Oxygen Targets in the ICU: Navigating Between Hypoxemia and Hyperoxia – Insights from ICU-ROX, HOT-ICU, and BOX Trials

Dr Neeraj Manikath , claude.ai

Abstract

Background: Oxygen therapy remains one of the most ubiquitous interventions in critical care, yet optimal targeting strategies continue to evolve. Recent landmark trials have challenged traditional liberal oxygen approaches, providing evidence-based guidance for contemporary practice.

Objective: To synthesize findings from major randomized controlled trials examining oxygen targets in critically ill patients, with particular emphasis on ICU-ROX, HOT-ICU, and BOX trials, and provide practical guidance for clinicians.

Methods: Comprehensive review of pivotal oxygen targeting trials, mechanistic studies, and current guidelines, with critical analysis of study methodologies and clinical implications.

Results: Conservative oxygen strategies (SpO2 88-92% or PaO2 55-70 mmHg) appear non-inferior to liberal strategies in most ICU populations, with potential mortality benefits in specific subgroups. However, optimal targets may vary by patient population, illness severity, and clinical context.

Conclusions: A nuanced, individualized approach to oxygen targeting is emerging, moving away from the "more is better" paradigm toward precision oxygen therapy.

Keywords: Oxygen therapy, mechanical ventilation, critical care, hyperoxia, hypoxemia, ICU outcomes

Introduction

Oxygen therapy represents the most commonly administered drug in intensive care units worldwide, yet its optimal dosing remains surprisingly contentious. For decades, the prevailing wisdom favored liberal oxygen administration under the assumption that "more oxygen is safer than less." However, mounting evidence suggests that hyperoxia may be as detrimental as hypoxemia, fundamentally challenging our approach to oxygen management in critically ill patients.

The past decade has witnessed a paradigm shift driven by landmark randomized controlled trials that have systematically examined conservative versus liberal oxygen targeting strategies. Three pivotal studies—ICU-ROX, HOT-ICU, and BOX—have provided crucial insights into optimal oxygen management, each contributing unique perspectives to our understanding of oxygen toxicity and therapeutic targeting.

This review synthesizes the current evidence base, examines the biological mechanisms underlying oxygen toxicity, and provides practical guidance for implementing evidence-based oxygen strategies in contemporary critical care practice.

Historical Context and Rationale for Conservative Oxygen Therapy

The Evolution of Oxygen Thinking

Historically, oxygen administration followed a "more is better" philosophy rooted in the fundamental understanding that oxygen delivery is essential for cellular metabolism. Early critical care practice emphasized maintaining supranormal oxygen saturations (>95%) to ensure adequate tissue oxygenation, particularly in critically ill patients with compromised cardiovascular function.

This liberal approach was reinforced by several factors:

Fear of undetected hypoxemia
Intermittent monitoring capabilities
Misconception that excess oxygen is harmlessly eliminated
Focus on oxygen delivery rather than utilization

Emerging Concerns About Hyperoxia

The recognition of oxygen toxicity began shifting clinical thinking in the 2000s. Observational studies consistently demonstrated associations between hyperoxia and adverse outcomes across various populations:

Mechanistic Insights:

Oxidative Stress: Excess oxygen generates reactive oxygen species (ROS) that overwhelm cellular antioxidant defenses
Vasoconstriction: Hyperoxia causes coronary, cerebral, and systemic vasoconstriction
Inflammatory Response: Oxygen toxicity triggers inflammatory cascades and endothelial dysfunction
Mitochondrial Dysfunction: Excessive oxygen impairs mitochondrial efficiency and ATP production

Clinical Observations:

Increased mortality in hyperoxic cardiac arrest patients
Worse neurological outcomes following stroke with high oxygen exposure
Association between hyperoxia and acute lung injury progression
Increased ICU mortality in patients with prolonged hyperoxia exposure

Landmark Trials: Design, Findings, and Implications

ICU-ROX Trial (2020)

Design and Population: The Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) was a pragmatic, multicenter, parallel-group, open-label randomized controlled trial conducted across 21 ICUs in Australia and New Zealand.

