in PRx over time may differ between survivors and non-survivors, although more data is clearly needed to elucidate this relationship. The relative importance of MAPOPT versus LLA and ULA remain unclear. It may be that LLA is a crucial physiologic parameter to target as thresholds below LLA are associated with cerebral oligemia and brain hypoxia 264. Importantly, the mean LLA (82 mmHg) in our cohort was also still markedly higher than post cardiac arrest guidelines for MAP > 65 mmHg. The importance of LLA and ULA as perfusion targets in HIBI requires further research. 105 Our results are also consistent with a prior study using transcranial Doppler to assess cerebral autoregulation in patients following cardiac arrest which demonstrated a right shifted lower limit of autoregulation using transcranial Doppler 195. Furthermore, Ameloot et al. retrospectively calculated COx, a correlation coefficient between MAP and the rSO2 from NIRS to characterize autoregulation and found the mean MAPOPT in their cohort to be 85 mmHg 261. Using a similar, but prospective COx based assessment of cerebral autoregulation, our research group recently observed a mean MAPOPT to be 76 mmHg in a cohort of post cardiac arrest patients using COx 96. 5.3.2 THE RELATIONSHIP BETWEEN OPTIMAL MEAN ARTERIAL PRESSURE AND IMPROVED BRAIN TISSUE OXYGENATION We attempted to assess the physiologic relationship between MAPOPT and CDO2, as measured by PbtO2. Despite heterogeneity between patients, there appeared to be a non-linear relationship between MAPDIFF and PbtO2. When the actual MAP was more extreme than -10 mmHg below MAPOPT, there was a linear rise of PbtO2 as MAPDIFF approached -10 mmHg. Between MAPDIFF of -10 to +10 mmHg, there was a less steep rise in PbtO2, with this relationship becoming more attenuated at the top of this range. MAPDIFF above +10 mmHg was not associated with further improvements in PbtO2. This relationship highlights that perfusion within proximity of MAPOPT is associated with improved PbtO2 and its physiologic significance must be further evaluated. Importantly, perfusion beyond the MAPOPT was not associated with increasing PbtO2, thereby suggesting that uniformly increased MAP targets will unreliably lead to improved PbtO2 and could simply expose patients to the harmful effects of unnecessary exogenous vasopressors. Similar findings have been observed in patients with traumatic brain 106 injury where Jaeger et al. demonstrated that PbtO2 increased significantly as actual CPP approached optimal CPP derived from PRx 202. These findings were further corroborated with a physiologic study revealing that perfusion pressures associated with negative PRx (intact autoregulation) were associated with improved CDO2, cerebral oxygen metabolic rate and cerebral blood flow 265. In traumatic brain injury, the clinical significance of these observed physiologic benefits are illustrated as deviation of actual CPP from the optimal CPP is associated with worse long term neurological outcomes 28. We found over half of the actual MAP measurements were more than 5 mmHg from MAPOPT, suggesting an opportunity for future interventional research to target adherence to MAPOPT. 5.3.3 STRENGTHS AND LIMITATIONS Our study is novel and characterizes the cerebrovascular pathophysiological sequelae of HIBI after cardiac arrest. Strengths of our study include the high granularity of data collection (300Hz) with time-stamped neurophysiologic variables to facilitate examining the underlying relationships between various measures of brain oxygenation and CDO2. We gathered considerable longitudinal data over time with a mean duration of monitoring during the study of 46 hours and were able to evaluate the physiological profile of a key determinant of CDO2 (MAP) on brain oxygenation in HIBI. Finally, we demonstrated improved PbtO2 within proximity of MAPOPT, raising the possibility of beneficial targeted individualized perfusion targets in HIBI, however, this concept requires significant further physiologic and clinical delineation. Our study has important limitations. Our small sample size limits our ability to draw firm conclusions on HIBI pathophysiology and indeed suggests that there are likely distinct HIBI 107 phenotypes. This is particularly important when trying to examine for other factors that may confound the relationship between MAP and PbtO2, namely ETCO2 and temperature. This is the first study of its kind and necessarily is exploratory and hypothesis-generating in nature, we are unable to imply causal associations between MAP and MAPOPT with assessments of brain oxygenation. Instead, the observed associations in our study are intended to provide further justification to delineate their clinical and physiological significance in the future. Secondly, our definition of brain hypoxia (PbtO2 < 20mmHg) is extrapolated from traumatic brain injury literature 200 and may not reflect an important threshold in patients in HIBI. Owing to the reduced cerebral metabolic demand immediately after cardiac arrest, patients with HIBI may tolerate lower levels of PbtO2 245. Establishing HIBI specific PbtO2 thresholds in humans of brain hypoxia against gold standard assessments of CDO2 such as positron emission scanning is an essential gap in the current literature. In addition, the observed relationship between MAP and PbtO2 does not reflect the end organ balance of aerobic versus anaerobic metabolism. We used PRx as a measure of autoregulation, however, we acknowledge that PRx is an indirect estimator of dynamic autoregulation which relies upon repeated longitudinal integration between fluctuations in values of MAP and changes in CBF / cerebrovascular blood volume and downstream ICP fluctuations. Dynamic changes in CBF may occur from alternative physiologic stressors independent from MAP including changes in arterial carbon dioxide tension, cerebral metabolic rate and temperature fluctuations, thereby negating the accuracy of PRx. We attempted to control these variables in our study by mandating strict PaCO2 35 to 40mmHg, targeted temperature management (36oC) and intravenous sedation using propofol to target burst suppression during the study period. However, it is possible that such goals were uniformly achieved and have affected our results. 108 Importantly, the patients in our cohort primarily underwent cardiac arrest from pulseless electrical activity secondary to underlying causes that likely resulted in pre-circulatory arrest cerebral ischemia (hemorrhage, hypoxia) as opposed to primary sudden cardiac arrest from arrythmias. As such, our results must be interpreted under premise that the majority of patients in our cohort likely fall on the severe end of the HIBI pathophysiology spectrum. Therefore, our results should not be extrapolated to patients with sudden cardiac arrest from arrythmias who undergo immediate cardiopulmonary resuscitation and further work is needed to delineate the pathophysiology in this sub-population. Finally, increased MAP also may not translate into definitively increased CBF as we did not account for changes in cerebrovascular resistance. Future steps of study in this disease should evaluate direct measures of CBF as well as measures of cerebral metabolism using cerebral microdialysis and positron emission scanning. 5.3 STUDY 2 â SUMMARY Perfusion within proximity of MAPOPT, as determined by PRx, may be associated with improved PbtO2. Autoregulation, as measured by PRx, appeared to be dysfunctional in our cohort but individual patients exhibited considerable heterogeneity in the PRx over time after ROSC. Although the MAPOPT, LLA and ULA appeared to be significantly higher than current guideline recommendations, these autoregulation derived indices appeared to exhibit considerable heterogeneity in between patients and also longitudinally within individual patients. Further physiologic research is warranted to delineate the significance of these observations. 109 6 CHAPTER 6: INTRACRANIAL PRESSURE AND COMPLIANCE IN HYPOXIC ISCHEMIC BRAIN INJURY In patients with hypoxic-ischemic brain injury (HIBI) after cardiac arrest, cerebral edema occurs following return of spontaneous circulation (ROSC) from underlying mechanisms attributable partly to vasogenic edema and reperfusion injury from blood brain barrier disruption after ROSC4,266. Additionally, cerebral ischemia during circulatory arrest and following ROSC can lead to brain hypoxia with eventual formation of cytotoxic cerebral edema and elevated intracranial pressure (ICP)190. Elevated ICP itself can further reduce cerebral blood flow leading to a cycle of worsening ischemia and elevated ICP which may culminate in trans-tentorial herniation and neurologic death39,183. Observational studies have demonstrated that the presence of cerebral edema on computed tomography after ROSC is associated with adverse neurologic outcome267â269. Furthermore, increased ICP â as determined using ultrasound measurement of the optic nerve sheath diameter â is associated with adverse neurological outcome after cardiac arrest270,271. However, non-invasive techniques for estimating ICP, such as at the aforementioned optic nerve sheath ultrasonography and computed tomography, only provide intermittent estimates over time. Studies of invasive ICP monitoring using is limited to small case series and have yielded conflicting results with respect to the burden of intracranial hypertension272,273. Furthermore, these studies only measured ICP intermittently, thus there is limited granularity of data 273,272. As such, the precise evaluation of intracranial pressure â volume relationships over time in patients with HIBI is unknown. Furthermore, the associations between ICP and physiologic variables that may affect the intracranial pressure-volume relationships have not been well described in HIBI. 110 The specific aims of this study were to a) characterize the burden of intracranial hypertension (ICP > 20 mmHg), b) evaluate the changes in ICP and intracranial compliance over time; and c) examine the relationships between core body temperature and carbon dioxide tension with ICP in patients with HIBI after cardiac arrest 6.1 STUDY 3 â METHODS This current study is an a priori planned analysis of a previously published prospective interventional study using invasive multimodal neuromonitoring in patients with HIBI after cardiac arrest97. The study was approved by the University of British Columbia Clinical Research Ethics Board (H16-00466). Consent was obtained from the substitute decision maker for all participants prior to enrollment. 6.1.1 STUDY POPULATION AND SETTING The study was conducted in the intensive care unit (ICU) at Vancouver General Hospital, which is a provincial medical and surgical unit with subspecialty trained intensive care physicians. Our institution conducts invasive ICP monitoring in more than 50 neurocritically ill patients per year using direct intra-parenchymal and intra-ventricular approaches. The inclusion criteria for the study were: a) age > than 18 years; b) greater than 10 minutes from onset of cardiac arrest to ROSC; c) Glasgow Coma Score of < 9 or motor score < 5; d) enrollment within 72 hours of initial cardiac arrest. Exclusion criteria were: a) previous or concurrent history of traumatic brain injury, intracranial hemorrhage or ischemic stroke; b) concurrent or anticipated use of anti-platelet or anticoagulant medications; c) anticipated cardiac catheterization within the next 7 days; d) coagulopathy (international normalized ratio > 1.5, 111 prothrombin time < 40 seconds, platelets < 100 x 109 cells/ml) or e) anticipated withdrawal of life-sustaining therapy within 72 hours. 6.1.2 INTRACRANIAL PRESSURE AND COMPLIANCE MONITORING The following neurophysiologic data were collected: a) ICP (Camino®, Integra Lifesciences, Plainsboro, New Jersey, USA); b) invasively monitored mean arterial pressure (MAP); c) brain tissue oxygenation (PbtO2) (Licox®, Integra Lifesciences, Plainsboro, New Jersey, USA); d) end tidal carbon dioxide tension (ETCO2) and e) central core body temperature using an esophageal temperature monitoring. All physiologic data was displayed on our bedside monitors (Carescape®, General Electric, USA) and then subsequently slaved into the ICM+ monitoring software (Cambridge Enterprise, United Kingdom) using a USB to RS232 converter to serial DB9 cable at a frequency of 300Hz. Intracranial compliance can be estimated in real time using a correlation coefficient between the mean absolute ICP and mean pulse amplitude pressure of the ICP waveform, termed the compensatory reserve index (RAP)274. A RAP > 0.4 denotes limited intracranial compensatory reserve and intracranial compliance and has been primarily studied in patients with traumatic brain injury275,276. ICM+® software calculates RAP in real-time as a moving Pearson correlation coefficient between 30 consecutive, 10-second averaged values of mean absolute ICP and the mean pulse amplitude from ICP signals37. 