Paper: Nielsen FM et al. Lower vs higher oxygenation target and days alive without life support in COVID-19. The HOT-COVID Randomized Controlled Trial. JAMA 2024. PMID: 38501214
Clinical Question: In COVID-19 patients with severe hypoxemia, should clinicians be targeting a higher (90 mm Hg) or lower (60 mm Hg) PaO2?
Population: Adult patients (> 18 years of age) admitted to the ICU with COVID-19 and severe hypoxemia (defined as receiving supplemental O2 with a flow rate of at least 10L/min or receiving mechanical ventilation or non-invasive ventilation.
Intervention: Target PaO2 = 60 mm Hg
Control: Target PaO2 = 90 mm Hg
Outcome (primary): Absolute number of days without life support in 90 days defined as the absence of mechanical ventilation, circulatory support, or kidney replacement.
Outcomes (secondary):
- 90-day all-cause mortality.
- Adverse events in the ICU within 90 days (new shock, cerebral ischemia, myocardial infarction, or intestinal ischemia).
- Absolute number of days alive and out of hospital in 90 days.
Design: Multicenter, multinational, non-blinded, parallel-group randomized controlled trial.
Exclusion: Patients who could not undergo randomization within 12 hours of ICU admission, patients in whom consent could not be obtained, and those previously included in HOT-ICU or HOT-COVID trials.
Results:
Primary results
- 726 of the preplanned 780 patients were enrolled
- Trial stopped early due to slow enrollment in the last year of the study.
- Low O2 Group: n = 365
- Standard O2 Group: N = 361
- Primary outcome data available for 96% (697/726) of patients.
Critical results*Statistically significant difference
| High O2 Group | Low O2 Group | Bootstrapped Mean Difference (95% CI) | Statistically Significant? | ||
| Primary Outcome | Days Alive w/o Support | 72 days | 80 days | 5.8 days (0.2 – 11.5) | YES |
| Risk Ratio (98.6% CI) | |||||
| Secondary Outcomes | 90-day Mortality | 34.7% | 30.2% | 0.83 (0.66 – 1.13) | NO |
| Adverse Events | 51.7% | 47.5% | 0.94 (.79 – 1.13) | NO | |
| Days Alive Out of Hospital | 48 days | 59 days | NO |
Strengths:
- Asks a clinically important question and furthers our understanding of COVID-19.
- Multi-center, international study increases external validity
- Baseline characteristics were well-balanced between groups.
- Minimal exclusion criteria increasing generalizability of the data.
Limitations:
- Study was non-blinded: treating clinicians, patients and family members were all aware of which arm the patient was randomized to.
- This may bias clinicians in terms of interventions rendered to patients.
- There was not a standard protocol instituted for decisions to intubate or wean from therapy.
- Unclear how this bias affects outcomes.
- Investigator initiated enrollment instead of consecutive enrollment.
- Stopped early due to low enrollment
- This may lead to overestimation of the benefit of the intervention.
- Unclear if therapeutic interventions were balanced between the two groups as this data is not provided.
- Did not protocolize the measurement of PaO2 but 4 measurements per day were expected.
- Cohort was older (mostly > 65) and predominantly male which may reduce generalizability.
- Patients lost to follow up were excluded from the analysis.
Discussion
- PaO2 of 60 mm Hg vs 90 mm Hg is essentially an O2 sat difference of 90-92% vs 95-96%.
- Difference in oxygen levels between the control and intervention groups:
- Figure 2 in the manuscript demonstrates that there was a difference in PaO2 and O2 saturation between the two groups.
- The difference, however, was minimal:
- PaO2: 90 mm Hg vs 68 mm Hg
- O2 sat: 96% vs 93%
- With this small difference in oxygenation between groups, it’s important to try to understand why there was a difference in the primary outcome.
- The difference may have been driven by other features of care not discussed here. For instance, additional therapeutics including steroids, JAK inhibitors etc.
- More aggressive care to maintain a higher PaO2 may have been deleterious to patients:
- Mechanical ventilation, prone positioning and transfusions were all higher in the high PaO2 group.
- These interventions may have harmed patients instead of improving outcomes
- The absence of blinding and the non-consecutive enrollment introduce biases that may also influence the outcome.
- Accumulating evidence over the last decade has shown that an O2 sat of > 90% should be targeted in the critically ill and that a sat > 95% doesn’t bestow additional benefit in most circumstances. This data supports current practice of targeting a lower O2 sat.
Author Conclusion: “In adult ICU patients with COVID-19 and severe hypoxemia, targeting a PaO2 of 60mmHg resulted in more days alive without life support in 90 days than targeting a PaO2 of 90mmHg.”
Bottom Line: Targeting a lower PaO2/O2 sat (60 mm Hg/90-92%) resulted in better outcomes than targeting higher PaO2/O2 sat in patients with COVID-19 and severe hypoxemia.
Clinical Take Home Point: Titrate O2 therapy to an O2 sat > 90% but don’t strive for normoxia in COVID-19 patients with severe hypoxemia. Once again we see that less is often more. Interventions directed at increasing PaO2 levels above 60 mm Hg (O2 sat > 90%) did not result in better outcomes and appear to harm patients.
Read More
- REBEL EM: COVID-19 Archive
- EMRAP: Coronavirus 2019 (COVID-19)
Post Peer-Reviewed By: Marco Propersi DO (Twitter/X: @marco_propersi)
