Oxygen Therapy in ICU- The Circle of Uncertainty

Background 

Clinical practice guidelines give no recommendation for oxygenation targets in adult patients in the ICU owing to sparse evidence.

HOT- ICU Trial

Setting: 35 ICUs in Denmark, Switzerland, Finland, the Nether- lands, Norway, the United Kingdom, and Iceland

Design: Randomized study in permuted blocks. Stratified by center and the presence or otherwise of COPD and hematological malignancy

Study population

Inclusion

Acute respiratory failure, who were receiving at least 10 litres of oxygen per minute in an open system or who had a FiO2 of at least 0.50 in a closed system. Oxygen therapy expected to continue for at least 24 hours.

Exclusion

Patients who could not be randomized within 12 hours of ICU admission

Chronic mechanical ventilation for any reason

Home O2 therapy

Withdrawal of active therapies or death seemed imminent

Pregnancy

CO poisoning, CN– poisoning, methaemoglobinaemia, paraquat poisoning

Previous bleomycin treatment

Organ transplant within current hospital admission

Need for hyperbaric O2

Sickle cell disease

Intervention

PaO2 target of 60 mm Hg, maximum 90 days after randomization

                                                                Vs

PaO2 target of 90 mm Hg, maximum 90 days after randomization

Lowest and the highest PaO2 in predefined 12-hour intervals, along with concomitant values of arterial oxygen saturation (SaO2) and FiO2. Deviation by more than 7.5 mm Hg accepted only if FiO2 0.21 or 1.0. Oxygen therapy or ventilator support (invasive or non-invasive) was according to physician judgement. Try to maintain the SaO2 level for the assigned PaO2. Followed up 90 days.

Statistics

Sample size: Assumed 90-day mortality of 25% in the higher-oxygenation group. 2928 patients for 90% power to detect a 5 percentage absolute reduction in mortality at 90 days.

Analysis by intention to treat

4192 evaluated /1264 excluded – 

1441 in Conservative O2 Group Vs 1447 in Liberal O2 Group

Baseline

• Pneumonia: 57%
• ARDS: 12%
• Intubated, ventilated: 60%
• P/F: 118

Separation between groups

• PO2: 70.8 vs. 93.3
• FiO2: 0.43 vs. 0.56
• SaO2: 93. vs. 96%

Results

Higher-oxygenation group, median (IQR): 93.3 (87.1–98.7)

(IQR): 70.8 (66.6–76.5)

Primary outcome

All-cause mortality within 90 days of randomization

Lower vs. higher oxygen groups: 618 of 1441 patients (42.9%) vs.  613 of 1447 patients (42.4%)

Secondary outcomes

The median percentage of days alive without life support, (no mechanical ventilation, renal-replacement therapy, or vasopressor or inotrope infusion) at 90 d follow-up

Percentage of days discharged from hospital and alive at the 90-day follow-up

Number of patients with serious adverse events (new-onset shock, myocardial ischemia, cerebral ischemia, or intestinal ischemia)

Secondary analysis of the primary outcome based on age, type of ICU admission, presence or absence of metastatic cancer, and the SOFA score

Results were similar in the analysis after adjustment for baseline factors; the hazard ratio was similar as well after adjustment for stratification variables

Subgroup analysis of the primary outcome:

presence or absence of shock at randomization, invasive mechanical ventilation, COPD, traumatic brain injury, and post-cardiac arrest, type of ICU admission (medical, elective surgery, or emergency surgery): 

The trend towards benefit in favour of liberal O2 therapy except for COPD group.

Limitations

No blinding of physicians (outcome assessors were blinded)

A fairly large number of exclusions (30% of screened)

Would you really expect a difference between 70- and 90-mm Hg? (the target PO2 was 60)

Would lower PO2 levels be acceptable and safe (permissive hypoxia)

Much higher mortality than expected

LOCO2: 55-70 vs. 90-105 (greater separation); ventilated patients with ARDS. When the study was stopped, the between-group difference in the primary outcome of mortality at day 28, but there was significantly higher 90-day mortality in the lower-oxygenation group. Mesenteric ischemia in 5 patients

In the 332 patients with cardiac arrest in the present study, there was no clear between-group difference in 90-day mortality

The IOTA meta-analysis – 

In favour of Conservative O2 therapy

Conclusions

1. O2 Therapy in ICU is complex
2. One size fits all won’t work in terms of setting oxygen targets
3. Different subgroups need to be treated differently.
4. Need large RCTS targeting specific subgroups.
5. Need consensus on definitions of conservative vs liberal O2 therapy for consistency and better interpretation of future research.