112 Figure 6.1. The pressure volume relationship of the intracranial cavity and shows the compensatory reserve index (RAP) in each of the three distinct zones of the pressure volume curve. Re-printed with permission from Cambridge University Press: Neurocritical care Essentials: A Practical Guide 6.1.3 DATA COLLECTION In addition to demographic data, the following clinical data were collected: a) initial rhythm and cardiac arrest cause; b) witnessed or unwitnessed cardiac arrest; c) number of defibrillation attempts during resuscitation; d) epinephrine administration during resuscitation; e) episodes of post ROSC pre-hospital hypotension (systolic blood pressure < 90 mmHg) or hypoxia (pulse oximetry oxygen saturation < 90%); f) time from initial cardiac arrest to ROSC; g) time and date of ICU admission and h) time from initial cardiac arrest to insertion of invasive ICP monitoring. We collected the date and time of ICP monitor insertion and removal as well as any complications related to its use (hemorrhage or infection). In addition to the hourly dose of intravenous propofol (mcg/kg/min), we collected any therapeutic interventions for the management of intracranial hypertension: use and dose of mannitol, hypertonic saline or 113 barbiturates, and the use and temperature target for therapeutic hypothermia. Six-month neurological outcome was collected with the Glasgow Outcome Scale. 6.1.4 INTRACRANIAL PRESSURE MANAGEMENT All management decisions were decided by the attending intensivist. Patients with HIBI are managed in our unit with normothermia temperature management (temperature 35 to 36 ºC) for 24 to 48 hours. We use a management algorithm for increased ICP with an aim to maintain ICP < 20 â 25 mmHg in patients managed with multimodal neuromonitoring254 incorporating interventions pertaining to: a) intravenous sedation (propofol â 1st line, narcotic and midazolam â 2nd line); b) osmotherapy (2-3 ml/kg 5% hypertonic saline or 2 to 3ml/kg 20% mannitol intermittent intravenous boluses) and c) normocapnic ventilation. With refractory increased ICP, we selectively undertake therapeutic hypothermia (temperature 33 to 34 ºC) or intravenous barbiturate administration at the intensivistâs discretion. ICP monitoring was placed in the non-dominant frontal lobe via a single burr hole and bolt (Integra Lifesciences, New Jersey, USA). A follow up head computed tomography scan was conducted to ensure adequate placement. 6.1.5 STATISTICAL ANALYSES From the ICM+® software, all the neuromonitoring data was exported into Microsoft Excel (Redmond, WA, USA). From Microsoft Excel, data were transferred to RStudio software (version 3.4.1) for statistical analysis. In RStudio, we averaged data for physiologic variables over 10 minutes. Modeling ICP and RAP over time. We assessed the temporal relationships of ICP and RAP over time visually for all study subjects in the cohort. A mixed-methods linear regression 114 was used to analyze the temporal trends of RAP and ICP over time in each study subject (RStudio package lme4 277). Thereby, we were able to consider the within patient variability of data for ICP and RAP. To examine the change of ICP and RAP over time in survivors vs. non-survivors, we used a mixed effects linear regression model. The final model included an interaction between time (collapsed over 10 minutes) and favourable neurologic outcome as a dichotomous variable. We present the differences of ICP and RAP in survivors versus non-survivors and we considered p<0.05 to be a significant value. Modeling brain oxygenation PbtO2, ETCO2 and temperature versus ICP. We assessed these relationships by plotting PbtO2, ETCO2 and temperature against ICP for the entire cohort. Associations were modeled using a generalized linear model specifying âpatientâ as a random-effect (RStusdio package lme4 277). We used fractional polynomial regression (RStudio function mfp) to analyze the associations to interrogate the potential non-linear relationship between PbtO2, ETCO2 and temperature versus ICP. 6.2 STUDY 3 â RESULTS 6.2.1 SUMMARY RESULTS During the study period, 22 potential study subjects were identified and 10 patients fulfilled inclusion criteria as previously published97. Table 6.11 demonstrates the clinical and demographic data of each individual study subject. Table 6.2 reveals the ICP management interventions used in the cohort during the course of the study. 115 Table 6.1. Patient demographics and clinical outcome of study cohort. (Table adapted from Sekhon et al.13) Study ID Age Sex Arrest Etiology Rhythm Witnessed Time to ROSC (mins) Time to ICP monitoring (h) Duration of ICP monitoring (h) 6-month GOS 1 20 Male Hypoxia PEA No 12 16 24 4 2 47 Male Hypoxia PEA No 15 6 39 1 3 23 Male Hemorrhage PEA Yes 22 14 51 5 4 71 Female Hypoxia PEA No 14 8 37 1 5 31 Female VF VF Yes 25 43 94 5 6 57 Male Anaphylaxis PEA No 24 7 42 1 7 37 Male Drowning PEA Yes 36 6 18 1 8 67 Female Hypoxia PEA Yes 17 8 8 1 9 48 Male Opioid overdose PEA No 27 10 62 5 10 49 Male Asthma PEA Yes 18 9 47 1 Abbreviations: ID â Identification; VF â Ventricular fibrillation; ROSC â Return of spontaneous circulation; ICP â Intracranial pressure; GOS â Glasgow outcome scale 116 6.2.2 INTRACRANIAL PRESSURE AND COMPLIANCE OVER TIME Characterization of temporal patterns of ICP The mean ICP was 14 mmHg (SD 11) across the entire cohort. There were 2419 data points pertaining to ICP values and of these, 279 (11%) had an ICP above 20 mmHg. Patients were exposed to intracranial hypertension (ICP > 20 mmHg) for an average of 22% (range 0-100) of the total time of invasive neuromonitoring. Figure 6.2 demonstrates the ICP longitudinally for each study subject in the cohort. Most study subjects exhibited normal ICP over time; however, two demonstrated refractory increased ICP despite maximal medical management (Figure 6.2, patients 7 & 8). The mean ICP was 12 mmHg (SD 5) in survivors and 16 mmHg (SD 15) in non-survivors (p=0.27). Figure 6.2. Each individual panel represents patients 1 â 10 in the cohort and plots intracranial pressure (mmHg, y-axis) versus time (hours, x-axis). The dotted line denotes an intracranial pressure > 20 mmHg as the threshold for intracranial hypertension. The solid lines displayed in cyan are referent to survivors, and in black to non-survivors. Reproduced with permission from Sekhon MS et al. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019. 117 Figure 6.3. Each individual panel represents patients 1 â 10 in the cohort and plots RAP (y-axis) versus time (hours, x-axis). The dotted line denotes RAP >0.4 as the threshold for limited intracranial compensatory reserve and brain compliance. The solid lines displayed in cyan are referent to survivors, and in black to non-survivors. Reproduced with permission from Sekhon MS et al. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019. 6.2.3 BURDEN OF INTRACRANIAL HYPERTENSION AND LIMITED COMPLIANCE Description of intracranial compliance using RAP For the entire cohort, the mean RAP was 0.58 (SD 0.34). Considering all RAP data points (1849), 76% were greater than 0.4, indicating a large burden of limited compensatory reserve and intracranial compliance across the entire cohort. There was no difference in mean RAP in survivors [0.58 (SD 0.37)] compared to non-survivors [0.58 (SD 0.32), p=0.90)]. The percentage 118 of time with a RAP of greater than 0.4 was 78% (range 57 â 97) within individual study subjects thereby demonstrating limited intracranial compliance despite normal absolute ICP in most patients. Figure 6.3 demonstrates the RAP longitudinally for each patient. Overall, all patients presented patterns of depleted compensatory reserve when visually inspecting RAP over time (RAP >0.4). For instance, Patient 7 displayed an inverse relationship between ICP and ICP pulse amplitude (RAP close to -1) after reaching the ICP upper breakpoint, a pathological state indicative of complete exhaustion of the intracranial compensatory reserve (Figure 6.5, panel A). 6.2.4 RELATIONSHIP BETWEEN INTRACRANIAL PRESSURE AND TEMPERATURE AND CARBON DIOXIDE By plotting the relationship between PbtO2, ETCO2, temperature and ICP, there was not any obvious relationship. Relationships between ICP and PbtO2, ETCO2 and temperature during the monitoring period are presented in figure 6.4. Figure 6.4 Panel A shows the scatterplot relationship between intracranial pressure and PbtO2. The red line represents the best fit line of the whole cohort. Panel B shows the scatterplot relationship between intracranial pressure and ETCO2. The red line represents the best fit line of the whole cohort. Panel C shows the scatterplot relationship between intracranial pressure and temperature. The red line represents the best fit line of the whole cohort. Reproduced with permission from Sekhon MS et al. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019. 119 6.2.5 INTRACRANIAL PRESSURE MANAGEMENT The mean ETCO2 was 32 mmHg (SD 6), mean arterial carbon dioxide tension was 40 mmHg (SD 7) and mean core body temperature was 35.7 ºC (SD 0.8). The median duration of intravenous sedation was 44 hours (range (8 â 106) and the mean dose of propofol was 63 ug/kg/min (SD 24). Six patients (60%) received hypertonic saline boluses and 4 patients (40%) received 20% mannitol boluses. 120 Table 6.2. Intracranial pressure guided interventions in all cohort patients. Study ID Temp (oC, mean, SD) Sedation (h) Propofol dose (ug/kg/min, mean, SD) 2nd line Sedative ETCO2 (mmHg, mean, SD) PaCO2 (mmHg, mean, SD) HTS bolus Mannitol 1 36.9 (0.1) 29 31 (7) No 45 (7) 35 (2) 0 0 2 35.9 (1.9) 41 86 (21) No 36 (1) 40 (1) 2 2 3 35.2 (0.8) 39 89 (12) No 31 (3) 35 (3) 1 0 4 36.4 (1.5) 44 37 (27) No 28 (2) 36 (2) 0 0 5 36.9 (1.6) 108 37 (27) No 27 (2) 41 (1) 4 4 6 35.3 (1.9) 42 35 (50) No 26 (10) 38 (8) 1 0 7 35.0 (0.5) 24 100 (0) No 28 (6) 33 (0) 2 2 8 35.0 (0.1) 8 62 (35) No 24 (19) 40 (11) 0 0 9 35.2 (0.8) 63 73 (35) No 30 (6) 49 (1) 1 0 10 35.8 (0.2) 54 79 (14) Yes 38 (13) 57 (7) 2 1 121 6.3 STUDY 3 â DISCUSSION The main findings of our study are that there was a relatively low burden of intracranial hypertension (ICP > 20 mmHg) in the cohort overall but there appeared to be a significant heterogeneous nature of ICP patterns over time between individual patients. Most patients in our cohort demonstrated increased RAP, suggesting a state of limited intracranial compensatory reserve and compliance in HIBI. 6.3.1 THE SIGNIFICANCE OF NORMAL INTRACRANIAL PRESSURE AFTER CARDIAC ARREST In HIBI, cerebral edema can lead to limited intracranial compensatory reserve, compliance, elevated ICP and secondary brain hypoxia induced injury 4,7,278. In lieu of these pathophysiologic sequelae, authors have attempted to delineate the importance of ICP in HIBI. You et al. demonstrated an association with adverse neurological outcome and increased ICP using cerebral spinal fluid pressure assessment and increased optic nerve sheath diameter (ONSD) via bedside ultrasonography in conducted 83 post-cardiac arrest HIBI270. These findings corroborate prior observational studies also demonstrating associations between increased ONSD, using ultrasonography and computed tomography, with adverse neurological outcome in HIBI268,271 and traumatic brain injury279,280,281. Recently, our research group sought to establish the validity of non-invasive estimators of ICP versus invasively monitored ICP in HIBI patients. We found a significant linear relationship between ICP and ONSD ultrasonography in this cohort as part of a sub-study282. Although intriguing, non-invasive methods of ICP evaluation are associated with limitations pertaining to inter-observer reliability and evaluation of intracranial pressure â volume dynamics at single time points. 122 Previous reports using invasive ICP monitoring have yielded conflicting results 272,273. Naito et al. demonstrated, in a cohort of nine cardiac arrest patients, increased ICP during the rewarming period only after therapeutic hypothermia from 6 mmHg (4-9) mmHg to 16 mmHg (12-26)272, remaining under the accepted threshold of intracranial hypertension (ICP < 20 mmHg)272. Similarly, Sakabe et al. observed that intracranial hypertension only occurred in one of six HIBI patients after cardiac arrest273, thereby suggesting a low burden of intracranial hypertension. Importantly, both studies were limited to intermittent measurements and lacked high resolution data to delineate longitudinal patterns and relationships between associated physiologic variables. We observed a relatively low burden of intracranial hypertension overall with the percentage of time of ICP > 20 mmHg being ~22% (0 â 100). Two patients in our cohort (patient 7 and 8) developed refractory intracranial hypertension while the remaining patients did not (Figure 6.2). Importantly, the interpretation of absolute ICP values must be observed in the context of concomitant therapies aimed at reducing ICP. Given the intensity of active management for ICP control in our cohort (Table 6.2), it is possible the burden of intracranial hypertension may have been far greater if the clinicians were blinded to the ICP monitoring data and may have blunted the natural history of cerebral edema formation and ICP over time. Additionally, we acknowledge that our management trigger for increased ICP is extrapolated from the traumatic brain injury literature200. Currently, it is unknown what the specific threshold of intracranial hypertension is in HIBI patients or if management of increased ICP is associated with improved outcome. 