Breakfast club

John Slattery

9/6/17

The CLOSE trial

Rationale • Oxygenation

o No RCTs investigate the effects of different oxygenation targets during MV

o Conventionally liberal O2 - based on normal physiological values & the

belief that it is safe

o Increasing recognition of harm from hyperoxia

• Aim o Obtain preliminary data on safety of conservative oxygenation to inform

the design of subsequent larger trials

• Hypothesis o Conservative oxygen therapy is feasible on ITU in mechanically ventilated

patients

Methods • Pilot RCT

• Prospective

• Multicentre – 4 university affiliated multidisciplinary ITUs o Australia

o New Zealand

o France

• Randomised

• Parallel groups

• Informed consent from patient/legal surrogate

• Human research & ethics committee approval

• Monitored by independent board

Methods • Inclusion criteria

o ITU patients ≥ 18 years

o Invasive MV for < 24 hours

o Expected MV for ≥ 24 hours

• Exclusion criteria o Pregnancy

o Imminent risk of death

o “Treating clinician lacked equipoise for the patient to be enrolled”

• Randomisation o Computer generated permuted blocks – opaque sealed envelopes

• Nurse titrated FiO2 (0.21 – 0.8) to achieve SpO2 o Conservative = 88-92%

o Liberal = ≥ 96%

• Ventilator settings & O2 parameters recorded 4° for 7 days

Methods • Primary endpoints

o Mean AUC for SpO2, SaO2, PaO2 & FiO2 on days 0-7

• Secondary endpoints o Sequential Organ Failure Assessment score

o PaO2/FiO2

o New ARDS

o Creatinine

o Incidence of haemodynamic instability (arrest/≥ 2 vasopressors/inotropes)

o Vasopressor free days

o Arrhythmia free days

o Ventilator free days until day 28

o ITU mortality

o 90 day mortality

Results • Median 6% time off

target

• Conservative – 14%

• Liberal – 3%

Conservative 1% Liberal 0.3%

Conservative 4% Liberal 22%

Results • More time at FiO2 0.21 in conservative arm

• More frequent ABGs in conservative arm

• No difference in: o Ventilator parameters (VT, MV, PEEP, PPEAK)

o Net fluid balance

o Mean Hb/transfusions

• % time on mandatory ventilation (OR 0.36) o Conservative 34%

o Liberal 46%

Results

Results Adjusted

hazard ratio for

death by day

90 in

conservative

arm as

compared to

liberal arm =

0.77 (95% CI

0.4-1.5, P=0.44)

Discussion • Confirmed treatment feasibility – separation in

oxygenation measures

• No significant difference in secondary endpoints –

new organ dysfunction/mortality

• No harm from conservative oxygenation

• Less vasopressor dose with liberal O2 –

vasoconstriction

• Lower use of mandatory MV in conservative O2 -

?earlier attempts to wean patients o No change in duration of MV/ventilator free days

Appraisal • Pros

o Multicentre

o Prospective

o RCT

• Cons o N = 103 (mainly medical)

o Feasibility study - Not powered to test superiority of different O2 strategies or demonstrate safety of conservative O2 (Type 2 error)

o Non-blinded

o Missing endpoints – neurocognitive outcome/delirium

o Ability to alter O2 targets – bias

o “lack of equipoise” – why?

o Did not measure plateau pressures - ?predictor of ARDS outcome

o Mean SpO2 in conservative arm was above target range – FiO2 > 0.21

Conclusion

It could always be worse

Questions?