The #ICUROXtrial has been published today in @NEJM. The 1st author (and our #ICUROXtrial project manager extraordinaire) is @dianemackle
nejm.org/doi/full/10.10…
nejm.org/doi/full/10.10…
This #tweetorial is to highlight what we did, what we found, what I think is means, & what next.
We enrolled 1000 mechanically ventilated adults who were anticipated to require ventilation in ICU beyond the calendar day after randomisation.
Patients were assigned to conservative oxygen therapy or usual oxygen therapy.
The primary end point was days alive and free from mechanical ventilation.
We chose this end point because we reasoned that conservative use of O2 would reduce O2 exposure and thereby diminish pulmonary and systemic oxidative injury leading to an increase in ventilator-free days.
Patients allocated to conservative O2 spent a lot more of their time in ICU breathing air (this should, in theory at least, diminish pulmonary oxidative injury) 
Patients allocated to conservative O2 spent a lot more time in a ‘green zone’ of SpO2 from 91% to 96% where they would not be expected to be exposed to either hypoxaemia or hyperoxaemia (this should, in theory at least, diminish systemic oxidative injury)
Compared with usual oxygen therapy conservative O2 did not statistically significantly alter ventilator-free days [absolute difference of −0.3 days CI, −2.1 to 1.6; P = 0.80)]
At 180 days, the rate of death was higher in the conservative oxygen group than in the usual-oxygen group (35.7% vs. 34.5%), for a relative risk of 1.03 (95% CI, 0.87 to 1.23).
There was substantial heterogeneity in the effect of conservative oxygen therapy on the number of ventilator-free days in patients with suspected hypoxic–ischemic encephalopathy vs others..
In post hoc analyses of the subgroup with suspected HIE performed at 180 days, death was reported in 43% of the conservative-oxygen group and 59% in the usual-oxygen group (relative risk, 0.73; 95% CI, 0.54 to 0.99)
People will say that the liberal arm of ICU-ROX was not liberal enough to show harm. Our aim was not to harm patients; it was to show that more being more conservative with O2 administration than usual benefited patients.
jamanetwork.com/journals/jama/…
It is notable that although the liberal arm of the oxygen-ICU trial was described as more liberal in terms of provision of O2 than our usual care arm, the PaO2 values that were observed with their liberal arm were actually similar to our usual care arm.
It is notable that although the liberal arm of the oxygen-ICU trial was described as more liberal in terms of provision of O2 than our usual care arm, the PaO2 values that were observed with their liberal arm were actually similar to our usual care arm.
While these findings provide a degree of reassurance that the apparent increased mortality risk associated with liberal oxygen therapy in the previous single centre oxygen-ICU trial might represent type 1 error, they are not definitive.
Based on the observed data distribution in ICU-ROX, there is a 46% chance that conservative oxygen therapy increases absolute mortality by more than 1.5% and a 19.3% chance that conservative oxygen therapy decreases absolute mortality by more than 1.5% compared with usual O2.
Clearly, either an increase or decrease in absolute mortality of 1.5% would have profound implications for global public health because oxygen is given to the millions of people around the world requiring mechanical ventilation in ICU every year.
We now plan to conduct #MEGAROX, a multicentre, multinational, randomized clinical trial to compare conservative oxygen therapy with usual oxygen therapy in mechanically ventilated patients who are either non-electively admitted to the ICU or intubated in the ICU.
Assuming a control group mortality rate of 29%, a sample size of 37,860 provides 90% power to detect an absolute mortality difference of 1.5% using a two tailed hypothesis at an alpha of 0.05. We’re going to round it up to 40,000!
An ICU trial of this size has never been attempted and will require a novel approach. Accordingly, rather than collecting study data using case report forms, we plan to use existing national ICU data registries in respective participating countries.
One common criticism of prior multicentre RCTs in ICU patients has been failure to account sufficiently for potential heterogeneity of treatment response.
#ICUROXtrial suggests that in relation to responses to conservative O2, such hetereogeneity is significant and needs to be considered in future research
In the Mega Randomised Registry-embedded OXygen (#MegaROX) trial, subgroups of significant numerical size where a differential effect of oxygen therapy is plausible will be investigated in nested trials that will be conducted within the overall participant sample.
In #MegaROX we plan to adjust randomisation ratios so that patients within such subgroups receive the oxygen therapy regimen associated with the lowest risk of death based on accumulated trial data.
In a sense, this means that every patient in #MegaROX will benefit from the information gained from previous patients. Patients will benefit from trial participation.
If you want to get involved, get in touch. If you have questions or comments about the #ICUROXtrial or #MegaROX, get in touch.
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