123 6.3.2 THE SIGNIFICANCE OF LIMITED INTRACRANIAL COMPLIANCE AFTER CARDIAC ARREST Although we did not demonstrate an impressive burden of intracranial hypertension in our study, assessment of the intracranial compensatory reserve and compliance may provide insights into the degree of cerebral edema over time. Previous authors have suggested absolute ICP is a crude measure of the overall bulk of cerebral edema in HIBI278. In instances of limited intracranial compliance, ICP only becomes elevated once compensatory mechanisms have been exhausted39,183. RAP, a correlation coefficient between the mean and fundamental component of the ICP waveform, varies between -1 and +137,283. Values nearing zero indicate normal intracranial compliance and whereas values approaching +1 suggest limited compensatory reserve183. In the setting of exhaustion of compensatory reserve, RAP may approach -1 as the ICP waveform assumes a rounded morphology36,39. RAP was elevated in all study subjects consistently > 0.4 during the monitoring period, indicating a state of limited compensatory reserve183. This result suggests that although the numerical ICP remained low in most patients in our cohort, elevated RAP indicates that study subjects were at the steep portion of the intracranial pressure â volume relationship. As such, significant perturbations in physiological variables that can alter this relationship dynamically could cause a precipitous shift up the curve towards developing intracranial hypertension and herniation. In particular, overly aggressive rewarming after targeted temperature management, permissive hypercapnia and exacerbation of cerebral edema from hyponatremia could all lead to increased ICP272. On an individual patient level, there appeared to be significant heterogeneity in the patterns of ICP over time after ROSC. Overall, there appeared to be 3 distinct patterns of ICP 124 and compensatory reserve observed (Figure 6.3). The heterogeneous nature of the ICP and RAP profiles could reflect a spectrum of underlying disease severity and cerebral edema. Furthermore, the pre-morbid volume of cerebral parenchymal bulk likely factors into the heterogeneity of overall pressure â volume dynamics, with older patients exhibiting an increased capacity of compensatory reserve stemming from age related cerebral atrophy. The nature of our study and small cohort preclude us from drawing definitive conclusions or eliciting predictive methods for identifying which patients could be at risk of developing intracranial hypertension. Figure 6.5. Visual description of 3 distinct patterns of ICP and intracranial compliance in HIBI. Panel A demonstrates increased ICP and RAP. On the far right in panel A, refractory intracranial hypertension results in trans-tentorial herniation with resultant decreased in the ICP amplitude and RAP. Panel B shows a patient with low ICP but increased RAP. Finally, panel C demonstrates low ICP and RAP. Sekhon MS et al. Intracranial pressure and compliance in hypoxic ischemic brain injury patients after cardiac arrest. Resuscitation. 2019. 125 6.3.3 LIMITATIONS Our study adds to the existing literature detailing the ICP patterns over time and evaluation of intracranial compliance in HIBI. Strengths of our study include our longitudinal measurements, high resolution of data acquisition and invasive nature of ICP monitoring. Our study has significant limitations with which the results must be interpreted. The first is that the small sample size and lack of comparative controls which prohibits causal conclusions to be drawn with respect to the relationships between carbon dioxide tension and temperature with ICP. Other ICP lowering interventions including intravenous sedation and osmotherapy (mannitol and 5% hypertonic saline) were used by clinicians and may have blunted any significant relationships that may be present. Furthermore, we acknowledge our data is not generalizable to the post cardiac arrest HIBI patients who are managed with therapeutic hypothermia (temperature 32 â 34oC). Due to potential risks of hypothermia induced coagulopathy and intracranial hemorrhage associated with invasive neuromonitoring, we were unable to characterize the intracranial pressure-volume physiology below normothermia (35 â 36oC). It is unclear whether increased ICP is a therapeutically modifiable factor or rather a sign of disease severity in HIBI. Further physiologic and clinical studies are needed to clarify these important questions. 6.4 STUDY 3 â SUMMARY We demonstrate the relatively low burden of intracranial hypertension but abnormal intracranial compliance in HIBI after cardiac arrest. On an individual patient level, there appears to be heterogeneity with ICP and intracranial compliance from cerebral edema in HIBI. 126 7 BRAIN HYPOXIA SECONDARY TO DIFFUSION LIMITATION IN HYPOXIC ISCHEMIC BRAIN INJURY Hypoxic ischemic brain injury (HIBI) is the primary determinant of neurological outcome after cardiac arrest7. HIBI pathophysiology is characterized by a primary injury during circulatory arrest stemming from cessation of cerebral blood flow (CBF) and secondary injury following return of spontaneous circulation (ROSC)1 from post-resuscitation cerebral ischemia1. This may be modifiable by optimizing cerebral oxygen delivery (CDO2) to improve neurological outcome243. CDO2 is directly dependent upon CBF, which is proportional to cerebral perfusion pressure (CPP) (mean arterial pressure [MAP] â intracranial pressure [ICP]). Reduced CBF can lead to secondary injury7 and studies have linked hypotension13,284,285 and hypocapnia12,173,286, which decrease CBF, to adverse neurological outcome. Despite goal-oriented management aimed at optimizing CDO2, HIBI patients can still experience brain hypoxia97,287. Uniform MAP augmentation has not resulted in improved neurologic outcomes 15. This discrepancy between the importance of preventing secondary ischemic injury and the paucity of evidence supporting routine CDO2 optimization strategies suggests gaps in the pathophysiological mechanisms underlying brain hypoxia in HIBI. Diffusion limitation of oxygen in the microvasculature is a mechanism of brain hypoxia234 in TBI. Correlation to pathological specimens suggests the physiology is underpinned by microvascular collapse and perivascular edema234. Furthermore, modulation of CBF in this context was associated with impaired ability to increase oxygen extraction, confirming diffusion limitation234. 127 Similarly, HIBI pathophysiology is partly characterized by blood brain barrier (BBB) breakdown and vasogenic edema288â290. These sequelae suggest that perivascular edema and microvascular collapse may occur in HIBI1. If true, then diffusion limitation of oxygen delivery is a plausible mechanism of post-resuscitation brain hypoxia. As such, the aims of the study were to a) determine the difference between PvO2 â PbtO2 in HIBI patients with brain hypoxia versus normoxia.; and b) to determine the relationship between the PvO2 â PbtO2 gradient and CPP in patients with brain hypoxia vs. normoxia. 7.1 STUDY 4 â METHODS 7.1.1 STUDY SUBJECTS AND MANAGEMENT The study was conducted at the Vancouver General Hospital intensive care unit from November 2016 to January 2019. Inclusion criteria were: a) age > 18; b) time to ROSC > 10minutes; c) post ROSC Glasgow Coma Score < 9; and d) enrollment within 72 hours of cardiac arrest. Exclusion criteria were: a) concurrent coagulopathy (international normalized ratio > 1.5, prothrombin time > 40 seconds, platelets < 100 x 109 cells/ml; b) concurrent or anticipated anticoagulant or anti-platelet therapy; c) anticipated withdrawal of care within next 24 hours; and d) prior or concurrent history of TBI, intracranial hemorrhage or ischemic stroke. Subjects were managed in accordance with our neuromonitoring guideline291 which aims to achieve ICP < 20 â 25mmHg and PbtO2 > 20mmHg. Patients underwent targeted temperature management (35 to 36oC) for 24 to 48 hours using surface cooling devices. Propofol was the primary sedative and norepinephrine was the primary vasopressor. Midazolam was used a secondary intravenous sedative and intermittent dosing of intravenous rocuronium (1mg/kg) was administered to ameliorate shivering during targeted temperature management. Passive 128 rewarming was undertaken to a maximum 37.5oC at 0.5oC per hour. Normocapnic ventilation (arterial carbon dioxide tension [PaCO2] 35 to 45mmHg) and arterial normoxia (arterial oxygen tension [PaO2] 80 to 100mmHg) were strictly targeted. 7.1.2 DEFINITION OF BRAIN NORMOXIA VERSUS HYPOXIA Stratifying subjects by normoxia versus hypoxia Subjects were stratified into the normoxia (PbtO2 was > 20mmHg) or hypoxia groups (PbtO2 was < 20mmHg). The mean value of PbtO2 was obtained using data from the monitoring period from ICM+. This definition of brain hypoxia was extrapolated from TBI200. Univariable comparisons of physiologic and blood gas measurements comparing normoxia to hypoxia were performed using a linear mixed model (STATA command xtreg) specifying âpatientâ as a random-effect to account for the within-subject nature of the data. 7.1.3 NEUROMONITORING Neuromonitoring was undertaken with PbtO2 (Licox®, Integra Lifesciences, Plainsboro, NJ, USA) and ICP (Camino®, Integra Lifesciences, Plainsboro, NJ, USA) monitoring. The catheters were placed via a dual lumen bolt situated in the right frontal lobe. A JVB oximetric catheter (Pediasat®, Edwards Lifesciences, USA) was inserted into the dominant jugular vein identified by bedside ultrasonography. Catheter position was confirmed with skull base x-ray. MAP, CPP, end tidal carbon dioxide tension (ETCO2), core body temperature (esophageal temperature probe) and pressure reactivity index (PRx), were recorded in real time and incorporated into ICM+® monitoring software (Cambridge University Enterprises, Cambridge, United Kingdom) from our bedside monitors (Carescape®, General Electric, USA) at 300Hz. 129 Data for PbtO2, CPP, MAP, ICP, PRx, temperature and ETCO2 were averaged over a 10-minute period (5 minutes before and 5 minutes after the precise time of the arterial and JVB samples). 7.1.4 BLOOD GAS DATA COLLECTION Spatial pathophysiological heterogeneity in TBI meant that measurement of PvO2 â PbtO2 gradients in our earlier TBI study necessitated measurement of local PvO2 in the vicinity of the PbtO2 probe with oxygen positron emission tomography (15O-PET), but the relatively global insult of HIBI allowed jugular venous bulb (JVB) sampling to measure PvO2. Simultaneous JVB and arterial blood gas samples were drawn approximately every 4 hours. From the JVB sample, we obtained pH, PvO2, jugular venous bulb carbon dioxide tension (PvCO2), jugular venous bulb hemoglobin saturation (SjvO2) and lactate. From the arterial sample, we obtained pH, arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), hemoglobin concentration (Hb), arterial hemoglobin saturation (SaO2) and lactate. The date and time for samples were recorded. 130 Figure 7.1. This figure depicts the study design. We used simultaneous arterial, jugular venous bulb gas measurements and parenchymal brain oxygenation recordings to estimate the barrier to microvascular oxygen delivery. The PaO2 was kept stable at 80 to 100mmHg and PaCO2 35 to 45mmHg in the study. This figure is original for this manuscript. 7.1.5 SECONDARY MEASURES AND CALCULATIONS We calculated the gradient between venous and parenchymal brain oxygen tension (PvO2 â PbtO2) to estimate the diffusion gradient of oxygen delivery. The cerebral oxygen extraction fraction (O2EF), arterial to JVB difference in oxygen content (AJDO2), difference in JVB to arterial carbon dioxide tension (ÎPCO2), difference of JVB to arterial lactate (VADL) and the lactate oxygen index (LOI) were calculated. The full equations used are displayed in the list of equations (page 22-23). 7.1.6 COMPUTED TOMOGRAPHY Head CT (Somatom® Sensation 32 scanner, Siemens, Germany) was undertaken within 24 hours of monitoring insertion to confirm placement and assess for complications. Grey-white 131 matter differentiation and cerebral edema assessment was ascertained from neuroradiology attending reports and a study investigator (MS). 7.1.7 STATISTICAL ANALYSES Determine the presence of diffusion limitation of oxygen delivery We visually assessed the relationship of PvO2 â PbtO2 and CPP by scatterplot and overlaid the scatterplot with locally weighted scatterplot smooths for each individual. We fitted a linear mixed model between PvO2 â PbtO2 and CPP with âpatientâ as a random effect (STATA command xtreg). To assess for effect modification of the relationship between PvO2 â PbtO2 and CPP by hypoxia (vs. normoxia), we included an interaction term between CPP and the dichotomous variable hypoxia. We calculated the marginal and conditional R2 as a measure of the variance explained. 