Peri-operative haemodynamic therapy: The OPTIMISE trial Rupert Pearse Senior Lecturer in Intensive Care Medicine William Harvey Research Institute Barts and the London School of Medicine and Dentistry

Surgery can and should be survivable

Why measure cardiac output….? Shoemaker WC. Chest 1992

Pulmonary artery catheterisation does not affect outcome

Minimally invasive measurement of cardiac output

Intra-operative Goal Directed Therapy

Fluid challenge

Prof David Bennett Preliminary work: Georges trial

SaO 2  94%, Hb  8-10 g dl -1, Temperature  37  C, Heart rate <100bpm or <20% increase Normal saline at 1.5 ml kg -1 hr -1 SaO 2  94%, Hb  8-10 g dl -1, Temperature  37  C, Heart rate <100bpm or <20% increase Normal saline at 1.5 ml kg -1 hr -1 Maintain mean arterial pressure between 60 and 100 mmHg using GTN or Noradrenaline as required Maintain mean arterial pressure between 60 and 100 mmHg using GTN or Noradrenaline as required Urine output below 0.5 ml kg -1 hr -1 for two hours or two consecutive hourly serum lactate rises (to >2 mmol l -1 ) then reveal cardiac output data to clinical staff Cardiac index  2.5 ml min -1 m -2 then continue current management Fluid challenge with 250 ml boluses of colloid until CVP reaches plateau value for 20 minutes and continue as required Fluid challenge with 250 ml boluses of colloid until stroke volume reaches plateau for 20 minutes and continue as required If DO 2 I < 600 ml min -1 m -2 add dopexamine up to 1.0 µg kg -1 min -1 to reach this goal Fluid challenge with 250 ml boluses of colloid until stroke volume reaches plateau for 20 minutes and continue as required If DO 2 I < 600 ml min -1 m -2 add dopexamine up to 1.0 µg kg -1 min -1 to reach this goal Cardiac index <2.5 ml min -1 m -2 then commence epinephrine

Oxygen delivery in GDT and control groups Pearse et al. Crit Care : R687

Complications in GDT and control groups Pearse et al. Crit Care : R687

Incidence of myocardial injury following post-operative GDT Pearse et al. Cardiovasc Disorders : 10

Peri-op haemodynamic therapies: Systematic reviews

Oesophageal Doppler guided fluid therapy: Complications after major abdominal surgery Abbas S, Hill A. Anaesthesia 2008; 63: 44–51.

Oesophageal Doppler guided fluid therapy: Mortality after major abdominal surgery Abbas S, Hill A. Anaesthesia 2008; 63: 44–51.

Low dose dopexamine and surgical mortality Pearse R et al. Crit Care Med; : Odds ratio = 0.50 (0.3–0.9)

Low dose dopexamine and surgical mortality Gopal S et al. Anaesthesia; : Relative risk = 0.75 (0.5–1.2)

Both analyses support the argument for a large clinical trial Meta-analyses of the effects of dopexamine in major surgery: Do all roads lead to Rome? JJ Pandit

Peri-op haemodynamic therapies: Do we understand how they work?

Preliminary work: Barts & The London

Effect of dopexamine on tissue hypoperfusion due to surgery and endotoxaemia Bangash et al unpublished data

Effect of dopexamine on liver injury due to surgery and endotoxaemia Bangash et al unpublished data

Effect of dopexamine on renal injury due to surgery and endotoxaemia Bangash et al unpublished data

Microvascular flow after major surgery Jhanji S et al. Intensive Care Med 2009; 35:

Effect of flow guided therapy on DO 2 Jhanji et al unpublished data

Effect of flow guided therapy on sublingual microvascular flow Jhanji et al unpublished data

Effect of flow guided therapies on cutaneous microvascular flow Jhanji et al unpublished data

Effect of flow guided therapy on tissue oxygenation Jhanji et al unpublished data

Effect of fluid and inotropes on DO 2 and ScvO 2 Jhanji et al 2009 unpublished data

Peri-operative oxygen cascade Trachea Microcirculation Alveolus Arterial blood Mitochondria PO 2 Vasodilators Goal Directed Therapy CPAP or Ventilation O 2 & Airway maintenance Future agents ?

Optimisation of Peri-operative Cardiovascular Management to Improve Surgical Outcome OPTIMISE Trial

Does the use of minimally invasive cardiac output monitoring to guide intra-venous fluid and low dose inotropic therapy decrease the number of patients who develop complications within 28 days of major gastro-intestinal surgery? Research Question

Participants Major abdominal surgery involving gut Age over 65 years or… Age over 50 years plus high-risk criteria: –Urgent & Emergency surgery –Risk factors for Cardiac or Respiratory disease –Diabetes –Renal impairment

Organisation 12 NHS Trusts in England and Scotland Trial management hosted by ICNARC Sponsor: Queen Mary’s University of London Funder: National Institute for Health Research NIHR portfolio trial

Duration & Location Theatre and Post-Anaesthetic or Critical Care Unit Induction of anaesthesia to six hours post-op Critical care admission not essential

250 ml colloid boluses according to conventional assessment (Central Venous Pressure)‏ 250 ml colloid boluses according to conventional assessment (Central Venous Pressure)‏ 250 ml colloid boluses to achieve sustained rise in Stroke Volume Dopexamine at 0.5 µg/kg/min 250 ml colloid boluses to achieve sustained rise in Stroke Volume Dopexamine at 0.5 µg/kg/min SaO 2  94%, Hb  8 g/dl, Temperature 37  C, Heart rate <100bpm Mean arterial pressure between 60 and 100 mmHg 5% Dextrose at 1 ml/kg/hr SaO 2  94%, Hb  8 g/dl, Temperature 37  C, Heart rate <100bpm Mean arterial pressure between 60 and 100 mmHg 5% Dextrose at 1 ml/kg/hr

Intervention Group 250ml fluid challenges with colloid solution to achieve a sustained 10% rise in stroke volume Dopexamine at fixed rate of 0.5  g/kg/min Reduce dose if patient develops tachycardia Effectiveness trial

Control Group Usual care: 250ml colloid challenges as indicated by conventional clinical assessment (central venous pressure recommended)‏

Choice of iv colloid Pragmatic trial Not possible to restrict fluid selection Available data suggest dose more important

Monitoring Minimally invasive arterial waveform analysis Uncalibrated technology Requires arterial catheter Suitable for conscious patients

Randomisation Web-based Open study group allocation Stratified by… Centre Surgical procedure category Urgency of surgery

Outcome Data Complications (pre-defined criteria)‏ Complications (POMS)‏ Mortality to 180 days (ONS tagging) Duration of hospital stay Critical care free days EQ-5D

Primary outcome measure Difference in the number of patients developing post-operative complications within 28 days following randomisation between study groups

Secondary outcome measures 28 day mortality 180 day mortality POMS morbidity (day 8) Duration of hospital stay Infectious complications Critical care free days Cost effectiveness Healthcare costs

Sample size Reduction in number of patients developing complications from 50% to 37.5% 90% power and 5% Type I error rate 5% 3% cross-over 367 patients per group (734 in total)

Recruitment rate One patient per centre per week 12 centres x 46 weeks = 16 months recruitment + 6 month follow-up = 22 months Expect to commence recruitment late 2009

Protocol ‘violatons’ Incorrect dopexamine dose / not administered Use of dopexamine in control group patient Cardiac output monitoring in control group patient

OPTIMISE Large pragmatic effectiveness trial Major ‘high-risk’ surgery involving the gut Usual care vs ‘Goal directed’ algorithm Open study group allocation Critical care admission optional

Questions..?