Key Design Elements:

Population: 1,000 mechanically ventilated adults expected to receive invasive ventilation for ≥24 hours
Intervention: Conservative oxygen (SpO2 88-92%) vs. usual care (no upper limit specified)
Primary Outcome: Ventilator-free days at day 28
Follow-up: 180 days for mortality

Results and Clinical Impact:

Primary Findings:

Ventilator-free days: No significant difference (20.5 vs. 20.8 days, p=0.82)
ICU mortality: 16.6% (conservative) vs. 20.2% (usual care), RR 0.82 (95% CI 0.64-1.05)
Hospital mortality: 24.2% vs. 30.4%, RR 0.80 (95% CI 0.66-0.98, p=0.03)
180-day mortality: 30.4% vs. 34.7%, RR 0.88 (95% CI 0.73-1.05)

Key Secondary Outcomes:

Shock occurrence: 59% vs. 65% (p=0.07)
Liver failure: 4.8% vs. 8.8% (p=0.01)
Cognitive function at 180 days: No significant difference

Clinical Pearls from ICU-ROX:

🔹 The "Sweet Spot" Concept: Targeting SpO2 88-92% appears safe and may confer mortality benefit 🔹 Organ Protection: Conservative oxygen showed hepatoprotective effects and reduced shock incidence 🔹 Implementation Success: Achieved excellent protocol adherence (median SpO2: 91% vs. 96%) 🔹 Heterogeneity of Effect: Benefits appeared more pronounced in certain subgroups

HOT-ICU Trial (2021)

Design Innovation: The Handling Oxygenation Targets in the ICU (HOT-ICU) trial employed a 2×2 factorial design, simultaneously examining oxygen targets and temperature management in comatose patients after out-of-hospital cardiac arrest.

Study Characteristics:

Population: 789 comatose adults after out-of-hospital cardiac arrest
Design: Randomized, controlled, assessor-blinded, 2×2 factorial trial
Oxygen Arms: Restrictive (8-10 kPa/60-75 mmHg PaO2) vs. Liberal (13-15 kPa/98-113 mmHg PaO2)
Primary Outcome: Death or severe disability (CPC 3-4) at 90 days

Distinctive Methodological Features:

Precise PaO2 targeting: Unlike SpO2-based studies, HOT-ICU used arterial blood gas targets
Narrow target ranges: Ensured clear separation between groups
Post-cardiac arrest population: Addressed oxygen sensitivity in vulnerable population
Factorial design: Examined interaction effects with temperature management

Results and Implications:

Primary Outcomes:

Death or severe disability: 54.8% (restrictive) vs. 54.1% (liberal), RR 1.01 (95% CI 0.94-1.09)
90-day mortality: 48.7% vs. 47.6%, RR 1.02 (95% CI 0.92-1.14)

Protocol Performance:

Excellent target achievement: median PaO2 9.0 kPa (restrictive) vs. 14.0 kPa (liberal)
No significant differences in secondary outcomes
No interaction between oxygen and temperature interventions

Clinical Insights from HOT-ICU:

🔹 PaO2 vs. SpO2 Targeting: Direct PaO2 measurement may be superior for precise oxygen management 🔹 Population Specificity: Post-cardiac arrest patients may have unique oxygen requirements 🔹 Safety of Lower Targets: PaO2 60-75 mmHg appears safe even in vulnerable populations 🔹 Implementation Precision: Tight glycemic-style control is achievable for oxygen therapy

BOX Trial (2022)

Unique Design Elements: The Bleeding and Oxygenation in Cardiac Surgery (BOX) trial specifically examined oxygen targets in cardiac surgical patients, representing a more homogeneous population with predictable physiological perturbations.

