Cerebral autoregulation based blood pressure management in the neuroscience inte

Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2020 Cerebral Autoregulation-Based Blood Pressure Management In The Neuroscience Intensive Care Unit: Towards Individualizing Care In Ischemic Stroke And Subarachnoid Hemorrhage Andrew Silverman Follow this and additional works at: https://elischolar.edu/ymtdl Recommended Citation Silverman, Andrew, "Cerebral Autoregulation-Based Blood Pressure Management In The Neuroscience Intensive Care Unit: Towards Individualizing Care In Ischemic Stroke And Subarachnoid Hemorrhage" (2020). Yale Medicine Thesis Digital Library.edu/ymtdl/3951 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact elischolar@yale.

Cerebral autoregulation-based blood pressure management in the neuroscience intensive care unit Towards individualizing care in ischemic stroke and subarachnoid hemorrhage A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine by Andrew Silverman Class of 2020 ABSTRACT The purpose of this thesis is to review the concept of cerebral autoregulation, to establish the feasibility of continuous bedside monitoring of autoregulation, and to examine the impact of impaired autoregulation on functional and clinical outcomes following subarachnoid hemorrhage and ischemic stroke. Autoregulation plays a key role in the regulation of brain blood flow and has been shown to fail in acute brain injury. Disturbed autoregulation may lead to secondary brain injury as well as worse outcomes. Furthermore, there exist several methodologies, both invasive and non-invasive, for the continuous assessment of autoregulation in individual patients.

Resultant autoregulatory parameters of brain blood flow can be harnessed to derive optimal cerebral perfusion pressures, which may be targeted to achieve better outcomes. Multiple studies in adults and several in children have highlighted the feasibility of individualizing mean arterial pressure in this fashion. The thesis herein argues for the high degree of translatability of this personalized approach within the neuroscience intensive care unit, while underscoring the clinical import of autoregulation monitoring in critical care patients. In particular, this document recapitulates findings from two separate, prospectively enrolled patient groups with subarachnoid hemorrhage and ischemic stroke, elucidating how deviation from dynamic and personalized blood pressure targets associates with worse outcome in each cohort.

While definitive clinical benefits remain elusive (pending randomized controlled trials), autoregulation-guided blood pressure parameters wield great potential for constructing an ideal physiologic environment for the injured brain. The first portion of this thesis discusses basic autoregulatory physiology as well as various tools to interrogate the brain’s pressure reactivity at the bedside. It then reviews the development of the optimal cerebral perfusion pressure as a biological hemodynamic construct. The second chapter pertains to the clinical applications of bedside neuromonitoring in patients with aneurysmal subarachnoid hemorrhage.

In this section, the personalized approach to blood pressure monitoring is discussed in greater detail. Finally, in the third chapter, a similar autoregulation-oriented blood pressure algorithm is applied to a larger cohort of patients with ischemic stroke. This section contends that our novel, individualized strategy to hemodynamic management in stroke patients represents a better alternative to the currently endorsed practice of maintaining systolic blood pressures below fixed and static thresholds. ACKNOWLEDGMENTS This work would not have been possible without the leadership and encouragement of Dr.

I could not have asked for a more insightful, creative, and patient mentor. It has been an extraordinary opportunity learn about physiology, critical care, and balancing research and clinical work from such a dedicated and kind role model. Many thanks also to our larger research team, which includes Sumita Strander, Sreeja Kodali, Alex Kimmel, Cindy Nguyen, Krithika Peshwe, and Anson Wang. Sumita and Sreeja, now first-year medial students at Harvard and Yale, respectively, were incredible teammates throughout my research year.

They helped enroll patients, problem solve, and run new scripts. Their energy and friendship sustained me during some of the longer days (and nights) of neuromonitoring and abstract construction before midnight deadlines. More gratitude to my thesis committee and mentors in the Neurology Department, including Dr. Emily Gilmore, Dr.

Kevin Sheth, Dr. Charles Wira, and Dr. In particular, Dr. Gilmore volunteered her time to adjudicate clinical and radiologic scores for over 30 patients with subarachnoid hemorrhage.