7.2 STUDY 4 â RESULTS 7.2.1 SUMMARY RESULTS Twenty-six consecutive patients were screened, with fourteen included. Seven (50%) subjects exhibited a mean PbtO2 â¤ 20mmHg (hypoxia group) and seven (50%) had a mean PbtO2 > 20mmHg (normoxia group). The median percentage of time with PbtO2 < 20mmHg was 72% (31 â 100) and 12% (1 â 48) in the hypoxia and normoxia groups, respectively. Clinical demographics are shown in table 7.1. There were 37 data points in the hypoxia group with a median of 5 (4 â 7) data points per patient and 38 data points with a median of 4 (4 â 9) data 132 points per patient in the normoxia group. The PbtO2 catheter position was confirmed in the sub-cortical white matter of the right frontal lobe in all subjects. No adverse events were noted. Table 7.1 Patient demographics in study subjects with brain normoxia versus hypoxia. Variable Normoxia (n = 7) Hypoxia (n = 7) Age (median, years, range) 31 (20 â 71) 48 (47 â 65) Gender (male, %) 4 (57%) 5 (71%) Time to ROSC (median, mins, range) 14 (10 â 25) 17 (12 â 36) Time of ROSC to study monitoring (median, h, range) 17 (8 â 68) 13 (10 â 34) Witnessed (yes / no) 3 (43%) 4 (57%) Rhythm VT / VF (n) Pulseless electrical activity (n) Asystole 1 3 3 1 4 2 Epinephrine doses (median, n, range) 1 (0 â 25) 2 (1 â 4) PCAC 2 (2 â 4) 2 (2 â 4) Post ROSC GCS 4 (3 â 6) 3 (3 â 6) 6-month GOS 5 â full recovery 4 â moderate disability 3 â severe disability 2 â Vegetative state 1 â Death 4 1 0 0 2 2 0 0 0 5 APACHE 25 (16 â 38) 25 (19 â 32) Lactate 7.7 (1.2 â 19.3) 9.2 (5.3 â 13.4) Creatinine 106 (71 â 185) 132 (101 â 202) Bystander CPR 4 (57%) 5 (71%) OHCA 5 (71%) 7 (100%) Abbreviations: PEA â Pulseless electrical activity; VF â Ventricular fibrillation; VT â Ventricular tachycardia; ROSC â Return of spontaneous circulation; GCS â Glasgow coma scale; GOS â Glasgow outcome score; CPR â Cardiopulmonary resuscitation; OHCA â Out of hospital cardiac arrest; APACHE â Acute physiology and chronic healthy enquiry; PCAC â Pittsburgh cardiac arrest category 7.2.2 DESCRIPTION OF DIFFUSION LIMITATION Table 2 demonstrates the differences in both groups with respect to cerebral oxygenation. The PvO2 â PbtO2 gradient was significantly lower in the normoxia group (16mmHg [SD 6] vs. 39mmHg [SD 11], p < 0.001). This difference was primarily attributable to lower PbtO2 in the 133 hypoxia group (14mmHg [SD 4] vs. 29mmHg [SD 9], p< 0.001). Figure 7.2 is a dot plot and illustrates the differences in the PvO2 â PbtO2 for each subject in both groups. Figure 7.2. This is a dot plot of the PvO2 â PbtO2 gradient (x axis, mmHg) for individual patients in the cohort (y axis) stratified by the hypoxia versus normoxia groups. The numbers on the y axis refer to each patientâs study number. Each individual dot represents a single data point for each patient. Reproduced with permission from Sekhon MS et al. Brain hypoxia secondary diffusion limitation of oxygen delivery in hypoxic ischemic brain injury after cardiac arrest. Critical Care Medicine 2019. 7.2.3 DETERMINANTS OF CEREBRAL OXYGEN DELIVERY The physiologic differences between the groups are shown in table 7.2. The CPP was higher in the normoxia group (80mmHg [SD 7] vs. 72mmHg [SD 6], p = 0.01). The ICP was lower in the normoxia group (7mmHg [SD 4] vs. 17 [SD 8], p = 0.02) and there was no difference in the MAP (table 7.2). The arterial pH (7.41 [SD 0.04] vs. 7.33 [SD 0.06], p =0.002) 134 was higher in the normoxia group as was the jugular venous bulb pH (7.37 [SD 0.04] vs. 7.31 [SD 0.06], p = 0.01). The PaCO2 group (35mmHg [SD 3] vs. 43 [SD 7], p = 0.007) and PvCO2 (41mmHg [SD 3] vs. 47 [SD 8], p = 0.04) were lower in the normoxia group. There was no difference in the arterial (23mmol/L [SD 3] vs. 22mmol/L [SD 3], p = 0.46) or venous (23mmol/L [SD 2] vs. 23mmol/L [SD 3], p = 0.30) bicarbonate. The was no difference in the mean propofol dose administered in both groups (66mcg/kg/min [SD 18] vs. 80mcg/kg/min [SD 17], p = 0.47). Table 7.2. Physiology of study subjects with brain normoxia versus hypoxia. Variable Normoxia (n = 7) Hypoxia (n = 7) P - value Neurophysiology (mean, SD) CPP (mmHg) MAP (mmHg) ICP (mmHg) PRx ETCO2 (mmHg) Temp (oC) Hb (g/L) 80 (7) 87 (7) 7 (4) 0.05 (0.27) 32 (5) 35.7 (0.4) 112 (19) 72 (6) 89 (12) 17 (8) 0.24 (0.3) 32 (3) 35.5 (0.5) 127 (12) 0.01 0.76 0.02 0.09 0.71 0.42 0.32 Abbreviations: CPP â Cerebral perfusion pressure; MAP â Mean arterial pressure; ICP â Intracranial pressure; PRx â pressure reactivity index; ETCO2 â End tidal carbon dioxide; Temp â Core body temperature; Hb â Hemoglobin; 7.2.4 DIFFUSION LIMITATION OF OXYGEN DELIVERY The relationship between PvO2 â PbtO2 and CPP is presented in figure 7.3. There was a significant difference in the relationship between PvO2 â PbtO2 and CPP when comparing hypoxia and normoxia (p=0.004). In the normoxia group, PvO2 â PbtO2 decreased by 0.36 mmHg (95%CI: -0.54 to 0.18, p<0.001) for each 1 mmHg increased in CPP versus no relationship in the hypoxia group (coefficient -0.029, 95:CI: -0.17 to 0.11, p=0.73). The 135 difference between the marginal and conditional R2 values observed indicates marked between-patient variability in the effects of PvO2 â PbtO2 and CPP. Figure 7.3. The PvO2 â PbtO2 gradient (y axis, mmHg) is plotted against CPP (x axis, mmHg) in the normoxia group (left graph) and the hypoxia group (right graph). The dots are the scatterplot between the two variables. Light grey lines are locally weighted scatterplot smoothing function for each patient. The black line is the overall regression line between PvO2 â PbtO2 and CPP. R2m is the marginal R2. R2c is the conditional R2. Reproduced with permission from Sekhon MS et al. Brain hypoxia secondary diffusion limitation of oxygen delivery in hypoxic ischemic brain injury after cardiac arrest. Critical Care Medicine 2019. 7.2.5 SECONDARY DERIVATIVES OF METABOLISM The normoxia group demonstrated a significantly higher AJDO2 (3.6 [2.4] vs. 0.6 [0.3], p<0.001) and lower LOI (0.1 [0.1] vs. 1.1 [1.1], p<0.001). There was no difference in ÎPCO2 (5mmHg [3] vs. 4mmHg [2], p=0.19) between both groups but the hypoxia group had a significantly higher ÎPCO2 / AJDO2 ratio (1.6 [0.9] vs. 7.4 [4.7], p<0.001). 136 Table 7.3. Cerebral oxygenation and metabolism data in patients with brain normoxia versus hypoxia. Physiologic variable Normoxia (n = 7) Hypoxia (n = 7) P - value Oxygen, mean (SD) PbtO2 (mmHg) PvO2 (mmHg) PvO2 â PbtO2 (mmHg) O2EF (%) PaO2 (mmHg) SaO2 (%) SjvO2 (%) AJDO2 (vol%) Carbon dioxide, mean (SD) PaCO2 (mmHg) PvCO2 (mmHg) ÎPCO2 (mmHg) Metabolism, mean (SD) Ratio (ÎPCO2/ AJDO2) JB Lactate (mmol/L) Arterial lactate (mmol/L) VADL (mmol/L) LOI ([mmol/L]/vol%) 29 (9) 45 (9) 16 (6) 24 (13) 98 (9) 96 (1) 74 (12) 3.6 (2.4) 36 (4) 41 (4) 5 (3) 1.6 (0.9) 2.6 (0.9) 2.3 (0.9) 0.3 (0.1) 0.1 (0.1) 14 (4) 53 (8) 39 (11) 13 (6) 103 (7) 96 (1) 84 (5) 0.6 (0.3) 43 (9) 47 (9) 4 (2) 7.4 (4.7) 3.5 (2.9) 2.9 (2.3) 0.6 (0.6) 1.1 (1.1) <0.001 0.03 <0.001 0.04 0.34 0.61 0.04 <0.001 <0.001 <0.001 0.19 <0.001 0.22 0.29 0.08 0.03 Abbreviations: PbtO2 â Brain tissue oxygenation; PvO2 â Jugular venous bulb oxygen tension; O2EF â Oxygen extraction fraction; PaO2 â Arterial oxygen tension; SaO2 â Arterial hemoglobin oxygen saturation; PvCO2 â Jugular venous bulb carbon dioxide tension; SjvO2 â Jugular venous bulb oxygen saturation; AJDO2 â Arteriojugular oxygen difference; PaCO2 Arterial carbon dioxide tension; PvCO2 â Jugular venous bulb carbon dioxide tension; ÎPCO2 â Veno-arterial delta of carbon dioxide tension; JB â Jugular bulb; VADL â Veno-arterial lactate difference; LOI â Lactate oxygen index 7.2.6 COMPUTED TOMOGRAPHY In the hypoxia group, two patients demonstrated grey to white difference loss on the computed tomography scan, with diffuse cerebral edema. In the normoxia group, grey to white matter differentiation was preserved in all patients but one patient had cerebral edema. 7.3 STUDY 4 â DISCUSSION In HIBI patients with brain hypoxia, in contrast to normoxia, there is an increased PvO2 - PbtO2gradient that is unrelated to varying CPP. These data suggest diffusion limitation of oxygen delivery as a mechanism of brain hypoxia in HIBI. Conversely, increased CPP is associated with 137 a decreased PvO2 â PbtO2 gradient in normoxic patients, suggesting that this HIBI phenotype demonstrates a perfusion dependent state of cellular oxygen delivery. 7.3.1 THE SIGNIFICANCE OF DIFFUSION LIMITATION OF OXYGEN DELIVERY HIBI pathophysiology is characterized by dysfunction and tissue damage in numerous components of the neurovascular units1,6. Specifically, BBB breakdown is an established pathologic injury pattern that can occur with resultant extravasation of intravascular fluid shifts culminating in vasogenic edema288â290,292 which can increase the diffusion barrier distance from the capillary bed to neurons. Authors have demonstrated biomarkers of cerebrovascular endothelial injury and BBB breakdown are associated with adverse neurological outcome in HIBI 143; however, the precise mechanism of how this injury pattern contributes to secondary injury is not well elucidated. Our results suggest an increased diffusion gradient and diffusion limitation is a novel mechanism of brain hypoxia in HIBI. Similar physiology has been shown in human TBI patients previously73,234. Menon et al. demonstrated diffusion limitation physiology234 in peri-contusion brain tissue following TBI, and found pathologic correlates of BBB breakdown with resultant peri-vascular edema and microvascular collapse. This study used 15Oxygen positron emission tomography to calculate local PvO2 in order to account for regional differences in pathophysiology in TBI. Given the more global insult produced by HIBI, we used JVB sampling to estimate PvO2. Our results are in keeping with TBI, in that the increased PvO2 â PbtO2 gradient was predominantly driven by the reduced PbtO2 as opposed to an increased PvO2234. Furthermore, Menon et al. showed that in the setting of hypocapnia-induced decreased CBF, patients with brain hypoxia were unable to increase offloading of oxygen from hemoglobin 138 in the microvasculature, thereby confirming diffusion limitation234. Rather than use the challenge of hypocapnic CBF reductions to alter cerebrovascular physiology, we explored whether we could modulate oxygen delivery (and hence PbtO2) by analyzing the impact of varying CPP. In the normoxia group, there was an inverse relationship with a decreasing PvO2 â PbtO2 gradient as CPP increased. However, we did not observe any relationship between CPP and the PvO2 â PbtO2 gradient in the hypoxia group. The hypoxia group also demonstrated a significantly increased SjvO2 (table 7.3) and decreased OEF (table 7.3) compared to the normoxia group, which provide corroborative evidence of impaired oxygen unloading in the cerebrovascular bed of the hypoxic patients. Interestingly, these findings were present despite lower pH and decreased CPP in the hypoxia group; conditions that would favor CDO2 and oxygen offloading in the microvasculature293,294. Although we found an increased PvO2 â PbtO2 gradient and diffusion limitation in the hypoxic group, we are unable to determine the precise microvascular mechanisms responsible for this physiology as we did not have pathologic tissue correlates or gold standard measures of cerebral metabolism. As such, an alternative explanation for our results could be accounted for mitochondrial dysfunction or irreversible neuron death295. We attempted to address this by analyzing the differences in VADL and LOI between both groups. Increased VADL and LOI in the hypoxia group suggest an anaerobic metabolic state296â298 compared to the normoxia group. It is unclear whether these findings are the result of post-ROSC brain hypoxia from diffusion limitation, or represent evidence of ischemia stemming from the initial circulatory arrest with resultant mitochondrial failure. We also observed differences in the ÎPCO2 / AJDO2 ratio between the two groups. Past studies have suggested that the ÎPCO2 / AJDO2 ratio may represent differences in tissue oxygen unloading and CO2 uptake, which reflect differences in 139 tissue perfusion296,298 and possibly diffusion limitation. We did not demonstrate a significant difference between ÎPCO2 between both groups thereby suggesting that irreversible neuron death was not the sole explanation of our results. This inference is supported by our imaging findings - while CT is known to be insensitive in detecting ischemic injury, only two patients in the hypoxia group had evidence of loss of grey to white matter differentiation. Furthermore, two patients in the hypoxia group experienced full neurological recovery and five died. It is possible that diffusion limitation physiology may be a sign of the underlying severity of HIBI but we lack the appropriate number of patients to make definitive associations to clinical outcome. Future studies must include simultaneous measures of metabolism with cerebral microdialysis or positron emission tomography to delineate the underlying mechanisms of increased PvO2 â PbtO2 gradient in HIBI patients and provide pathologic correlates of the neurovascular unit. 7.3.2 CLINICAL IMPLICATIONS OF DIFFERENTIAL PATHOPHYSIOLOGY The demonstration of differential pathophysiologic phenotypes in HIBI patients of diffusion limitation (hypoxia group) versus perfusion dependence (normoxia group) may have important clinical implications. Recently, there has been increasing attention directed towards identifying optimal post resuscitation care strategies, specifically aimed at interventions to optimize CDO215,243,299. Strategies aimed at increasing CDO2 including increased MAP targets, permissive hypercapnia and red blood cell transfusion thresholds may not offer a clinical or physiologic benefit to patients with diffusion limitation to cellular oxygen delivery and expose them to the adverse effects of exogenous vasopressors, increased ICP or transfusion reactions, respectively. Consequently, increased attention should be directed towards delineating correlates 140 of neuroimaging or biomarkers to identify patient specific physiologic HIBI phenotypes and then to aid in individualized resuscitation depending on the underlying pathophysiology. 