Study Framework:

Population: 2,463 adults undergoing cardiac surgery with cardiopulmonary bypass
Intervention: Restrictive oxygen (FiO2 0.35 targeting SpO2 88-92%) vs. Liberal oxygen (FiO2 0.80 targeting SpO2 ≥95%)
Setting: Perioperative period from anesthesia induction through ICU stay
Primary Outcome: Composite of death, myocardial infarction, stroke, or acute kidney injury requiring dialysis at 30 days

Novel Aspects:

Perioperative focus: Extended oxygen management from OR through ICU
Homogeneous population: Cardiac surgery patients with predictable physiology
Composite primary endpoint: Addressed multiple organ systems
Industrial medicine approach: Systematic protocol implementation

Results and Clinical Significance:

Primary Findings:

Primary composite outcome: 16.3% (restrictive) vs. 17.2% (liberal), RR 0.95 (95% CI 0.83-1.09, p=0.45)
Individual components:
- Death: 1.8% vs. 2.1%
- Myocardial infarction: 11.5% vs. 12.1%
- Stroke: 1.4% vs. 1.2%
- Acute kidney injury requiring dialysis: 2.9% vs. 3.3%

Secondary Outcomes:

ICU length of stay: No significant difference
Hospital length of stay: Median 7 days in both groups
Mechanical ventilation duration: No significant difference

BOX Trial Clinical Pearls:

🔹 Surgical Population Safety: Conservative oxygen is safe in cardiac surgical patients 🔹 Perioperative Implementation: Oxygen protocols can span OR-ICU continuum 🔹 Composite Outcomes: No single organ system showed significant benefit or harm 🔹 Real-world Feasibility: Large-scale implementation is achievable with systematic approaches

Mechanisms of Oxygen Toxicity: Understanding the Biology

Cellular and Molecular Mechanisms

Reactive Oxygen Species (ROS) Generation: Hyperoxia increases intracellular oxygen concentration, overwhelming the capacity of cytochrome c oxidase and leading to electron leakage from the mitochondrial electron transport chain. This process generates superoxide anions (O2•−), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH), which collectively cause oxidative damage to cellular components.

Antioxidant System Overwhelm: Normal cellular antioxidant mechanisms include:

Enzymatic defenses: Superoxide dismutase, catalase, glutathione peroxidase
Non-enzymatic scavengers: Vitamin E, vitamin C, glutathione
Metal chelators: Transferrin, ceruloplasmin

Hyperoxia saturates these protective systems, leading to unopposed oxidative stress.

Organ-Specific Toxicity Mechanisms

Pulmonary Toxicity:

Alveolar epithelial damage: Direct ROS injury to pneumocytes
Surfactant dysfunction: Oxidative modification of surfactant proteins
Inflammatory cascade: Activation of NF-κB pathways
Fibroblast proliferation: Progressive pulmonary fibrosis

Cardiovascular Effects:

Coronary vasoconstriction: Direct oxygen effect on vascular smooth muscle
Reduced cardiac output: Decreased venous return due to peripheral vasoconstriction
Myocardial stunning: ROS-mediated contractile dysfunction
Arrhythmogenesis: Altered calcium handling and ion channel function

Neurological Impact:

Cerebral vasoconstriction: Reduced cerebral blood flow despite increased oxygen content
Seizure threshold reduction: Hyperoxia lowers seizure threshold
Neuroinflammation: Microglial activation and cytokine release
Blood-brain barrier disruption: Enhanced permeability and edema formation

Renal Consequences:

Afferent arteriole constriction: Reduced renal blood flow
Tubular epithelial damage: Direct ROS injury to nephrons
Inflammatory infiltration: Interstitial nephritis
Altered autoregulation: Impaired pressure-natriuresis relationship

Clinical Implementation: Practical Oxygen Management

Target Selection Framework

Risk Stratification Approach:

High-Risk Populations (Consider Lower Targets):

Post-cardiac arrest patients
Acute coronary syndromes
Traumatic brain injury
Patients with COPD exacerbations
Septic shock with organ dysfunction

Moderate-Risk Populations (Standard Conservative Targets):

General medical ICU admissions
Post-operative patients
Pneumonia without ARDS
Most mechanically ventilated patients

Special Considerations (Individualized Approach):

Carbon monoxide poisoning
Severe anemia (Hgb <7 g/dL)
Cyanotic heart disease
Pulmonary hypertension
Pregnancy

Monitoring Strategies

SpO2 vs. PaO2 Considerations:

SpO2 Advantages:

Continuous, non-invasive monitoring
Real-time feedback for titration
Practical for routine implementation
Cost-effective approach

PaO2 Advantages:

More precise assessment
Accounts for hemoglobin variants
Useful in severe illness
Research standard

Clinical Pearl: For most ICU patients, SpO2 targeting is practical and effective, with PaO2 reserved for complex cases or research protocols.

