Barriers to the Use of Goal Directed Therapy in a High Risk Surgical Patient Group A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy Neil MacDonald William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London 1 DECLARATION I, Neil MacDonald, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by, others that this is duly acknowledged below, and my contribution indicated. The work in chapter three is a result of large collaborative project and my contribution is outlined in chapter two. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Neil MacDonald 2 LIST OF COLLABORATION AND PUBLICATIONS Rupert M. Pearse, David A. Harrison, Neil MacDonald, Michael A. Gillies, Mark Blunt et al for the OPTIMISE study group. Effect of a Perioperative, Cardiac Output–Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery: A Randomized Clinical Trial and Systematic Review JAMA. 2014 Jun 4;311(21):2181-90 N MacDonald, T. Ahmed, O. Mohr, J. Kirk-Bailey, I. Moppett et al. Dynamic preload markers to predict fluid responsiveness during and after major gastrointestinal surgery: an observational substudy of the OPTIMISE trial. BJA 2015 Apr;114(4):598-604 N MacDonald and RM Pearse. Are we close to the Ideal intravenous fluid? BJA 2017 Dec 1;119(suppl_1):i63-i71. Macdonald, Neil; Pearse, Rupert M.; Murray, Patrick T.; Inzitari, Rosanna; Doran, Peter; and Prowle, John R. The role of Goal Directed Therapy in the prevention of Acute Kidney Injury after Major Gastrointestinal Surgery: A sub-study of the OPTIMISE Trial submitted to the European Journal of Anaesthesiology and under review 3 PUBLICATIONS NOT INCLUDED IN THE THESIS Chaudery H, MacDonald N, Ahmad T, Chandra S, Tantri A et al; for the International Surgical Outcomes Study (ISOS) Group. Acute Kidney Injury and Risk of Death After Elective Surgery: Prospective Analysis of Data From an International Cohort Study. Anesth Analg. 2018 Nov 9. doi: 10.1213/ANE.0000000000003923. [Epub ahead of print] GL Ackland, TEF Abbott, D Cain, MR Edwards, P Sultan et al. Preoperative systemic inflammation and perioperative myocardial injury: prospective observational multicentre cohort study of patients undergoing non-cardiac surgery BJA doi.org/10.1016/.bja.2018.09.02 Abbott TEF, Goonernate M, Lee A, Levett DZH, Grocott MPW, Swart M, MacDonald N. for the ARCTIC study investigators. Inter-observer reliability of preoperative cardiopulmonary exercise test interpretation: a cross-sectional study. BJA 2018 Mar;120(3):475-483 4 SHORT ABSTRACT Background Goal directed therapy, the utilisation of fluids and inotropes to optimise cardiovascular performance of tissue oxygen delivery during surgery, has been shown in small studies to reduce complications after major surgery. The OPTIMISE trial was conducted to see if this benefit of morbidity reduction seen with the use of goal directed therapy was replicated in a larger pragmatic trial. I hypothesised that there were potential barriers to the use of goal directed therapy under these conditions that may reduce the clinical effectiveness of this treatment approach. Methods This thesis is based on sub-studies of the OPTIMISE trial examining the difficulties in utilising goal directed therapy as a treatment that focused primarily on the administration of fluids via an algorithm and the effect of goal directed therapy on a specific complication. Acute kidney injury was chosen as an important postoperative complication that was directly affected by fluid administration. Results OPTIMISE did not demonstrate a statistically significant effect of a reduction in complications in a population of 732 high risk surgical patients receiving goal directed therapy. Compliance to the goal directed therapy algorithm was mostly good across seventeen hospital sites. The use of dynamic fluid markers was not shown to be beneficial as indicators of when to give fluid boluses in the perioperative period. Goal directed therapy did not protect against acute kidney injury in the high risk surgical population. There was no difference in the incidence of acute kidney injury in the goal directed therapy group and the usual care group as measured by standardised criteria and measured by a urinary biomarker. 5 Conclusions Goal directed therapy did not result in a significant reduction in complications in a high risk surgical population. However, there are some barriers to the use of goal directed therapy particularly the evidence base for the effectiveness of goal directed therapy and understanding the mechanisms, if any, by which goal directed therapy improves outcomes. Further work should focus on establishing supporting the current evidence base for goal directed therapy and seeking the mechanism by which this may improve outcomes. 6 SCIENTIFIC SUMMARY Background Major surgery initiates an inflammatory state that is not particularly well understood but if not appropriately managed can develop into complications that significantly impact the patient’s health. Alongside the immediate effects of complications arising from surgery, such as increased use of critical care resources and length of hospital stay, complications after surgery have also been associated with long term adverse effects including poorer quality of life and reduced survival. A predefined high risk surgical patient group accounts for a small amount of the surgery performed but for disproportionately large amount of post-operative morbidity and mortality. Targeting this group of patients with treatments designed to reduce morbidity and mortality has the potential to significantly to improve patient outcomes. The use of inotropes and fluid boluses to optimise cardiac output and thus oxygen delivery has been shown in small studies and subsequent meta-analyses to reduce complications in the high-risk surgical patient group undergoing major gastrointestinal surgery. It is unclear how effective this therapy is in this surgical population outside the setting of small trials. My aim in this thesis was to establish the barriers to treatment of the high-risk patient group using goal directed therapy. Goal Directed Therapy This thesis uses data from the OPTIMISE trial. In this trial goal directed therapy did not lead to a statistically significant reduction in complications using a composite of all complications although there was a non-significant clinical effect noted in favour of goal directed therapy. The current evidence base suggests that goal directed therapy improves morbidity and mortality in an older high risk surgical population undergoing major gastrointestinal surgery. There was a reduction in the overall 7 complication rate in the patient group receiving goal directed therapy and when this data were combined with those from other trials of goal directed therapy. In an updated meta-analysis the findings did suggest a benefit for those patients receiving goal directed therapy. There are potential confounders in bigger trials designed to reflect clinical practice including compliance with the algorithm, simplification of the algorithm leading to reduced clinical effectiveness, inconsistent fluid choice and if goal directed therapy using fluid and inotropes has a discrete effect on reducing organ injury. I decided to investigate any benefit in prevention of acute kidney injury as the next most likely organ to have a beneficial effect from goal directed therapy Compliance Compliance with the algorithm in the trial was measured by research staff supervising the intervention. Self-assessment was undertaken on all aspects of the intervention and deviations from protocols were noted in protocol deviation forms. I evaluated the ability of different hospitals to follow our prespecified goal directed therapy algorithm. Dynamic predictors of fluid responsiveness Fluid excess is associated with poor outcomes after major surgery. The OPTIMISE algorithm used stroke volume as the haemodynamic parameter that fluid challenges were given against. This potentially could lead to excess fluid administration as a fluid challenge is required to establish stroke volume responsiveness even in euvolemic patients. Dynamic parameters such as pulse pressure variation and stroke volume variation had been shown to provide a useful predictor of fluid responsiveness under specific, well-controlled conditions. I wished to evaluate the practical use of these parameters by 8 assessing their accuracy in predicting fluid responsiveness. Dynamic parameters were average to poor in their ability to predict fluid responsiveness in the OPTIMISE patient cohort. Acute Kidney Injury Previous work has suggested that goal directed therapy may have a beneficial effect on kidney injury. Acute