7.3.3 LIMITATIONS AND FUTURE STEPS Our study has important strengths that further the understanding of brain hypoxia mechanisms in HIBI. We present a novel description of a pathophysiologic mechanism to account for brain hypoxia after ROSC. Previous studies of JVB oximetry after cardiac arrest have attempted to correlate elevated SjvO2 or decreased O2EF to adverse neurological outcome79,81,300 but their physiologic significance had not been well elucidated. We used invasive multimodal neuromonitoring in conjunction with JVB oximetry to characterize the differential physiologic phenotypes and provide a novel explanation of brain hypoxia in HIBI. We also collected highly granular data (300Hz) of neurophysiologic variables and repeated measures of arterial and jugular venous bulb blood gases over time for each patient. There are several limitations of our study that must be considered. First, we used a focal measure of PbtO2 but a global monitor for PvO2 sampling. As such, we extrapolated the PvO2 measured at the jugular bulb to be representative of the PvO2 within proximity to the PbtO2 catheter. Importantly, though resulting from a global insult, HIBI pathophysiology can be heterogenous and preferentially affect structures such as the thalami, basal ganglia, cortex, hippocampi and cerebellar vermi1,5,301. Therefore, the PvO2 at the jugular bulb is representative of the relative contribution of venous return from all these critical care structures and may over or underestimate the PvO2 â PbtO2 gradient in the regions that are preferentially affected in HIBI. Second, there is marked between-subject heterogeneity as evident by the differences between the conditional and marginal R2. Third, we sought to determine the presence of 141 diffusion limitation by plotting CPP against PvO2 â PbtO2 in the hypoxia versus normoxia groups as a post-hoc analysis. Unfortunately, we did not have an absolute measure of CBF to definitively make this assertion and instead extrapolated that CPP is directly proportional to CBF. Future studies must aim to investigate the presence of diffusion limitation in HIBI by using a measure of CBF prospectively and incorporate an intervention to modulate it. Finally, HIBI pathophysiology is characterized by a no reflow phenomenon early after ROSC and then hyperemia can ensue. As such, the cerebral hemodynamics are dynamic and can change longitudinally. The median duration from ROSC to commencement of JVB / arterial blood gas sampling and neurophysiologic monitoring was 17 and 13 hours (table 7.1) in the normoxia and hypoxia groups, respectively. Therefore, we are unable to assess the potential differences in the microvascular physiology of HIBI early after no reflow versus the timeframe captured in our study. Future studies should aim at delineating the changes in the HIBI pathophysiology immediately after ROSC and over time. 7.4 STUDY 4 â SUMMARY An increased PvO2 â PbtO2 gradient is present in HIBI patients with brain hypoxia when compared to those without. Diffusion limitation of cellular oxygen delivery may be a mechanism of brain hypoxia in HIBI patients after ROSC. 142 8 RED BLOOD CELL TRANSFUSION IN HYPOXIC ISCHEMIC BRAIN INJURY AFTER CARDIAC ARREST Preventing secondary ischemic injury after hypoxic ischemic brain injury (HIBI) is a cornerstone of post resuscitation management of HIBIpatients1. This is achieved by optimizing cerebral oxygen delivery (CDO2), which in turn is dependent upon cerebral blood flow and arterial oxygen content (CaO2)14,55. The principal component of CaO2, hemoglobin concentration (Hb), has recently become a target of post resuscitation research. In general, restrictive transfusion strategies (hemoglobin < 70g/L) have demonstrated equivalence or superior outcomes in non-bleeding critically ill populations62, however, optimal transfusion practices in neurocritically ill sub-populations remain controversial60. Animal models of brain injury suggest that superimposed anemia is associated with additive secondary ischemic injury19 and observational studies corroborate this pathophysiology63,64. Specifically in HIBI, recent observational reports suggest that anemia at admission302 and during the first week of hospitalization65 after return of spontaneous circulation (ROSC) are associated with adverse neurological outcome. Furthermore, authors have demonstrated an association between reduced regional oxygen saturation (rSO2) on near infrared spectroscopy (NIRS) and anemia post-cardiac arrest159. Although the association of anemia with adverse clinical outcome and decreased rSO2 is important, there is a paucity of physiological data to suggest that augmenting CaO2 with red blood cell (RBC) transfusion can improve CDO2 in HIBI. In traumatic brain injury, RBC transfusion has been shown to increase brain tissue oxygenation67,68 but these observations are not elucidated in HIBI. Therefore, we conducted a prospective interventional study investigating the effect of RBC transfusion on CDO2 using jugular venous bulb oximetry and 143 rSO2 in HIBI patients after cardiac arrest. The aim of the study was to investigate the effect of red blood cell transfusion on the SjvO2 in HIBI patients. 8.1 STUDY 5 â METHODS We performed a prospective observational study in 12 HIBI patients who received TBC transfusion as part of clinical care. The study was approved by the University of British Columbia Clinical Research Ethics Board (H16-03114) and informed consent was obtained. The study was conducted in accordance with the Helsinki declaration. 8.1.1 STUDY SUBJECTS AND STUDY SITE The study was conducted in the Vancouver General Hospital intensive care unit, which is a closed 34-bed mixed medical and surgical unit. It is staffed by sub-specialty trained intensivists with a 1:1 nursing ratio. Approximately 60 post cardiac arrest patients are admitted to our ICU annually. We included patients who met the following inclusion criteria: a) age > 18, b) time to return of spontaneous circulation > 10 minutes, c) post resuscitation un-confounded Glasgow coma score < 9 and d) hemoglobin concentration < 90g/L. Subjects were excluded if they met any one of the following exclusion criteria: a) anticipated withdrawal of life-sustaining therapies with the next 72 hours, b) pregnancy, c) previous history of transfusion related adverse event or d) religious beliefs precluding blood product transfusion. 144 8.1.2 PATIENT MANAGEMENT Our unit utilizes a post cardiac arrest management protocol which targets normothermia (core body temperature at 35-36oC) for 24 to 48 hours using surface cooling methods. Intravenous propofol and fentanyl are used as the first line sedatives and mean arterial pressure (MAP) targets are set in accordance with guidelines. Shivering is managed using intermittent doses of rocuronium. We maintain struct normocapnia (PaCO2 35 â 45mmHg) and normoxemia (PaO2 > 80mmHg). RBC transfusion to maintain hemoglobin concentration > 90g/L is standard of care in our ICU for neurologically injured patients. RBC transfusion is administered over 30 minutes in the non-bleeding critically ill patient. 8.1.3 NEUROMONITORING NIRS monitoring (INVOS®, Medtronic, Minneapolis MN, USA) was applied to the study subjectâs forehead bilaterally after being cleansed with sterile alcohol swabs. A single lumen jugular venous bulb catheter (Arrow®, USA) was inserted retrograde into the dominant jugular vein identified by bedside ultrasonography. Optimal positioning (tip at or above the ipsilateral mastoid process) was confirmed with anterior-posterior and lateral skull base x-ray. Core body temperature was monitored centrally using an esophageal temperature probe and end tidal carbon dioxide tension (ETCO2) was recorded. A radial arterial catheter was used to monitor MAP. All physiologic data was displayed on our bedside (Carescape®, General Electric, USA) monitors and recorded in real time into ICM+ monitoring software (Cambridge University Enterprises®, United Kingdom) at 300Hz. 145 8.1.4 BLOOD GAS DATA COLLECTION Patient demographic characteristics were collected pertaining to: a) age, b) gender, c) duration until return of spontaneous circulation (ROSC), d) etiology of cardiac arrest, e) bystander cardiopulmonary resuscitation, f) witnessed versus unwitnessed arrest, g) co-morbidities, h) duration from arrest to RBC transfusion, i) defibrillation attempts and j) epinephrine doses. Arterial blood gases were collected at these timepoints for pH, arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), arterial hemoglobin saturation (SaO2), bicarbonate, Hb and serum sodium. Jugular venous bulb samples were collected for pH, venous oxygen tension (PvO2), venous carbon dioxide tension (PvCO2), bicarbonate and jugular venous bulb hemoglobin saturation (SjvO2). The following data was collected: hemoglobin concentration, SjvO2, SaO2, arterial pH, PaO2, arterial bicarbonate ion centration, PaCO2, jugular venous bulb pH, PvO2, PvCO2, jugular venous bulb bicarbonate ion centration, MAP, ETCO2, temperature, rSO2, minute ventilation, tidal volume, positive end expiratory pressure, fraction of inspired oxygen, propofol and norepinephrine doses. All data elements were collapsed into mean values for the following six timepoints: 1) before RBC transfusion (-2 hours to hour 0), b) after RBC transfusion completion (0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 12 hours and 12 to 24 hours). 8.1.5 SECONDARY MEASURES AND CALCULATIONS Both CaO2 and the jugular venous bulb venous oxygen content (CvO2) were calculated from the sum of the hemoglobin bound O2 and dissolved portion arterial and venous system, respectively. The oxygen extraction fraction (O2EF) was calculated by the difference between 146 the CaO2 and CvO2, which was then divided by the CaO2 and multiplied by 100. The cerebral metabolism was estimated by analyzing the delta difference between the PvCO2 and the PaCO2 (ÎPCO2). The arterial-jugular difference in oxygen content (AJDO2) was calculated by subtracting the CaO2 subtracted by the CvO2. The ratio of ÎPCO2 / AJDO2 was calculated to estimate the balance of oxygen offloading and carbon dioxide uptake as a measure of tissue perfusion. 8.1.6 RED CELL TRANSFUSION Red blood cell transfusion in each study participant was undertaken over 30 minutes to 60 minutes, as per our institutional protocol, via an in situ intravenous line. Monitoring for transfusion related complications was undertaken by the bedside nursing staff. Patients cross-matching was undertaken in the laboratory prior to the red cell unit being released. Each red blood cell unit (~350ml of intravascular volume) is kept in the Vancouver General Hospital hematopathology lab refrigerated and was released without warming. As per provincial guidelines of blood product distribution, Vancouver General Hospital receives aged blood products; however, the precise date and age of the blood products administered was not available. 8.1.7 STATISTICAL ANALYSES Sample Size. As a sample size of convenience, twelve patients represented the number of HIBI patients that could be included within the studyâs time frame. Analysis Plan. We used R Studio to analyze our data. We described categorical data, normally distributed data, and non-normally distributed data using proportions (percent; 95% 147 confidence intervals [CI]), mean (standard deviation [SD]) and median (interquartile range [IQR]) respectively. We used Chi-squared and independent t tests for categorical and normally distributed bivariate analysis respectively. Non-normally distributed continuous data was analyzed using the Wilcoxon rank sum test. All tests were 2-sided and we considered a P-value <0.05 to be statistically significant. A repeated measure ANOVA analysis was used to compare the statistical significance between timepoint 1 (before transfusion) versus the remaining study timepoints. In a pre-specified sub-analysis, patients with a pre-transfusion SjvO2 < 70% were analyzed separately to determine the differences in the primary outcome (SjvO2) and associated variables before after RBC transfusion in an attempt to account for diffusion limitation physiology. 8.2 STUDY 5 â RESULTS 8.2.1 SUMMARY RESULTS A total of 20 patients were screened and twelve patients included in the study from April 2017 to September 2018. Screened patients were excluded for the following reasons: 7 â anticipated withdrawal of life sustaining therapies within the next 72 hours; 1 â patient religious beliefs not in keeping with transfusion of blood products. The median age of the cohort was 47 years (range 20 â 71) and 7 of 12 were male. The median time to ROSC was 22 minutes (range 12 â 36) and time from ROSC to neuromonitoring was 15 hours (range 6 â 44). The remaining patient demographic data are presented in Table 8.1. No adverse events were noted. Pre and Post RBC Transfusion physiologic data 148 We did not find significant changes in the SjvO2 across all timepoints after RBC transfusion when compared to the baseline data. The mean SjvO2 before RBC transfusion was 67.92% (SD 10.45) and for the following timepoints: timepoint 2 - 69.25% (SD 8.61); timepoint 3 - 71.83% (SD 9.11); timepoint 4 - 71.33% (SD 10.25); timepoint 5 - 70.33% (SD 8.06); timepoint 6 - 69.33% (SD 9.78). We did demonstrate significant increases in the mean hemoglobin concentration at timepoints 2 (9.98g/dL SD [1.06]), 3 (10.02g/dL SD [1.08]), 4 (10.05g/dL SD [1.01]), and 5 (9.82g/dL SD [1.00]) compared to baseline (8.87g/dL SD [1.06]) (table 8.2). Similarly, we also demonstrated significant increases in CaO2 and CvO2 at timepoints 2, 3, 4, and 5 compared to baseline (table 8.2). Figure 8.1 demonstrates the significant increases in Hb, CaO2 and CvO2 post RBC transfusion on timepoints 2 â 5, compared to baseline. We did not observe significant differences in the remaining physiologic variables pertaining to: MAP, ETCO2 and temperature (table 8.2). We also did not observe significant differences in the remaining physiologic variables that were collected from both the arterial and jugular venous bulb gases at all timepoints following RBC transfusion compared to baseline. 