Titration Protocols

Step-by-Step Oxygen Management:

Initial Assessment:
- Patient risk stratification
- Baseline oxygenation status
- Hemodynamic stability
- Neurological function
Target Setting:
- Conservative: SpO2 88-92% or PaO2 55-70 mmHg
- Liberal: SpO2 ≥94% or PaO2 >80 mmHg
- Institutional protocol alignment
Monitoring Frequency:
- Continuous SpO2 monitoring
- ABG q6-12h initially
- Clinical assessment q4h
- Trending analysis
Titration Guidelines:
- FiO2 adjustments in 0.1 increments
- PEEP optimization concurrent
- Reassess after 30-60 minutes
- Document rationale for deviations

Special Populations and Clinical Scenarios

Post-Cardiac Arrest Patients

Pathophysiological Considerations: Post-cardiac arrest syndrome involves global ischemia-reperfusion injury, making these patients particularly susceptible to hyperoxia toxicity. The "post-resuscitation disease" includes:

Myocardial dysfunction
Systemic ischemia-reperfusion response
Brain injury
Precipitating pathology

Evidence-Based Recommendations:

Target SpO2 88-92% or PaO2 60-75 mmHg
Avoid hyperoxia in first 24-48 hours
Monitor neurological function closely
Consider neuroprotective protocols

ARDS and Acute Lung Injury

Oxygen Management Complexity: ARDS patients present unique challenges due to:

Severe hypoxemia
V/Q mismatch
Risk of ventilator-induced lung injury
Need for higher PEEP strategies

Balanced Approach:

Prioritize lung-protective ventilation
Accept permissive hypoxemia (SpO2 88-90%)
Optimize PEEP before increasing FiO2
Consider prone positioning
Monitor for signs of oxygen toxicity

Clinical Hack: Use the "FiO2/PEEP ladder" – increase PEEP before FiO2 when SpO2 <88%, decrease FiO2 before PEEP when SpO2 >92%.

Septic Shock

Oxygen Delivery vs. Utilization: Sepsis creates a complex scenario where:

Oxygen delivery may be impaired (cardiac dysfunction, anemia)
Oxygen utilization is altered (mitochondrial dysfunction)
Inflammatory response modulates oxygen toxicity
Hemodynamic instability affects titration

Management Strategy:

Focus on perfusion optimization first
Conservative oxygen targets once hemodynamically stable
Monitor ScvO2 or SvO2 when available
Consider lactate trends as metabolic marker

Controversial Areas and Future Directions

Unresolved Questions

Population-Specific Targets:

Optimal targets for specific disease states
Age-related considerations (pediatric vs. geriatric)
Genetic factors affecting oxygen sensitivity
Comorbidity-adjusted targeting

Timing and Duration:

Optimal duration of conservative oxygen therapy
Transition strategies from ICU to ward
Long-term neurological outcomes
Weaning protocols for oxygen-dependent patients

Technology Integration:

Closed-loop oxygen delivery systems
Artificial intelligence-guided titration
Advanced monitoring (tissue oximetry, microdialysis)
Predictive analytics for oxygen needs

Emerging Research Areas

Precision Oxygen Medicine: Future approaches may incorporate:

Genetic markers of oxygen sensitivity
Biomarkers of oxidative stress
Real-time tissue oxygenation monitoring
Individualized oxygen-hemoglobin dissociation curves

Novel Therapeutic Strategies:

Antioxidant co-therapy during hyperoxia
Intermittent hypoxia protocols
Oxygen carrier alternatives
Targeted oxygen delivery systems

Clinical Pearls and Practical Wisdom

🔹 The "Goldilocks Principle" of Oxygen Therapy

Just as Goldilocks sought porridge that was "just right," optimal oxygenation requires finding the sweet spot between the dangers of hypoxemia and hyperoxia. This typically falls in the SpO2 88-92% range for most ICU patients.

