icu-rox trial editorial comment rox editorial.pdf · as physicians, we are programmed to react to...
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Laveena Munshi MD, MScAssistant Professor, Critical Care PhysicianInterdepartmental Division of Critical Care MedicineMount Sinai Hospital/University Health NetworkUniversity of Toronto
ICU-ROX TrialEditorial Comment
DISCLOSURE
1. Control group selection
2. Heterogeneity of treatment effect
5 minutes = 2 Points
As physicians we are programmed to react to the rapidly dropping oxygen saturation…
While this response is appropriate, there are many settings in which excess oxygen is administered
indiscriminately for extended periods
Life on earth has learned to adapt to conditions of hypoxia over time
Oscillations in atmospheric oxygen concentrations to at some points as low as 0.10 has selected out species who were not able to survive conditions of
extreme hypoxia
- Berner 2007
It is biologically plausible that humans may be less well equipped to adapt to potential harms induced by
hyperoxia
Local effects of high inspired oxygen therapy:
O2O2
O2
O2
O2
O2
N2
surfactant
Mucociliaryclearance
Tracheo-bronchitis
Aerobic Cellular Metabolism
Reactive Oxygen Species (ROS)
Systemic effects of hyperoxemia:
ROS
ROSROS
ROSROS
Exogenous Stimuli
Oxidative Stress
Cell Damage
Cell Death
Inflammation
Undesirable byproduct of ATP synthesis
Many studies demonstrate an association between excess oxygen use and harm across the acute care
setting over time
1970 1985 1999 2005 2015 20192010 2017
OXYGEN-ICU TRIAL ICU-ROX TRIAL
1. Control group selection
2. Heterogeneity of treatment effect
5 minutes = 2 Points
APPROPRIATE CONTROL GROUP?
“USUAL CARE”
Titrate FiO2 to maintain SpO2 >90%
Do not wean FiO2 lower than 0.30 Oxygen-ICU trial (Control Group - 97-100%)
many of the previous trials (more liberal oxygen strategies)
USUAL CARE =/= LIBERAL OXYGEN
Nurse-led oxygen titration strategy
Recall… “Usual”/Liberal Care:FiO2: ~0.35 (0.34-0.45)/10d
Ontario Snap Shot of Usual Care (cross section)
ICU #1 0.50 (0.42-0.58)
ICU #2 0.40 (0.30-0.60)
ICU #3 0.35 (0.25-0.37)
ICU #4 0.40 (0.30-0.55)
ICU #5 0.40 (0.30-0.50)
ICU Obs Study 0. 53 (0.40-0.59)Panwar et al Obs Study 2013 0.42 (0.41-0.44)
Temporal changes in practice over time?
0 10 20 30 40 50 60 70 80 90 100
Usual O2
Conservative O2
SpO2 <91% SpO2 91-96% SpO2 >96%
Percent of hours in given SpO2 category
62%
25% 75%
75% of time in the ICU, patients had a
saturation >96%
…in 2013
0 10 20 30 40 50 60 70 80 90 100
Usual O2
Conservative O2
SpO2 <91% SpO2 91-96% SpO2 >96%
Percent of hours in given SpO2 category
62%
45%
Is this a sufficient enough of a difference in intervention?
But 45% of the hours of the usual O2 arm was also
in the “green zone”
55%
RECALL: conservative O2 target saturation“green zone” was a SpO2 of 91-96%
Only 55% of time in the ICU, patients had
a saturation >96%
…in 2019
1. Control group selection
2. Heterogeneity of treatment effect
5 minutes = 2 Points
Heterogeneity of treatment effect was noted
0%10%20%30%40%50%60%70%80%90%
100%
Entire Cohort Hypoxic IschemicEncephalopathy
Sepsis
Mortality According to Subgroups
Usual Conservative
Potential benefit from conservative oxygen in
hypoxic-ischemic encephalopathy
Potential harm from conservative oxygen in sepsis cohort (in press)
*limited to trials of intubated patients
Mild Hyperoxia Moderate Hyperoxia Extreme Hyperoxia
Wound Healing
Vasodilatory Shock Reversal
Surgical Site Infection*
Traumatic Brain Injury
Stroke
Sepsis?
Post-cardiac arrest
Third trimester pregnancy
ICU patients, MV patients
Higher severity of illness
Certainty of evidence
Evidence suggests benefit of hyperoxia
Evidence unclear
Evidence suggests harm of hyperoxia
No Evidence of harm
ICU patients, MV patients
Hypothesis: Perhaps excess oxygen likely has a differential impact across different conditions
Severity of IllnessIntensity of Exogenous
Stimuli
Perhaps there is no specific threshold of oxygen that induces harm but it changes in the face of severity of illness/underlying condition
Increasing severity of illness likely important factor driving whether oxygen use induces
harm
How has the ICU-ROX trial advanced our knowledge and will it change my practice in the ICU?
• In a setting where usual care involves close titration of oxygen, a more conservative oxygen approach is not superior to usual care
• Usual care likely varies around the world• Usual care=/= hyperoxia and liberal/excess oxygen
• In units that use a more liberal strategy it would be incorrect to conclude that their liberal strategy is safe
How has the ICU-ROX trial advanced our knowledge and will it change my practice in the ICU?
• There are important subgroups that need to be further delineated
• A conservative oxygen approach is not associated with increased adverse events/harm (pending sepsis results)
• I will aim to maintain a conservative oxygen strategy across hypoxic-ischemic encephalopathy
• I will continue to avoid hyperoxemia/hyperoxia• I will always aim to use the lowest FiO2 to maintain SpO2 >90%
Severity of illness across the population
..last point…
Was the population “Sick enough”?
N2
surfactant
with oxygen tension
Aerobic Cellular Metabolism
Undesirable byproduct of ATP synthesis
Reactive Oxygen Species (ROS)
RECALL: Systemic effects of hyperoxemiamay require an exogenous stimuli
ROSROS
ROS
ROSROS
Exogenous StimuliMicrobes
ToxinsChemotherapy
RadiationOther pathologic processes
Oxidative Stress
Cell Damage
Cell Death
Inflammation
Pre-specified clinically important “sicker” subgroups:
Hypoxic Ischemic EncephalopathySeptic Shock
PaO2/FiO2 <300
ICU-ROX population “Sicker” than ICU-Oxygen trial 2/3 mechanically ventilated; 1/3 shock; 20% mortality
Despite no difference seen across the general ICU
population,
outside of hypoxic-ischemic encephalopathy,
Could there be a relationship between mortality and a
increasing severities of illness across “usual care”/liberal
oxygen ?
0
10
20
30
40
50
60
SOFA LOW SOFA LOWMOD
SOFA MOD SOFA MODHIGH
SOFA HIGH
Mortality by Severity of Illness?
Usual Conservative