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

0 4 8 12 160

2

4

6

8

Right atrial pressure(mmHg)

Ca

rdia

c o

utp

ut

/ V

en

ou

s r

etu

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(lm

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)

Fluid challenge

Prof David Bennett

Preliminary work: Georges trial

SaO2 94%, Hb 8-10 g dl-1, Temperature 37 C, Heart rate <100bpm or <20% increase

Normal saline at 1.5 ml kg-1hr-1

SaO2 94%, Hb 8-10 g dl-1, Temperature 37 C, Heart rate <100bpm or <20% increase

Normal saline at 1.5 ml kg-1hr-1

Maintain mean arterial pressure between 60 and 100 mmHgusing GTN or Noradrenaline as required

Maintain mean arterial pressure between 60 and 100 mmHgusing GTN or Noradrenaline as required

Urine output below 0.5 ml kg-1hr-1 for two hours or two consecutive hourly serum lactate rises (to >2 mmol l-1) then reveal cardiac output data to clinical staff

Urine output below 0.5 ml kg-1hr-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

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 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 DO2I < 600 ml min-1m-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 DO2I < 600 ml min-1m-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

Cardiac index <2.5 ml min-1 m-2 then commence epinephrine

Oxygen delivery in GDT and control groups

Pearse et al. Crit Care 2005 9: R687

0 1 2 3 4 5 6 7 8 9

450

550

650

750ControlGDT

Time (hours)

DO

2I

(ml m

in-1

m-2

)

Total Infection Heart and Lung Other0

15

30

45

60

75

90

ControlGDT

*

**

Nu

mb

er

of

co

mp

lic

ati

on

s

Complications in GDT and control groups

Pearse et al. Crit Care 2005 9: R687

Incidence of myocardial injury following post-operative GDT

Pearse et al. Cardiovasc Disorders 2007 7: 10

0 1 2

0.0

0.5

1.08.5

9.0

Post-operative day

Tro

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nin

T (

g l

-1)

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1.0

1.5

2.0

2.5

3.0

Post-operative day

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; 2008 36: 1323-9.

Odds ratio = 0.50 (0.3–0.9)

Low dose dopexamine and surgical mortality

Gopal S et al. Anaesthesia; 2009 64: 589-94.

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

Preliminary work: Barts & The London

Sham Control Dop 0.5 Dop 1.0 Dop 2.0

0

1

2

3

4

5

6 ****

L

acta

te (

mm

ol/

l)

Sham Control Dop 0.5 Dop 1.0 Dop 2.0

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-10

-5

0

5

* B

ase

exce

ss (

mm

ol/

l)

Effect of dopexamine on tissue hypoperfusion due

to surgery and endotoxaemiaBangash et al. 2009 unpublished data

Sham Control Dop 0.5 Dop 1.0 Dop 2.0

0

50

100

150

200

250******

AL

T (

IU/l

)

Sham Control Dop 0.5 Dop 1.0 Dop 2.0

0

250

500

750 **

AS

T (

IU/l

)

Effect of dopexamine on liver injury due to surgery

and endotoxaemiaBangash et al. 2009 unpublished data

Microvascular flow after major surgery

Jhanji S et al. Intensive Care Med 2009; 35: 671-7.

0 2 4 6 80

1

2

3

* * *

Time after Surgery (Hours)

MF

I

0 2 4 6 8

400

500

600

700

SV

SV plus dopex

Control

**

Time (hours)

DO

2I

ml/

kg/m

in

Effect of flow guided therapy on DO2

Jhanji et al. 2009 unpublished data

0 2 4 6 8

-2

-1

0

1

2

SV

SV plus dopex

Control

*

Time (hours)

P

erfu

sed

ves

sel d

ensi

ty (

n/m

m)

Effect of flow guided therapy on sublingual

microvascular flowJhanji et al. 2009 unpublished data

0 2 4 6 8

40

60

80

100

120

SV

SV plus dopex

Control

*

Time (hours)

Hyp

erae

mic

res

po

nse

(A

U)

Effect of flow guided therapies on cutaneous

microvascular flowJhanji et al. 2009 unpublished data

0 2 4 6 8

-1

0

1

2

3

SV

SV plus dopex

Control

**

Time (hours)

PtO

2 (k

Pa)

Effect of flow guided therapy on tissue

oxygenationJhanji et al. 2009 unpublished data

Peri-operative oxygen cascade

Trachea

Microcirculation

Alveolus

Arterial blood

Mitochondria

PO2

Vasodilators

Goal Directed Therapy

CPAP or Ventilation

O2 & 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)

ml colloid boluses according 250

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

SaO2 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

SaO2 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..?