🔹 The "Oxygen Debt vs. Oxygen Toxicity" Balance

Consider oxygen like a medication with both therapeutic effects and dose-dependent toxicity. The goal is to provide sufficient oxygen to meet metabolic demands while avoiding supraphysiological levels that cause harm.

🔹 The "Less is More" Philosophy

Moving from "normoxia" (SpO2 >95%) to "appropriate oxemia" (SpO2 88-92%) represents a fundamental shift in critical care thinking. Lower oxygen levels are often safer and may improve outcomes.

🔹 The "Time-Dose Relationship"

Both the magnitude and duration of hyperoxia matter. Brief periods of higher FiO2 during procedures may be acceptable, but sustained hyperoxia should be avoided.

🔹 Implementation Success Factors

Staff education and buy-in
Clear protocols and order sets
Regular monitoring and feedback
Quality improvement integration
Leadership support

Oysters (Common Misconceptions)

❌ Myth: "Higher oxygen is always safer"

Reality: Hyperoxia can be as harmful as hypoxemia. Conservative oxygen targets are safe and may improve outcomes.

❌ Myth: "SpO2 >95% is always the goal"

Reality: SpO2 88-92% is appropriate for most mechanically ventilated patients and may be optimal.

❌ Myth: "Oxygen toxicity only affects the lungs"

Reality: Hyperoxia causes systemic toxicity affecting cardiovascular, neurological, and renal systems.

❌ Myth: "More sick patients need more oxygen"

Reality: Critically ill patients may be more susceptible to oxygen toxicity, not less.

❌ Myth: "Conservative oxygen increases mortality risk"

Reality: Multiple trials show conservative oxygen is safe and may reduce mortality.

Evidence-Based Recommendations

Class I Recommendations (Strong Evidence)

Target SpO2 88-92% for most mechanically ventilated ICU patients (Level of Evidence: A)
Avoid routine use of SpO2 >94% unless specific clinical indications exist (Level of Evidence: A)
Implement systematic oxygen protocols with regular monitoring and titration (Level of Evidence: B)
Use conservative oxygen targets in post-cardiac arrest patients (Level of Evidence: B)

Class IIa Recommendations (Moderate Evidence)

Consider PaO2 60-75 mmHg targets for precise oxygen management in complex cases (Level of Evidence: B)
Prioritize PEEP optimization over FiO2 increases in patients with ARDS (Level of Evidence: B)
Monitor for signs of oxygen toxicity during prolonged mechanical ventilation (Level of Evidence: C)

Class IIb Recommendations (Weak Evidence)

Individualize oxygen targets based on patient-specific factors and comorbidities (Level of Evidence: C)
Consider tissue oxygen monitoring in selected high-risk patients (Level of Evidence: C)

Quality Improvement and Implementation

Systematic Implementation Approach

Phase 1: Preparation

Stakeholder engagement
Protocol development
Staff education
Technology optimization

Phase 2: Pilot Implementation

Small-scale testing
Feedback collection
Protocol refinement
Outcome monitoring

Phase 3: Full Implementation

Institution-wide rollout
Ongoing education
Quality metrics tracking
Continuous improvement

Key Performance Indicators

Process Measures:

Percentage of time within target SpO2 range
Mean daily FiO2 exposure
Protocol adherence rates
Staff satisfaction scores

Outcome Measures:

ICU mortality
Ventilator-free days
Length of stay
Organ failure rates

Balancing Measures:

Hypoxemia episodes
Code blue events
Unplanned intubations
Patient/family satisfaction

Future Research Priorities

Critical Knowledge Gaps

Optimal targets for specific populations:
- Pediatric patients
- Elderly patients (>75 years)
- Patients with chronic hypoxemia
- Pregnancy and critical illness
Timing and duration questions:
- Optimal length of conservative oxygen therapy
- Transition strategies
- Long-term neurocognitive outcomes
- Weaning protocols
Mechanistic understanding:
- Genetic factors affecting oxygen sensitivity
- Biomarkers of oxygen toxicity
- Tissue-specific oxygen requirements
- Interaction with other therapies
Technology development:
- Automated oxygen delivery systems
- Real-time tissue oxygenation monitoring
- Predictive algorithms
- Point-of-care oxidative stress markers

