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

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

• [article] Effect of Conservative vs. Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit
• [further reading] Oxygen in the ICU: Too Much of a Good Thing?
• [further reading] Conservative vs. Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial
• [further reading] Metrics of Arterial Hyperoxia and Associated Outcomes in Critical Care
• [further reading] Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial

Metadata

Summary author: David Slessor
Summary date: 13.10.2016.
Peer-review editor: Duncan Chambler