Many thanks overall to the Divisions of Vascular Neurology and Neurocritical Care for hosting me and providing me with a suitable workspace for an entire year. Thank you to Yale’s amazing Office of Student Research: Donna Carranzo, Kelly Jo Carlson, Reagin Carney, and Dr. Without their coordination efforts and sponsorship, I would not have been able to obtain funding from the American Heart Association, practice presenting my work at research in progress meetings, or learn about my peers’ awesome project developments – not to mention all the coffee and snacks they provided. Much gratitude, as always, to my grandma, my mom, my older brother, and to Lauren.

Although they are not in the medical field and will probably never read this thesis, they have continually been enthusiastic and unconditionally supportive. Finally, I would like to thank the patients and families who volunteered to participate in our studies. Research reported in this publication was supported by the American Heart Association (AHA) Founders Affiliate training award for medical students as well as the Richard A. Moggio Student Research Fellowship from Yale.

TABLE OF CONTENTS PART I. Introduction: a brief history of autoregulation research. Cerebral blood flow regulation and physiology. Methods to measure cerebral autoregulation.

Autoregulation indices and signal processing. Comparisons between autoregulatory indices. Optimal cerebral perfusion pressure. Clinical relevance of autoregulation following subarachnoid hemorrhage.

Pilot study on autoregulation monitoring in subarachnoid hemorrhage. Results of the subarachnoid hemorrhage pilot study. Large-vessel occlusion (LVO) ischemic stroke. Clinical relevance of autoregulation following ischemic stroke.

Pilot study on autoregulation monitoring in ischemic stroke. Results of the ischemic stroke pilot study. Concluding remarks and future studies.138 LIST OF PUBLICATIONS AND ABSTRACTS Peer-reviewed original investigations 1. Silverman A, Kodali S, Strander S, Gilmore E, Kimmel A, Wang A, Cord B, Falcone G, Hebert R, Matouk C, Sheth KN, Petersen NH.

Deviation from personalized blood pressure targets is associated with worse outcome after subarachnoid hemorrhage. Silverman A*, Petersen NH*, Wang A, Strander S, Kodali S, Matouk C, Sheth KN. Exceeding Association of Personalized Blood Pressure Targets With Hemorrhagic Transformation and Functional Outcome After Endovascular Stroke Therapy. Silverman A*, Petersen NH*, Wang A, Strander S, Kodali S, et al.

Fixed Compared to Autoregulation-Oriented Blood Pressure Thresholds after Mechanical Thrombectomy for Ischemic Stroke. (*equally contributed) Abstracts and presentations 1. Silverman A, Kodali S, Strander S, Gilmore E, Kimmel A, Cord B, Hebert R, Sheth K, Matouk C, Petersen NH. Deviation from Dynamic Blood Pressure Targets Is Associated with Worse Functional Outcome After Subarachnoid Hemorrhage.

Platform Presentation, Congress of Neurological Surgeons Annual Meeting, San Francisco 2019. Silverman A, Wang A, Strander S, Kodali S, Sansing L, Schindler J, Hebert R, Gilmore E, Sheth K, Petersen NH. Blood Pressure Management Outside Individualized Limits of Autoregulation is Associated with Neurologic Deterioration and Worse Functional Outcomes in Patients with Large-Vessel Occlusion (LVO) Ischemic Stroke. Platform Presentation, American Academy of Neurology Annual Meeting, Philadelphia 2019.

Silverman A, Wang A, Kodali S, Strander S, Cord B, Hebert R, Matouk C, Sheth K, Gilmore E, Petersen NH. Dynamic Cerebral Autoregulation and Personalized Blood Pressure Monitoring in Patients with Aneurysmal Subarachnoid Hemorrhage (aSAH). Poster Presentation, American Academy of Neurology Annual Meeting, Philadelphia 2019. Silverman A, Wang A, Kodali S, Strander S, Cord B, Hebert R, Matouk C, Gilmore E, Sheth K, Petersen NH.