149 Table 8.1. Patient demographics in study subjects. Variable Cohort (n = 12) Age (median, years, range) 64 (29-82) Sex (male, %) 10 (83) Time to ROSC (median, mins, range) 15 (5-40) Witnessed 7 (58) Rhythm VT / VF (n) Pulseless electrical activity (n) 1 11 Epinephrine doses (median, n, range) 3 (2-4) Post ROSC GCS 4 (3-5) Etiology of cardiac arrest Acute coronary syndrome Hypoxia Hemorrhage Hyperkalemia 3 6 2 1 Bystander CPR (%) 10 (83) OHCA (%) 10 (83) Abbreviations: PEA â Pulseless electrical activity; VF â Ventricular fibrillation; VT â Ventricular tachycardia; ROSC â Return of spontaneous circulation; GCS â Glasgow coma scale; GOS â Glasgow outcome score; CPR â Cardiopulmonary resuscitation; OHCA â Out of hospital cardiac arrest 150 8.2.2 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFUSION RESULTS â OVERALL COHORT Table 8.2 Pre and Post red blood transfusion data in the cohort Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 MAP (mmHg) median (IQR) 77.00 (74.85, 80.88) 77.15 (75.52, 79.73) 80.40 (73.05, 83.10) 77.10 (74.02, 84.45) 79.90 (75.27, 86.42) 80.15 (77.38, 83.77) mean (sd) 79.42 ± 7.20 79.91 ± 9.16 80.02 ± 10.68 81.70 ± 11.42 82.20 ± 10.51 82.55 ± 8.55 ETCO2 (mmHg) median (IQR) 4.15 (3.63, 4.53) 4.05 (3.40, 4.73) 4.10 (3.45, 4.73) 4.15 (3.70, 4.75) 3.85 (3.48, 4.73) 3.90 (3.68, 4.55) mean (sd) 4.01 ± 0.90 4.16 ± 0.89 4.19 ± 0.94 4.28 ± 0.90 4.06 ± 0.89 4.09 ± 0.68 Temperature (oC) median (IQR) 36.15 (35.90, 36.80) 36.15 (36.03, 36.70) 36.35 (35.95, 36.80) 36.20 (35.95, 36.58) 36.30 (36.12, 36.65) 36.40 (36.10, 36.70) mean (sd) 36.27 ± 0.55 36.27 ± 0.44 36.34 ± 0.50 36.29 ± 0.56 36.33 ± 0.72 36.38 ± 0.70 Propofol (mcg/kg/min) median (IQR) 60.00 (50.00, 72.50) 60.00 (50.00, 72.50) 60.00 (50.00, 72.50) 60.00 (50.00, 72.50) 60.00 (50.00, 72.50) 60.00 (50.00, 72.50) mean (sd) 56.67 ± 23.87 56.67 ± 23.87 56.67 ± 23.87 56.67 ± 23.87 56.67 ± 23.87 56.67 ± 23.87 pH_JB median (IQR) 7.34 (7.30, 7.38) 7.34 (7.32, 7.35) 7.33 (7.31, 7.37) 7.34 (7.33, 7.36) 7.35 (7.33, 7.37) 7.36 (7.33, 7.38) mean (sd) 7.34 ± 0.04 7.34 ± 0.03 7.34 ± 0.04 7.34 ± 0.03 7.35 ± 0.02 7.35 ± 0.04 PvO2_JB (mmHg) median (IQR) 43.50 (33.50, 48.00) 40.50 (36.75, 44.25) 40.00 (39.00, 46.50) 43.50 (38.00, 47.00) 43.50 (36.75, 45.00) 43.50 (36.50, 48.75) mean (sd) 41.42 ± 8.61 41.17 ± 7.25 44.17 ± 9.05 44.42 ± 9.43 42.17 ± 6.64 42.50 ± 8.38 151 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 PvCO2_JB (mmHg) median (IQR) 49.00 (46.50, 53.50) 50.00 (44.50, 53.50) 49.00 (45.50, 50.50) 48.50 (46.50, 52.25) 47.00 (45.75, 49.50) 47.50 (45.25, 49.50) mean (sd) 49.33 ± 8.79 49.67 ± 8.71 49.75 ± 9.67 49.83 ± 9.00 48.33 ± 6.81 48.25 ± 6.96 HCO3_JB (mEq/L) median (IQR) 25.00 (21.75, 27.50) 24.50 (21.00, 27.75) 23.50 (21.75, 26.25) 25.00 (22.00, 27.25) 24.00 (23.00, 25.50) 24.50 (23.75, 27.00) mean (sd) 24.50 ± 7.27 24.50 ± 6.04 24.17 ± 6.52 25.00 ± 5.58 25.00 ± 4.84 25.67 ± 4.62 SjvO2 (%) median (IQR) 70.50 (58.75, 75.75) 69.50 (64.75, 72.75) 71.50 (64.75, 76.00) 68.50 (64.50, 78.50) 71.50 (66.00, 75.00) 69.50 (64.25, 76.00) mean (sd) 67.92 ± 10.45 69.25 ± 8.61 71.83 ± 9.11 71.33 ± 10.25 70.33 ± 8.06 69.33 ± 9.78 pH_ABG median (IQR) 7.38 (7.36, 7.41) 7.39 (7.35, 7.42) 7.39 (7.35, 7.41) 7.39 (7.37, 7.40) 7.39 (7.38, 7.41) 7.39 (7.37, 7.42) mean (sd) 7.38 ± 0.04 7.38 ± 0.04 7.38 ± 0.05 7.38 ± 0.04 7.39 ± 0.04 7.39 ± 0.04 PaO2_ABG (mmHg) median (IQR) 100.00 (82.00, 106.50) 97.00 (86.00, 113.75) 108.00 (97.25, 119.25) 99.00 (90.50, 113.75) 100.50 (95.00, 107.50) 98.50 (92.00, 109.00) mean (sd) 99.17 ± 23.40 105.42 ± 29.26 116.50 ± 37.73 107.25 ± 37.82 102.00 ± 15.61 103.92 ± 18.01 PaCO2_ABG (mmHg) median (IQR) 40.50 (37.00, 47.75) 39.00 (37.75, 44.75) 39.00 (37.00, 44.75) 41.00 (37.50, 44.25) 40.50 (36.75, 42.25) 39.50 (36.75, 43.25) mean (sd) 42.25 ± 9.47 41.92 ± 6.95 42.33 ± 9.21 43.25 ± 10.18 41.33 ± 7.22 41.17 ± 7.33 152 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 HCO3_ABG (mEq/L) median (IQR) 24.50 (20.00, 26.50) 23.50 (20.00, 26.50) 24.00 (20.75, 25.25) 24.00 (21.00, 26.00) 24.00 (22.00, 26.25) 24.50 (22.00, 26.00) mean (sd) 23.92 ± 6.82 24.08 ± 5.98 24.17 ± 5.34 24.50 ± 5.11 25.17 ± 4.91 25.33 ± 4.74 SaO2 (%) median (IQR) 96.00 (93.75, 96.25) 96.00 (94.00, 97.00) 96.00 (95.00, 96.00) 96.00 (94.00, 96.00) 96.00 (95.75, 96.00) 96.00 (96.00, 96.00) mean (sd) 95.17 ± 1.99 95.50 ± 1.68 95.67 ± 1.61 94.67 ± 2.10 95.33 ± 1.37 95.67 ± 1.15 FiO2 (%) median (IQR) 45.00 (33.75, 50.00) 45.00 (33.75, 50.00) 45.00 (33.75, 50.00) 45.00 (33.75, 50.00) 45.00 (33.75, 50.00) 45.00 (33.75, 50.00) mean (sd) 42.08 ± 12.15 42.08 ± 12.15 42.08 ± 12.15 42.08 ± 12.15 42.08 ± 12.15 42.08 ± 12.15 Hb (g/dL) median (IQR) 8.70 (8.45, 8.83) 9.90 (9.38, 10.12) 9.75 (9.40, 10.25) 9.75 (9.47, 10.15) 9.85 (9.20, 10.03) 9.60 (9.02, 10.20) mean (sd) 8.87 ± 1.06 9.98 ± 1.06 10.02 ± 1.08 10.05 ± 1.01 9.82 ± 1.00 9.62 ± 0.98 CaO2 median (IQR) 11.57 (11.18, 11.84) 13.23 (12.59, 13.79) 13.01 (12.56, 14.10) 12.78 (12.54, 13.52) 12.98 (12.31, 13.47) 12.84 (12.14, 13.56) mean (sd) 11.77 ± 1.41 13.28 ± 1.39 13.39 ± 1.51 13.26 ± 1.43 13.03 ± 1.30 12.83 ± 1.23 CvO2 median (IQR) 8.23 (6.83, 9.29) 9.18 (8.68, 9.79) 9.49 (9.17, 10.17) 9.36 (8.94, 10.43) 9.48 (8.71, 10.00) 9.27 (7.94, 10.19) mean (sd) 8.37 ± 2.05 9.56 ± 1.87 9.96 ± 2.05 9.93 ± 2.19 9.54 ± 1.68 9.24 ± 1.85 153 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 O2EF (%) median (IQR) 23.81 (22.68, 40.04) 28.51 (23.27, 32.40) 26.13 (21.67, 32.54) 26.55 (16.95, 33.07) 25.09 (22.73, 31.70) 26.76 (21.82, 33.86) mean (sd) 29.35 ± 10.94 28.28 ± 8.80 25.79 ± 10.11 25.40 ± 10.96 26.96 ± 8.48 28.30 ± 10.11 MAP = mean arterial pressure; ETCO2 = end tidal carbon dioxide tension; PvO2 = partial pressure of oxygen in jugular venous bulb, JB = jugular venous bulb; HCO3- = bicarbonate ion; PaO2 = partial pressure of arterial oxygen tension; SjvO2 = jugular venous bulb oxygen saturation; O2EF = oxygen extraction fraction; PaCO2 = arterial carbon dioxide tension; PvCO2 = jugular venous bulb carbon dioxide tension; CaO2 = arterial oxygen tension; CvO2 = jugular venous bulb oxygen content; SaO2 = arterial saturation of hemoglobin; Hb = hemoglobin concentration; FiO2 = fraction of inspired oxygen 154 Figure 8.1. The top left panel shows boxplot of the change in the arterial oxygen content at all study timepoints. The top right panel shows boxplot of the change in the venous oxygen content at all study timepoints. The bottom panel shows boxplot of the change in the hemoglobin concentration at all study timepoints. CaO2 = arterial oxygen content; CvO2 = jugular venous bulb oxygen content; Hb = hemoglobin concentration. This figure is original for this manuscript. Pre and Post RBC Transfusion physiologic data in patients with Pre-Transfusion SjvO2 < 75%. In total, 7 (58%) patients were transfused with a pre-transfusion SjvO2 < 65%. Figure 8.2 demonstrates the changes in hemoglobin concentration, CaO2, CvO2 and PaO2 at baseline (timepoint 1) and then at the following timepoints post RBC transfusion. We observed significant differences in the Hb and CaO2 at all timepoints following RBC transfusion compared 155 to baseline (table 8.3). We did observe a significant difference in the post RBC transfusion timepoint 3 (2 â 4h post transfusion) compared to baseline (61.00 SD [7.39] vs. 68.57 SD [8.28], p = 0.001). The remaining timepoints in this sub-cohort demonstrated a trend towards increased SjvO2 post RBC transfusion but did not reach statistical significance. We did not observe significant changes during the study in the remaining physiologic or blood gas data points after RBC transfusion compared with baseline (table 8.3). Figure 8.3 demonstrates the changes in SjvO2 after RBC transfusion compared with baseline in this sub-cohort. 156 8.2.3 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFUSION AND JUGULAR VENOUS BULB OXYGEN SATURATION IN PATIENTS WITH < 75% Table 8.3 Pre and Post red blood transfusion data in patients with jugular venous bulb oxygen saturation < 75% Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 MAP (mmHg) median (IQR) 75.80 (74.20, 77.00) 75.60 (73.90, 77.25) 73.90 (69.05, 80.40) 75.90 (74.45, 79.50) 75.30 (73.30, 79.90) 79.40 (75.65, 84.00) mean (sd) 78.03 ± 8.45 77.30 ± 7.48 76.66 ± 11.12 79.66 ± 11.07 79.41 ± 12.34 82.14 ± 9.82 ETCO2 (mmHg) median (IQR) 3.80 (3.55, 4.40) 3.80 (3.55, 4.60) 3.80 (3.55, 4.60) 3.90 (3.70, 4.55) 4.00 (3.60, 4.50) 3.90 (3.70, 4.35) mean (sd) 3.84 ± 1.06 4.07 ± 0.93 4.07 ± 0.94 4.13 ± 0.87 4.13 ± 0.94 4.07 ± 0.79 Temperature (oC) median (IQR) 36.50 (35.85, 36.80) 36.50 (36.00, 36.75) 36.60 (36.10, 36.85) 36.50 (36.05, 36.85) 36.50 (36.25, 36.80) 36.70 (36.40, 36.95) mean (sd) 36.31 ± 0.66 36.36 ± 0.51 36.47 ± 0.56 36.44 ± 0.67 36.41 ± 0.85 36.54 ± 0.83 Propofol (mcg/kg/min) median (IQR) 50.00 (50.00, 75.00) 50.00 (50.00, 75.00) 50.00 (50.00, 75.00) 50.00 (50.00, 75.00) 50.00 (50.00, 75.00) 50.00 (50.00, 75.00) mean (sd) 58.57 ± 18.64 58.57 ± 18.64 58.57 ± 18.64 58.57 ± 18.64 58.57 ± 18.64 58.57 ± 18.64 pH_JB median (IQR) 7.34 (7.31, 7.38) 7.35 (7.34, 7.36) 7.36 (7.32, 7.37) 7.34 (7.33, 7.37) 7.35 (7.32, 7.36) 7.38 (7.33, 7.38) mean (sd) 7.34 ± 0.05 7.35 ± 0.03 7.34 ± 0.04 7.34 ± 0.04 7.34 ± 0.03 7.36 ± 0.05 157 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 PvO2_JB (mmHg) median (IQR) 34.00 (32.00, 37.50) 37.00 (35.50, 38.50) 39.00 (38.00, 40.00) 39.00 (37.00, 44.00) 37.00 (35.50, 43.50) 37.00 (33.00, 39.00) mean (sd) 35.57 ± 5.77 36.57 ± 3.60 41.00 ± 7.79 40.00 ± 4.83 38.57 ± 5.13 36.86 ± 5.76 PvCO2_JB (mmHg) median (IQR) 48.00 (46.00, 49.00) 47.00 (44.00, 50.00) 48.00 (45.00, 49.00) 48.00 (46.00, 49.50) 47.00 (44.50, 48.00) 46.00 (42.50, 48.50) mean (sd) 45.71 ± 7.25 46.43 ± 4.89 46.43 ± 3.87 47.00 ± 4.55 46.29 ± 3.59 46.00 ± 5.80 HCO3_JB (mEq/L) median (IQR) 22.00 (19.00, 25.50) 21.00 (21.00, 24.50) 22.00 (21.50, 25.50) 22.00 (21.50, 25.00) 24.00 (22.00, 24.00) 24.00 (22.50, 24.50) mean (sd) 21.57 ± 6.24 22.29 ± 4.89 22.29 ± 5.19 22.71 ± 3.82 23.14 ± 3.08 23.71 ± 1.98 SjvO2 (%) median (IQR) 59.00 (56.00, 66.50) 65.00 (62.50, 68.50) 66.00 (64.50, 71.50) 65.00 (61.50, 71.50) 66.00 (65.00, 70.50) 65.00 (60.00, 67.50) mean (sd) 61.00 ± 7.39 64.29 ± 6.42 68.57 ± 8.28 66.43 ± 7.89 66.29 ± 7.59 63.29 ± 7.52 pH_ABG median (IQR) 7.41 (7.38, 7.42) 7.39 (7.38, 7.42) 7.40 (7.38, 7.41) 7.40 (7.39, 7.42) 7.41 (7.39, 7.42) 7.42 (7.38, 7.43) mean (sd) 7.39 ± 0.04 7.39 ± 0.04 7.39 ± 0.05 7.39 ± 0.05 7.39 ± 0.05 7.40 ± 0.04 PaO2_ABG (mmHg) median (IQR) 90.00 (77.50, 103.00) 88.00 (79.00, 107.50) 106.00 (86.00, 111.00) 98.00 (93.50, 118.50) 99.00 (95.00, 109.50) 97.00 (89.00, 103.50) mean (sd) 89.14 ± 15.10 93.29 ± 16.92 100.43 ± 19.17 104.29 ± 19.64 103.71 ± 17.39 98.57 ± 13.65 158 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 PaCO2_ABG (mmHg) median (IQR) 40.00 (36.00, 40.50) 39.00 (37.50, 39.00) 38.00 (36.50, 40.50) 38.00 (37.00, 41.00) 40.00 (36.00, 41.00) 37.00 (36.00, 38.50) mean (sd) 37.00 ± 5.74 38.43 ± 2.70 38.29 ± 3.86 39.00 ± 3.83 39.14 ± 3.63 37.71 ± 3.20 HCO3_ABG (mEq/L) median (IQR) 22.00 (17.00, 25.50) 21.00 (19.50, 24.00) 22.00 (20.50, 24.00) 21.00 (21.00, 24.00) 22.00 (22.00, 24.00) 23.00 (22.00, 24.50) mean (sd) 21.29 ± 5.62 21.71 ± 3.99 22.29 ± 3.55 22.43 ± 3.26 23.29 ± 2.43 23.71 ± 2.21 SaO2 (%) median (IQR) 96.00 (93.00, 96.00) 96.00 (93.50, 96.00) 96.00 (94.50, 96.00) 96.00 (94.00, 96.00) 96.00 (96.00, 96.00) 96.00 (96.00, 96.00) mean (sd) 94.71 ± 2.06 95.00 ± 1.63 95.00 ± 1.53 95.00 ± 1.29 95.43 ± 1.51 95.43 ± 1.51 FiO2 (%) median (IQR) 45.00 (30.00, 47.50) 45.00 (30.00, 47.50) 45.00 (30.00, 47.50) 45.00 (30.00, 47.50) 45.00 (30.00, 47.50) 45.00 (30.00, 47.50) mean (sd) 40.71 ± 13.05 40.71 ± 13.05 40.71 ± 13.05 40.71 ± 13.05 40.71 ± 13.05 40.71 ± 13.05 Hb (g/dL) median (IQR) 8.50 (8.25, 8.75) 9.50 (9.20, 10.10) 9.50 (9.40, 9.85) 9.60 (9.45, 9.85) 9.70 (9.20, 10.00) 9.20 (8.95, 9.80) mean (sd) 8.49 ± 0.33 9.67 ± 0.66 9.64 ± 0.67 9.69 ± 0.50 9.57 ± 0.80 9.31 ± 0.89 CaO2 median (IQR) 11.39 (10.91, 11.58) 12.64 (12.14, 13.60) 12.65 (12.51, 13.21) 12.79 (12.53, 13.20) 13.01 (12.30, 13.42) 12.26 (12.02, 13.07) mean (sd) 11.20 ± 0.55 12.78 ± 0.95 12.76 ± 0.96 12.82 ± 0.64 12.72 ± 0.95 12.37 ± 1.04 159 Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 CvO2 median (IQR) 6.92 (6.56, 7.53) 8.69 (8.54, 8.92) 9.27 (8.73, 9.56) 8.95 (8.34, 9.26) 8.82 (8.25, 9.48) 7.96 (7.58, 8.72) mean (sd) 7.14 ± 0.84 8.55 ± 0.84 9.08 ± 0.86 8.85 ± 0.96 8.74 ± 1.22 8.12 ± 1.22 O2EF (%) median (IQR) 39.94 (28.88, 42.38) 31.92 (28.41, 35.58) 31.62 (26.13, 33.09) 32.93 (25.68, 35.71) 31.52 (26.13, 33.12) 33.07 (28.69, 38.44) mean (sd) 36.00 ± 9.28 32.88 ± 7.36 28.43 ± 9.91 30.77 ± 8.83 31.30 ± 7.93 34.33 ± 8.20 MAP = mean arterial pressure; ETCO2 = end tidal carbon dioxide tension; PvO2 = partial pressure of oxygen in jugular venous bulb, JB = jugular venous bulb; HCO3- = bicarbonate ion; PaO2 = partial pressure of arterial oxygen tension; SjvO2 = jugular venous bulb oxygen saturation; O2EF = oxygen extraction fraction; PaCO2 = arterial carbon dioxide tension; PvCO2 = jugular venous bulb carbon dioxide tension; CaO2 = arterial oxygen tension; CvO2 = jugular venous bulb oxygen content; SaO2 = arterial saturation of hemoglobin; Hb = hemoglobin concentration; FiO2 = fraction of inspired 160 Figure 8.2. The top left panel shows boxplot of the change in the arterial oxygen content at all study timepoints. The top right panel shows boxplot of the change in the venous oxygen content at all study timepoints. The bottom left panel shows boxplot of the change in the hemoglobin concentration at all study timepoints. The bottom right panel shows boxplot of the change in the partial pressure of arterial oxygen tension at all study timepoints. CaO2 = arterial oxygen content; CvO2 = jugular venous bulb oxygen content; Hb = hemoglobin concentration (g/dL); PaO2_ABG = arterial oxygen tension (mmHg). This figure is original for this manuscript. 