Normal Oxygenation Versus Hyperoxia in the Intensive Care Unit (ICU) (OXYGEN-ICU)

Giradis. JAMA 2016; published on-line October 2016. doi:10.1001/jama.2016.11993

Clinical Question

In critically ill adults, does conservative oxygen therapy compared to liberal oxygen therapy reduce mortality?

Design

Randomised controlled trial

Computerised random number generator

Allocation concealment maintained with use of sequentially numbered, closed, opaque envelopes

Non-blinded

Sample size calculation: 660 patients required to detect and absolute difference in mortality of 6% from a baseline of 23%, with a false negative rate of 20% and a false positive rate of 5% Study stopped after unplanned interim analysis following earthquake that led to reduction in study hospital beds and low recruitment

Modified intention-to-treat analysis Patients excluded if withdrew consent (n=2), lack of data during ICU stay/did not receive at least 1 arterial blood gas analysis per day (n=9), ICU stay <72 hours (n=35)

Intention-to-treat analysis also performed on all randomised patients excluding those that withdrew consent

Setting

Single medical-surgical ICU of University Hospital, Italy

Data collected March 2010 – October 2012

Population

Inclusion criteria: Aged ≥18 Admitted to ICU with expected length of stay of ≥72 hours

Exclusion criteria: Pregnancy ICU readmission Decision to withhold life sustaining treatment Immunosupression or neutropenia ARDS with P/F ratio <150 Acute decompensation of COPD Enrollment in another study

480 patients randomised, of whom 434 analysed in modified intention-to-treat population

Intervention

Conservative oxygen therapy: Target SpO2 94%-98% (n=236) Lowest possible FiO2 to maintain PaO2 of 70-100mmHg During intubation, airway suction, and hospital transfer patients only received supplemental oxygen if SpO2 <94%



Control

Standard oxygen therapy: Target SpO2 97%-100% (n=244) FiO2 of at least 0.4, allowing PaO2 of up to 150mmHg Patients received FiO2 of 1.0 during intubation, airway suction, hospital transfer



Comparing baseline characteristics in conservative vs. conventional group:

Age (median): 63 vs. 65

Surgical admission: 64% vs. 61%

Respiratory failure: 56% vs. 59.%

Mechanical ventilation: 66% vs. 68%

Shock: 31% vs. 33%

Liver failure: 19% vs. 21%

Renal failure: 15% vs. 16%

Infection: 38% vs. 40%

Simplified Acute Physiology Score II (median): 37 vs. 39

Comparing oxygen control in conservative vs. control group (for modified intention to treat population):

Median FiO2 was significantly lower (p<0.001) 0.36 (IQR 0.30-0.40) vs. 0.39 (IQR 0.35-0.42)

Median PaO2 was significantly lower (p<0.001) 87mmHg (IQR 79-97) vs. 102mmHg (IQR 88-116)



Outcome

Primary outcome: ICU mortality – significantly lower in conservative oxygen group 11.6% vs. 20.2% (Absolute risk reduction [ARR] 8.6%, 95% C.I. 1.7%-15%, p=0.01) Number needed to treat 12 Fragility index 3 patients

Secondary outcomes: comparing conservative vs. conventional group New organ failure during ICU stay Any new organ failure: no significant difference 19% vs. 25.7%, p=0.09 Respiratory failure: no significant difference 6.5% vs. 6.4% Shock: significantly lower in conservative group 3.7% vs. 10.6%, p=0.006 Fragility index 4 patients Liver failure: significantly lower in conservative group 1.9% vs. 6.4%, p=0.02 Fragility index 1 patient Renal failure: no significant difference 12% vs. 9.6%, p=0.42 New infections during ICU stay All new infections: no significant difference 18.1% vs. 22.9% Bacteraemia: significantly lower in conservative group 5.1% vs. 10.1%, p=0.049 Fragility index 0 patients

Post-hoc analysis Hospital mortality – significantly lower in conservative oxygen group 24.2% vs. 33.9% (ARR 9.9%, 95% C.I. 1.3%-18.2%, p=0.03) Mechanical ventilation free hours (median) – significantly higher in conservative oxygen group 72 vs. 48, p=0.02

Analysis of intention-to-treat population yielded results similar to those of modified intention-to-treat population with regard to primary and secondary outcomes

Authors’ Conclusions

For critically ill patients with an ICU length of stay of >72 hours, a conservative vs. a conventional protocol for oxygen therapy resulted in a lower ICU mortality

Strengths

Randomised control trial

Reporting of intention-to-treat analysis as well as modified intention-to-treat analysis

Clear difference achieved between median PaO2 for conservative and conventional groups

Weaknesses

Single centre

Non-blinded

Unplanned early termination of study – this is known to increase the likelihood of effect overestimation

Baseline imbalances in study population, favouring the conservative oxygen therapy group

The results had a low fragility index, meaning that if the outcomes had been different for a few patients, then the results reported would have no longer been statistically significant

The Bottom Line

This single centre under powered study found that for critically ill patients a conservative, compared with a conventional, oxygen strategy resulted in a dramatic mortality benefit. As the authors state, a further multi-centre study is needed to confirm these findings. I hope that future trials also investigate the use of permissive hypoxia, which this trial did not investigate. Whilst awaiting for these trials I will avoid hyperoxia.

External Links

Metadata

Summary author: David Slessor

Summary date: 13.10.2016.

Peer-review editor: Duncan Chambler