Autonomic dysfunction and perioperative outcome John Oliver Rafe Whittle University College London Thesis submitted for the degree of Doctor of Medicine (Research) 1 2 I, John Oliver Rafe Whittle, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed…………………………………….. 3 4 Abstract Abstract Objective: To examine the relationship between established autonomic dysfunction, measures of cardiopulmonary physiology and perioperative outcome in high-risk patients presenting for major surgery. Summary background data: Experimental data demonstrate that autonomic activity is a key modulator of both cardiovascular and immune function following tissue injury and inflammation. Autonomic dysfunction is associated with adverse outcomes across several medical populations. Whether pre-existing autonomic dysfunction is detrimental following controlled tissue injury (surgery) in humans is unknown. Summary of studies: Parasympathetic autonomic dysfunction (PAD), defined by impaired heart rate recovery after exercise, was associated with a distinct physiological profile in patients presenting for preoperative Cardiopulmonary Exercise Testing (CPET). This comprised impaired cardiac performance at peak exercise, reduced peak oxygen uptake and anaerobic threshold as well as chronotropic incompetence. Levels of GRK2, a regulator of beta adrenoreceptor and immune/inflammatory activity, in circulating lymphocytes were raised in cells derived from individuals with PAD. Retrospective analysis of outcomes from two prospectively collected colorectal surgical cohorts (n=1047) revealed PAD to be common (>30%) and associated with an increased length of hospital stay (12 days (95% CI: 9-16) vs. 8 days (95% CI: 6- 8.5), p=0.01), as well as increased risk of significant Clavien-Dindo defined morbidity, postoperative gastrointestinal function, sepsis and increased 90-day mortality (RR 1.1 (1.007-1.41), p=0.008). Intraoperative haemodynamic data indicated impaired cardiac contractility and increased risk of intraoperative hypotension, possibly contributing to detriments in postoperative outcome. 5 Abstract Sympathetic autonomic hyperactivity, defined by excessive anticipatory heart rate rise prior to starting loaded exercise was associated with a different CPET profile to that seen in PAD, defined by evidence of cardiac ischaemia during exercise, resulting in impaired cardiac contractile function at peak effort, but also associated with increased hospital length of stay. Patients with PAD did not necessarily demonstrate sympathetic hyperactivity, but when both were present, physiological performance and postoperative outcomes were further impaired. Conclusions: Both preoperative parasympathetic and sympathetic autonomic dysfunction are associated with impaired perioperative outcomes. These data demonstrate in high risk surgical patients that established autonomic dysregulation is associated with the development of sepsis, myocardial ischaemia, critical illness and mortality following major elective surgery. The autonomic nervous system represents an underexplored target for therapies aimed at reducing the morbidity burden of major surgery. 6 Contents Table of Contents Abstract ..................................................................................................................... 5 Table of Contents ..................................................................................................... 7 List of figures .......................................................................................................... 13 List of tables ........................................................................................................... 15 Abbreviations .......................................................................................................... 17 Acknowledgements ................................................................................................ 19 1 Introduction ....................................................................................................... 20 1.1 Introduction ................................................................................................. 20 1.1.1 Post-operative morbidity and mortality are important and incompletely understood issues in healthcare ........................................................................ 20 1.1.2 Mechanisms of postoperative morbidity ................................................ 22 1.2 The Autonomic Nervous System in health and disease ......................... 23 1.2.1 Intact autonomic function is central to maintaining biological stability ... 23 1.2.2 Autonomic dysfunction ........................................................................... 26 1.3 Autonomic Dysfunction and the surgical patient .................................... 27 1.3.1 Autonomic Dysfunction is likely to be common in higher risk surgical patients presenting for major surgery ................................................................ 27 1.3.2 Major surgery presents a severe challenge to the autonomic nervous system. .............................................................................................................. 28 1.4 Autonomic Dysfunction as a key mechanism underlying acute and chronic disease ................................................................................................... 29 1.4.1 Autonomic Dysfunction drives the development of critical illness .......... 29 1.4.2 Sympathetic nervous activation provides an adaptive response to physiological challenge ..................................................................................... 29 1.4.3 Autonomic activation is rapid and occurs in response to peripheral immune challenges ........................................................................................... 30 1.4.4 Loss of crucial signalling and receptor activity in autonomic dysfunction impairs the physiological response to critical illness ......................................... 31 1.5 Autonomic neural regulation of inflammation ......................................... 32 1.5.1 Evidence for an autonomic–immune interaction: anatomical and cellular… ........................................................................................................... 32 1.5.2 Sympathetic neural influence on immune function ................................ 33 1.5.3 Parasympathetic neural influence on immune function ......................... 34 1.5.4 Clinical implications of the vagal inflammatory reflex in surgical patients… .......................................................................................................... 38 1.6 Autonomic Dysfunction and the heart ...................................................... 39 1.6.1 Parasympathetic Autonomic Dysfunction and cardiac injury ................. 39 1.6.2 Sympathetic Autonomic Dysfunction and cardiac injury ........................ 41 1.6.3 Autonomic Dysfunction and Cardiac Failure .......................................... 43 1.6.4 The Parasympathetic Nervous System and Heart Failure ..................... 43 1.7 G-protein receptor kinases and autonomic function .............................. 46 1.7.1 G-protein receptor kinases play a key role in the pathophysiology of cardiac failure .................................................................................................... 46 7 Contents 1.7.2 The extra-cardiac GRK2 interactome is central to multiple pathophysiological processes ........................................................................... 49 1.7.3 Lymphocyte GRK2 as a biomarker in parasympathetic autonomic dysfunction ........................................................................................................ 49 1.8 Parasympathetic Autonomic Dysfunction and Postoperative Gastrointestinal Dysfunction ............................................................................. 51 1.9 The influence of Autonomic Dysfunction on the physiological response to anaesthesia ..................................................................................................... 52 1.9.1 Commonly used drugs in anaesthesia may exacerbate existing autonomic dysfunction ....................................................................................... 54 1.9.2 Autonomic dysfunction is likely to result in impaired outcomes both during and after anaesthesia ............................................................................. 56 1.10 Techniques for assessing autonomic function ..................................... 57 1.10.1 Selection of an appropriate autonomic testing modality for use in the high-risk surgical patient .................................................................................... 58 1.10.2 Heart Rate Dynamic Changes (deep breathing, Valsalva, postural change, sustained hand grip) ............................................................................ 59 1.10.3 Blood Pressure Responses ................................................................. 60 1.10.4 Heart Rate Variability Analysis ............................................................ 60 1.10.5 Heart Rate Variability as a measure of cardiac autonomic system activity… ............................................................................................................ 64 1.10.6 Resting Heart Rate .............................................................................. 65 1.11 Heart rate recovery after