Ongoing and Planned Trials

Several important trials are currently underway or planned:

Oxy-PICU: Pediatric oxygen targets
O2-ICU: Liberal vs. conservative oxygen in general ICU populations
MEGA-ROX: Large pragmatic trial across multiple countries
Neuro-Ox: Oxygen targets in traumatic brain injury

Conclusions

The landscape of oxygen management in critical care has undergone a dramatic transformation over the past decade. The convergence of evidence from ICU-ROX, HOT-ICU, BOX, and other landmark trials has established that conservative oxygen targeting (SpO2 88-92%) is not only safe but may be superior to liberal strategies in most ICU populations.

This paradigm shift from "normoxia" to "appropriate oxemia" represents more than a simple target adjustment – it embodies a fundamental change in our understanding of oxygen as a drug with both therapeutic benefits and dose-dependent toxicity. The traditional fear of hypoxemia, while still valid, must be balanced against the growing recognition of hyperoxia-induced harm.

The key clinical insights from recent trials can be summarized as:

Conservative oxygen targeting is safe across diverse ICU populations
Mortality benefits may exist with lower oxygen targets
Implementation is feasible with appropriate protocols and monitoring
Individualization remains important based on patient-specific factors
Precision oxygen therapy is emerging as the future standard

As we move forward, the focus should shift from simply asking "how much oxygen?" to "what is the optimal oxygen strategy for this specific patient at this specific time?" This nuanced approach requires integration of patient physiology, disease pathology, treatment goals, and emerging monitoring technologies.

The future of oxygen therapy lies in precision medicine approaches that account for individual patient characteristics, genetic factors, real-time physiological monitoring, and dynamic clinical conditions. Until such sophisticated systems are available, the evidence strongly supports conservative oxygen targeting as the standard of care for most critically ill patients.

For the practicing intensivist, the message is clear: embrace conservative oxygen strategies, implement systematic protocols, monitor carefully, and always remember that in critical care, sometimes less truly is more.

References

ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med. 2020;382(11):989-998.
Jakobsen JC, Wetterslev J, Winkel P, et al. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120.
Schjørring OL, Klitgaard TL, Perner A, et al. Lower or higher oxygenation targets for acute hypoxemic respiratory failure. N Engl J Med. 2021;384(14):1301-1311.
Meyhoff CS, Jorgensen LN, Wetterslev J, et al. Increased long-term mortality after a high perioperative inspiratory oxygen fraction during abdominal surgery: follow-up of a randomized clinical trial. Anesth Analg. 2012;115(4):849-854.
Young PJ, Mackle D, Bellomo R, et al. Conservative oxygen therapy for mechanically ventilated adults with suspected hypoxic ischaemic encephalopathy. Intensive Care Med. 2020;46(12):2411-2422.
Girardis M, Busani S, Damiani E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. JAMA. 2016;316(15):1583-1589.
Panwar R, Hardie M, Bellomo R, et al. Conservative versus liberal oxygenation targets for mechanically ventilated patients: a pilot multicenter randomized controlled trial. Am J Respir Crit Care Med. 2016;193(1):43-51.
Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, et al. Association between arterial hyperoxia and outcome in subsets of critical illness: a systematic review, meta-analysis, and meta-regression of cohort studies. Crit Care Med. 2015;43(7):1508-1519.
Palmer E, Post B, Klapaukh R, et al. The association between supraphysiologic arterial oxygen levels and mortality in critically ill patients: a multicenter observational cohort study. Am J Respir Crit Care Med. 2019;200(11):1373-1380.
Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. Crit Care. 2014;18(6):711.
de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Crit Care. 2008;12(6):R156.
Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Med. 2012;38(1):91-98.
Suzuki S, Eastwood GM, Peck L, et al. Current oxygen management in mechanically ventilated patients: a prospective observational cohort study. PLoS One. 2013;8(11):e78825.
Young PJ, Bellomo R, Bernard GR, et al. The role of oxygen therapy in the treatment of acute respiratory distress syndrome: a systematic review and meta-analysis. Intensive Care Med. 2019;45(10):1370-1378.
Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020;382(11):999-1008.

Sunday, September 14, 2025