161 Figure 8.3. The top panel shows boxplot of the change in the jugular venous bulb oxygen saturation at all study timepoints. SjvO2 = jugular venous bulb oxygen saturation. This figure is original for this manuscript. 162 8.2.4 RELATIONSHIP BETWEEN RED BLOOD CELL TRANSFUSION AND SECONDARY DERIVATIVES OF METABOLISM Table 8.4 demonstrates the changes in secondary measures of cerebral metabolism before RBC transfusion and then at all timepoints following RBC transfusion. We did not demonstrate significant differences in the AJDO2, ÎPCO2 or the ratio (AJDO2/ÎPCO2) as an estimator of tissue ischemia. Table 8.4 Pre and Post RBC Transfusion of secondary measures of ischemia and metabolism Variable Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5 Timepoint 6 AJDO2, mean SD (vol%) 3.2 (1.2) 3.5 (1.1) 3.2 (1.3) 3.1 (1.4) 3.3 (1) 3.4 (1.2) ÎPCO2, mean SD (mmHg) 7.1 (3.2) 7.8 (3.7) 7.4 (3.8) 6.6 (3.6) 7 (3.5) 7.1 (3.5) Ratio, mean SD (AJDO2/ÎPCO2) 2.2 (0.5) 2.4 (1.5) 2.5 (1) 2.3 (1) 2.2 (0.9) 2.2 (1) AJDO2 = Arterial-jugular difference in oxygen content; ÎPCO2 = Delta difference in venous to arteria carbon dioxide tension; Ratio = AJDO2 / ÎPCO2 163 8.3 STUDY 5 â DISCUSSION The main finding of this prospective interventional study demonstrates that the SjvO2 did not increase after RBC transfusion in HIBI patients despite the post transfusion CaO2 and hemoglobin concentration increasing. We did, however, demonstrate a consistent trend towards increased SjvO2 after RBC transfusion in HIBI patients with a pre-transfusion SjvO2 < 75%. 8.3.1 RED BLOOD CELL TRANSFUSION AND BRAIN OXYGENATION Optimization of CDO2 is a cornerstone of critical care HIBI management in preventing secondary injury after ROSC263. Numerous epidemiological studies have suggested that perturbations in clinical variables associated with decreased CDO2 such as hypotension, hypocapnia, hypoxemia and anemia, are associated with adverse clinical outcome10,11,13,31,303,304. Specifically with respect to arterial oxygen content, recent studies have shown associations with anemia and adverse clinical outcome in HIBI patients65,303. Although intriguing, numerous unmeasured clinical confounders likely obscure a direct link between anemia and neurological outcome after ROSC in that pre-admission anemia likely reflects a degree of severity of pre-morbid chronic disease. Importantly, limited data between anemia and concurrent brain hypoxia is available to extrapolate its role in exacerbating secondary injury after ROSC. Ameloot et al., in a retrospective study, reported that decreased hemoglobin levels with reduced regional oxygen saturation using near infrared spectroscopy159. Given the inherent shortcomings of regional oxygen saturation reflecting cerebral blood flow, brain oxygenation and CDO2, the validity and importance of this finding must be questioned. Additional data making this physiological link between brain oxygenation and anemia in HIBI patients is lacking. 164 Extrapolating from traumatic brain injury animal models, anemia appears to exacerbate secondary ischemic brain injury19. Furthermore, RBC transfusion studies in TBI demonstrate increases in PbtO2 post transfusion and provide links between anemia and brain hypoxia63,64,67,68. Regrettably, RBC transfusion has not been associated with improved cerebral metabolism or clinical outcomes in TBI, questioning its efficacy as an intervention in acute critical care management of brain injury69. Similar data has not been previously available in HIBI patients. The normal physiologic response to acute normovolemic anemia is characterized by microvascular cerebral vasodilation and augmentation of local blood flow to maintain overall net cerebral oxygen delivery. Crucial questions remain if this mechanism is intact after acute HIBI. We demonstrated that RBC transfusion did not routinely increase SjvO2 in HIBI patients and there were not observed changes in the indirect measures of cerebral metabolism what we analyzed (ÎPCO2 and AJDO2/ ÎPCO2). These findings are in keeping with interventional studies of RBC transfusion in traumatic brain injury69. The disconnect between the augmentation of CaO2 and lack of improvement in SjvO2 suggests that impairments in microvascular oxygen transport exists in the cerebral parenchyma. The presence of diffusion limitation of oxygen transport as a mechanism of brain hypoxia may account for the observed findings in our cohort. For example, we have previously demonstrated (Chapter 7) that augmentation of CDO2 with increased cerebral perfusion pressure, is not associated with improved PbtO2. Similar physiology may play a role with RBC transfusion in HIBI patients. 8.3.2 DIFFERENTIAL EFFECTS OF RED BLOOD CELL TRANSFUSION In an attempt to evaluate the contribution of diffusion limitation of as a factor in inhibiting the improved brain oxygenation and metabolism after RBC transfusion in HIBI, we 165 analyzed a sub-cohort of patients with a pre-transfusion SjvO2 < 75%. We observed a statistically significant increase in SjvO2 at timepoint 3 after RBC transfusion but perhaps more importantly, there appeared to be a trend towards increased SjvO2 after transfusion at all timepoints. Although the remaining post-transfusion measurements did not reach statistical significance, we were not powered to make definitive conclusions and this sub-analysis is hypothesis generating for future work. The clinical implication of this finding is that it raises the importance of differential effects of RBC transfusion in HIBI patients depending on their underlying microvascular oxygen transport phenotype. Physiologically, RBC transfusion increases CaO2 and by extension, CDO2. The logical improvement in brain oxygenation assumes normal microvascular oxygen transport across the blood brain barrier into the parenchyma and into neurons. In the setting of diffusion limitation physiology, microvascular oxygen transport is abnormal due to blood brain barrier disruption, perivascular edema or mitochondrial dysfunction. As such, augmentation of CDO2 from RBC transfusion would not lead to improved brain oxygenation and only expose the patient to the unwanted risks of blood transfusion. Future studies focusing on the benefits of augmenting CDO2, specifically with RBC transfusion must consider the underlying physiological phenotypes of perfusion dependence or diffusion limitation in HIBI. 8.3.3 LIMITATIONS AND FUTURE STEPS The results of this study should be interpreted within the context of limitations. Our small number of enrolled patients precludes definitive conclusions to be drawn with respect to the physiology of RBC transfusion in HIBI. Clearly, a major physiologic confounder is diffusion limitation of oxygen delivery at the level of the neurovascular unit in HIBI. We did not have 166 simultaneous PbtO2 and SjvO2 monitoring in this cohort to delineate which patients were definitively exhibiting diffusion limitation physiology. Instead, we extrapolated by analyzing the RBC transfusion physiology in a sub-cohort of patients with a pre-transfusion SjvO2 < 75% who we assumed were exhibiting normal microvascular oxygen transport. This sub-cohort was not powered adequately to make definitive conclusions on the RBC transfusion and brain oxygenation physiology in HIBI patients with perfusion dependence. Future studies should attempt to isolate this phenotype in examining the effects of augmenting CaO2 and CDO2 on brain oxygenation and metabolism. 8.4 STUDY 5 â SUMMARY RBC transfusion did not increase brain oxygenation as measured by SjvO2 or change indirect measures of cerebral metabolism in HIBI patients after cardiac arrest. There may be differential effects of RBC transfusion on brain oxygenation in HIBI patients who do not exhibit diffusion limitation of oxygen delivery physiology. 167 9 CONCLUSION 9.1 REVIEW OF OBJECTIVES AND CONCLUSIONS This thesis aimed to investigate the underlying cerebrovascular pathophysiology of HIBI after cardiac arrest by using a prospective approach to invasive multimodal neuromonitoring after cardiac arrest. Such a systematic prospective evaluation of HIBI pathophysiology had not been previously undertaken in humans and the insights from this thesis will inform future physiologic and interventional work in HIBI research and related patient care. This body of work aimed to establish the foundation of post-resuscitation brain hypoxia as a plausible mechanism secondary injury and thereafter investigate the underlying mechanisms responsible for brain hypoxia in HIBI. Finally, it aimed to investigate the physiological efficacy of augmenting CDO2 with red blood cell transfusion and its effect on brain oxygenation. Study 1 (Chapter 4) demonstrated a significant burden of brain hypoxia post-ROSC despite goal-oriented management aimed at optimizing CDO2. This study also established key significant relationships between PbtO2 and SjvO2 with MAP but failed to reveal any relationship between MAP and rSO2. The evaluation of autoregulation in real time using PRx in Study 2 (Chapter 5) demonstrated dysfunction in the regulation of CBF after ROSC. Most importantly, however there appeared to significant in between patient heterogeneity with respect to the regulation of CBF after ROSC. Evaluation of intracranial hypertension and ICP guided management has long been a cornerstone in the management of TBI in the intensive care setting. Evaluation of ICP and intracranial compliance has been limited in HIBI patients. The results of Study 3 (Chapter 6) demonstrate an overall low burden of increased ICP in HIBI but with the caveat that patients in 168 the study were actively managed to maintain an ICP < 20mmHg in accordance with the study protocol. Interestingly, we demonstrated abnormal intracranial compliance in HIBI indicating the presence of cerebral edema in HIBI patients after ROSC. Overall, despite the active management of attempting normalize PbtO2 with critical care interventions in the study, patients exhibited a significant burden of brain hypoxia after ROSC. Study 4 (Chapter 7) described a novel mechanism of brain hypoxia attributable to diffusion limitation of oxygen delivery at the level of the neurovascular unit. Interestingly, Study 4 demonstrated differential phenotypes of post ROSC pathophysiology which highlights the need to consider these differences in future studies of post ROSC care. Finally, Study 5 (Chapter 8) sought to delineate the effect of RBC transfusion on brain oxygenation. Although relationship with RBC transfusion and improved brain oxygenation was not demonstrated but it is possible differential effects of RBC transfusion may be present depending on the underlying state of diffusion limitation versus perfusion dependent physiology after ROSC in individual patients. Overall, the results of this research have provided important advances in the understanding the burden of brain hypoxia after ROSC in human HIBI patients. Furthermore, important relationships were delineated between physiologic determinants of CDO2 with PbtO2. The clinical implications of these relationships be researched in future studies to delineate their effect on mitigating pot ROSC secondary injury. 9.1.1 THE BURDEN OF BRAIN HYPOXIA Study 1 aimed to use invasive brain oxygenation monitoring to quantify the burden of brain hypoxia that HIBI patients experience after ROSC and to evaluate the relationships 169 between the determinants of CDO2 on brain oxygenation. In this study, the clinical team caring for the study patients employed invasive multimodal neuromonitoring data to guide resuscitation of the patients in the intensive care setting. Despite best attempts to mitigate post ROSC secondary injury, the study patients experienced a significant burden of time exposed to episodes of brain hypoxia. We also evaluated the relationships between the determinants of CDO2 and brain oxygenation. We were able to demonstrate significant linear relationships between MAP and CPP on PbtO2 across the cohort, although individual patients appeared to demonstrate heterogeneity with respect to the strength of this relationship. Study 1 demonstrated that there is ample opportunity to further delineate the pathophysiology and develop therapeutic interventions in the field of post-ROSC brain oxygenation optimization. Specifically, study 1 raised important research questions relating to the missing links in the underlying pathophysiology of brain hypoxia in HIBI and also established the foundation for future interventional work aimed at augmenting CDO2 to mitigate post-ROSC brain hypoxia and secondary injury. 