eprintid: 1557406 rev_number: 30 eprint_status: archive userid: 608 dir: disk0/01/55/74/06 datestamp: 2017-09-29 13:59:36 lastmod: 2021-09-24 21:59:11 status_changed: 2017-09-29 13:59:36 type: thesis metadata_visibility: show creators_name: Whittle, J title: Autonomic dysfunction and perioperative outcome ispublished: unpub divisions: UCL divisions: B02 divisions: C10 divisions: D16 divisions: G88 note: Third party copyright material has been removed from ethesis 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. 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. date: 2017-05-28 date_type: published oa_status: green full_text_type: other thesis_class: doctoral_open language: eng thesis_view: UCL_Thesis primo: open primo_central: open_green verified: verified_manual elements_id: 1296551 lyricists_name: Whittle, John lyricists_id: JWHIT61 actors_name: Whittle, John actors_id: JWHIT61 actors_role: owner full_text_status: public pages: 333 event_title: UCL (University College London institution: UCL (University College London) department: Division of Medicine thesis_type: Doctoral citation: Whittle, J; (2017) Autonomic dysfunction and perioperative outcome. Doctoral thesis , UCL (University College London). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1557406/10/John%20Whittle%20MDThesis%20final.pdf.REDACTED.pdf