Individualized blood pressure management after subarachnoid hemorrhage using real-time autoregulation monitoring: a pilot study using NIRS and ICP-derived limits of autoregulation. Platform Presentation, International Stroke Conference, Honolulu 2019. Acronyms Aneurysmal subarachnoid aSAH MAPOPT Optimal mean arterial pressure hemorrhage BP Blood pressure PRx Pressure reactivity index ICP Intracranial pressure TOx Tissue oxygenation index %time Percent time outside limits of NIRS Near-infrared spectroscopy outside LA autoregulation DCI Delayed cerebral ischemia OR Odds ratio MAP Mean arterial pressure CI Confidence interval IQR Interquartile range aOR Adjusted odds ratio CBF Cerebral blood flow CVR Cerebrovascular resistance CPP Cerebral perfusion pressure TCD Transcranial Doppler Optimal cerebral perfusion CPPOPT LA Limits of autoregulation pressure ULA Upper limit of autoregulation LLA Lower limit of autoregulation mRS Modified Rankin scale HH Hunt and Hess classification World Federation of mF Modified Fisher score WFNS Neurological Surgeons score Receiver operating LoC Loss of consciousness ROC characteristic TBI Traumatic brain injury LVO Large-vessel occlusion tPA Tissue plasminogen activator EVT Endovascular thrombectomy HT Hemorrhagic transformation HI Hemorrhagic infarction Symptomatic intracranial PH Parenchymal hematoma sICH hemorrhage National Institute of Health Alberta Stroke Program Early NIHSS ASPECTS Stroke Scale CT Score Endovascular Treatment for DWI or CTP Assessment with Small Core and Anterior Clinical Mismatch in the Triage ESCAPE trial Circulation Proximal Occlusion DAWN trial of Wake-Up and Late with Emphasis on Minimizing Presenting Strokes Undergoing CT to Recanalization Times Neurointervention with Trevo 1 PART I A. Introduction: a brief history of autoregulation research In 1959, Dr.

Niels Lassen published a pivotal review on cerebral blow flow and popularized the concept of cerebral autoregulation. [1] He writes, “Until about 1930 the cerebral circulation was generally believed to vary passively with changes in the perfusion pressure. This concept was based mainly on the Monro-Kellie doctrine of a constant volume of the intracranial contents, from which it was deduced that no significant changes in intracranial blood volume or vascular diameter were likely to occur.” In fact, Monro promoted this conceit regarding the skull’s non-compliance in 1783, and it wasn’t until 1890 that Roy and Sherrington submitted that cerebral blood flow might be dependent on both arterial pressure in conjunction with intrinsic cerebrovascular properties capable of autonomously regulating flow. [2, 3] In their letter to the Journal of Physiology, the authors speculate on the origins of these properties: “Presumably, when the activity of the brain is not great, its blood-supply is regulated mainly by the intrinsic mechanism and without notable interference with the blood-supply of other organs and tissues.

When, on the other hand, the cerebral activity is great, or when the circulation of the brain is interfered with, the vasomotor nerves are called into action, the supply of blood to other organs of the body being thereby trenched upon.” Then, in 1902, Sir W. Bayliss performed a series of experiments on anesthetized cats, dogs, and rabbits, observing peripheral vasoconstriction during increased blood pressure inductions. Bayliss points out that instead of merely returning to its original 2 volume when the blood pressure returns to baseline, the volume of the limb constricts considerably below its previous level before returning to normal. This phenomenon was later dubbed the Bayliss effect, referring to a pressure-reactive, myogenic vascular system.

Exemplary myogenic reactivity as demonstrated by W. Bayliss at the turn of the 20th century. [4] In the ensuing decades leading up to Lassen’s review, quantitative studies in both animal models and humans confirmed observations of autoregulation as an objective homeostatic phenomenon, first described by Forbes in 1928 and later by Fog in 1938. [5-8] Through direct observation of feline pial vessels through a pioneering cranial window (a so-called lucite calvarium), they noticed that systemic blood pressure increases resulted in surface vessel vasoconstriction, while pressure decrements yielded local vasodilation, thus 3 sustaining the Bayliss effect.

In summarizing these studies, Lassen found that optimal and constant cerebral blood flow tended to occur within a cerebral perfusion pressure range of roughly 50 to 150 mmHg. This autoregulatory doctrine has now made its way to first-year medical school classrooms and can be heard on neurocritical care rounds on a virtually daily basis (Figure 2). The evolution of the autoregulatory curve from Lassen’s original 1959 publication (left) to the instructive illustration that can be found in First Aid for the USMLE Step 1 (right).