9.1.2 RELATIONSHIPS BETWEEN DETERMINANTS OF CEREBRAL OXYGEN DELIVERY AND BRAIN TISSUE OXYGENATION Given the findings of brain hypoxia post ROSC despite goal-oriented therapy and the lack of uniformity in the relationships between CDO2 and improved PbtO2, study 4 led to further evaluations of the mechanisms of brain hypoxia in HIBI, namely diffusion limitation physiology. We found significant relationships between MAP and CPP with PbtO2 after ROSC, thereby providing the physiological foundation for future targeted hemodynamic interventional studies in HIBI. Although a significant relationship between CPP and SjvO2 was evident, it was less 170 robust than with PbtO2 and we did not observe any relationship between CDO2 variables rSO2. These relationships -or lack of - thereby question the utility of rSO2 as a valid monitoring technique in HIBI after ROSC. We did not have enough data to make definitive conclusions on the relationships of the remaining physiological variables of CDO2 and PbtO2; as such, this represents a necessary future area of research. 9.1.3 AUTOREGULATION AND OPTIMAL MEAN ARTERIAL PRESSURE The regulation of CBF via the inherent myogenic mechanism, autoregulation, is a key physiological concept that has not been previously studied in HIBI using invasive neuromonitoring. We demonstrated a significant burden of dysfunctional autoregulation that was highly individualized between patients in our cohort and identified distinct patterns of autoregulation longitudinally, demonstrating the cerebrovascular pathophysiology of HIBI is dynamic over time. We also were able to use PRx to derive MAPOPT, LLA and ULA in HIBI patients and although the mean values across the entire cohort were significantly higher than international guideline recommendations, there was tremendous between individual heterogeneity, thereby raising the importance of the concept of individualized perfusion targets in HIBI. 9.1.4 INTRACRANIAL PRESSURE AND COMPLIANCE Previous studies have only evaluated absolute in small retrospective cohorts of HIBI patients. In Chapter 6 (Study 3) we presented the first prospective evaluation of ICP in HIBI patients after ROSC. Importantly, the value of ICP monitoring is its extrapolation of using the absolute ICP value as a marker of cerebral edema and limited intracranial compliance. 171 Abnormal intracranial compliance can exist despite a normal ICP. We demonstrated that although the absolute ICP values in most patients were normal, the intracranial compliance was abnormal in nearly all patients, indicating an element of cerebral edema. In fact, we found distinct patterns of ICP and compliance in HIBI patients over time, thus indicating the pressure volume relationships in all HIBI patients exhibit significant variation in between patients. 9.1.5 DIFFUSION LIMITATION OF OXYGEN DELIVERY Preventing secondary injury post ROSC is a cornerstone in the critical care management of HIBI. To this extent, augmenting CDO2 is a widely accepted resuscitation strategy to achieve this goal. The augmentation of MAP, maintenance of normocapnia and avoiding anemia has been advocated for post cardiac arrest care. For these interventions to have efficacy in improving CDO2 and brain oxygenation, the oxygen transport mechanisms at the neurovascular unit must be assumed to be intact. Study 4 demonstrated that there appears to be unique physiological phenotypes of HIBI patients with respect to the unloading of oxygen into the parenchymal tissue from the cerebrovasculature. We found that diffusion limitation of oxygen delivery appears to be a mechanism of brain hypoxia in HIBI patients and is not solely accounted for neuron death or irreversible cell loss. The precise mechanism of diffusion limitation remains to be elucidated but will surely be an area of future research in the characterization of HIBI pathophysiology. 9.1.6 RED BLOOD CELL TRANSFUSION AND CEREBRAL OXYGEN DELIVERY Retrospective cohort studies have demonstrated a link between anemia and adverse outcome in HIBI. As such, maintenance of CaO2 has been advocated as part of post cardiac 172 arrest HIBI management in the intensive care setting. This can be achieved with RBC transfusion; however, physiologic data supporting this clinical intervention has not been well supported. In Study 5, we demonstrated that despite significant increases in CaO2 and hemoglobin concentration after RBC transfusion, the SjvO2 did not significantly improve. The precise mechanism underlying this lack of relationship is unclear but diffusion limitation of oxygen delivery may play a role. Further work is required to delineate the efficacy of RBC transfusion and the importance maintenance of CaO2 after ROSC in the mitigation of secondary injury. 9.2 CLINICAL IMPLICATIONS 9.2.1 OPTIMAL MEAN ARTERIAL PRESSURE Current international guidelines advocate for a one size fits all approach to perfusion targets after ROSC in HIBI patients. This recommendation has generally been recommended to maintain MAP > 65mmHg263. The period of no re-flow following ROSC is characterized by cerebral oligemia and can worsen secondary ischemic injury. Therefore, augmenting CBF via MAP augmentation seems like a logical management strategy. However, this approach assumes uniform pathophysiology in all patients after ROSC, which is clearly not the case in HIBI. Therefore, MAPOPT guided strategies seem attractive in personalizing the resuscitation after ROSC in HIBI. We have shown feasibility of deriving MAPOPT in real time in HIBI patients with PRx monitoring and have shown a relationship between perfusion with proximity to MAPOPT and improved PbtO2. Future studies must incorporate CBF and cerebral metabolism monitoring with individualized perfusion strategies to further delineate the importance of 173 perfusion within proximity of MAPOPT. Depending on their results, this work may inform interventional studies and guidelines of individualized perfusion targets in HIBI patients after ROSC to elucidate the effect on neurological outcome. 9.2.2 ABNORMAL INTRACRANIAL COMPLIANCE The development of cerebral edema can lead to increased ICP, reduced CPP, CBF and exacerbate secondary ischemic injury. This downward spiral ultimately culminates in brain death. ICP monitoring represents an opportunity to estimate the intracranial pressure volume relationships and state of intracranial compliance. We demonstrated that although there was a low burden of intracranial hypertension, the intracranial compliance was abnormal in nearly all patients. This, in the context of the study patients being actively managed to maintain normal ICP, means that HIBI patients may progress rapidly to limited intracranial compliance states and trans-tentorial herniation if not managed aggressively. Importantly, it is unknown whether ICP guided management is associated with improved outcome in HIBI patients. Notwithstanding, the recognition of limited intracranial compliance after ROSC from varying gradations of cerebral edema suggests to clinicians that meticulous attention should be paid to interventions that may alter the pressure volume relationships in the intracranial space suddenly during intensive care. 9.2.3 DIFFUSION LIMITATION OF OXYGEN DELIVERY Perhaps the most significant pathophysiologic finding of this thesis which has clinical implications is the demonstration of diffusion limitation physiology of oxygen transport after ROSC. Traditionally, HIBI has been presumed to have normal oxygen transport at the level of microvasculature and neurovascular unit. As such, interventions aimed at augmenting CDO2 174 have been advocated in post arrest care but without impressive effects on clinical outcomes. Diffusion limitation physiology may account for this discrepancy. The identification of diffusion limitation in individual patients has important clinical implications pertaining to the post arrest resuscitation strategy used for individual patients and also for the development of future interventional research trials in HIBI. Exposing patients with diffusion limitation to interventions aimed at augmenting CDO2 would not only be ineffective to mitigating secondary injury but would also expose these patients to risks associated with exogenous vasoactive drugs, transfusion adverse effects and potential increased ICP with permissive hypercapnia. Similar rationale would also significantly limit the efficacy related research pertaining to studying the effects of CDO2 augmenting interventions on clinical outcome in HIBI patients. 9.3 FUTURE DIRECTIONS 9.3.1 GAPS IN THE PATHOPHYSIOLOGY OF HYPOXIC ISCHEMIC BRAIN INJURY Significant gaps in the pathophysiology still exist in the understanding of the cerebrovascular biology of HIBI in humans. Although the main results and conclusions of this thesis provide useful insights and advances in HIBI pathophysiology, a further detailed appreciation of the metabolic changes in the neurovascular unit and parenchyma are essential to placing context to the results of this thesis. For example, the precise threshold indicative of brain hypoxia of HIBI is unknown without a simultaneous assessment of the balance in aerobic versus anaerobic metabolism. Therefore, future studies must utilize monitoring devices that can track metabolism in real time or via neuroimaging techniques. 175 An additional gap in the understanding of HIBI pathophysiology is the recognition of the heterogeneous pathophysiology in specific regions of the brain parenchyma. Certain critical structures such as the thalami, basal ganglia, cortex and cerebellar vermi are especially predisposed to HIBI. The neuromonitoring devices used in this thesis were unable to assess specific regions and doing so, would require a spatial representation of the brain using positron emission tomography or evolving MRI techniques. 9.3.2 INCORPORATING CEREBRAL BLOOD FLOW MONITORING A major limitation of this thesis was the inability to incorporate simultaneous continuous or intermittent assessment of CBF in conjunction with the monitoring techniques used for assessing brain oxygenation. We extrapolated that CPP would approximate CBF and while directly proportional and the strict requirement of maintaining normocapnia during the study period, the inability to measure cerebrovascular resistance precludes this assumption. Cerebrovascular resistance can be increased in HIBI secondary to mechanisms independent from PaCO2 including microvascular thrombi, depletion of nitric oxide and microvascular collapse from perivascular edema. Therefore, real time assessment of CBF is essential in understanding the state of autoregulation in HIBI and evaluating the relationships between CBF and variables such as ICP, PaCO2, temperature, viscosity and vasopressors. In future studies, continuous CBF monitoring can be undertaken with direct parenchymal pial arteriole flow using a thermal diffusion probe that is placed through a cranial burr hole via a bolt. Alternative techniques of CBF monitoring can be undertaken with volumetric transcranial Doppler or using advanced neuroimaging techniques: MRI perfusion, positron emission tomography or xenon computed tomography. 176 9.3.3 INCORPORATING BRAIN BIOMARKERS IN FUTURE STUDIES The results of this thesis demonstrate that the neurovascular unit is an anatomical region of interest with respect to vasomotor regulation and oxygen transport. Specifically, the description of diffusion limitation physiology is intriguing and drawing anatomical correlation to the underlying structural integrity of the neurovascular unit is imperative. Traditionally, this would require tissue specimens for pathologic assessment. Given the nature and sensitive of accessing brain tissue, this approach seems limiting. The advent of brain biomarkers which reflect damage if various regions of the neurovascular unit are of great interest. Drawing correlations of these brain biomarkers in making links to the observed cerebrovascular physiology may inform clinicians as to how best individualize the post arrest care to the underlying pathophysiology without having to place invasive neuromonitoring. Furthermore, using biomarkers to differentiate between perfusion dependence and diffusion limitation may inform the design of future interventional randomized control trials of HIBI critical care management aimed at improving CDO2. The use of biomarkers will be essentially to studying the microvascular physiology and anatomical changes that occur in HIBI, which are not necessarily identifiable with macroscopic imaging techniques such as computed tomography or MRI. 9.3.4 INTERVENTIONAL STUDY DESIGN IN HYPOXIC ISCHEMIC BRAIN INJURY Interventional studies of HIBI, to date, have assumed a uniform pathophysiology after ROSC. Given the results of this thesis, not surprisingly, these trials have failed to demonstrate efficacy of various interventions aimed mitigating secondary injury. Historically, therapeutic 177 hypothermia has been advocated as a standard of care in the management of HIBI in the intensive care setting; however, recent studies have challenged this dogma. 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Thesis/Dissertation
eng
Kinesiology
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
The pathophysiology of hypoxic ischemic brain injury after cardiac arrest
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