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Mechanical ventilation of ICU patients universally involves titration of the fraction of inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2). Despite decades of ICU practice, however, the optimal SpO2 target remains unknown. Current guidelines offer divergent recommendations as to the optimal SpO2 target. Therefore, we propose a 2,250-patient cluster-randomized cluster-crossover trial comparing a lower SpO2 target (90%; range 88-92%), an intermediate SpO2 target (94%; range 92-96%), and a higher SpO2 target (98%; range 96-100%) with regard to the outcome of days alive and free of invasive mechanical ventilation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lower SpO2 Target | Active Comparator | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 90% (range 88-92%). |
|
| Intermediate SpO2 Target | Active Comparator | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 94% (range 92-96%). |
|
| Higher SpO2 Target | Active Comparator | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 98% (range 96-100%). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lower SpO2 Target | Other | SpO2 target 90% (range 88-92%) |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Ventilator-free Days (VFDs) to Study Day 28 | Number of days alive and free from invasive mechanical ventilation between the final liberation from invasive mechanical ventilation before 28 days and study day 28. Patients who continue to receive invasive mechanical ventilation at day 28 or have died prior to day 28 will receive zero VFDs. For patients who return to invasive mechanical ventilation and are subsequently liberated from invasive mechanical ventilation prior to day 28, VFDs will be counted from final liberation from mechanical ventilation. | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| 28-day, In-hospital Mortality (Secondary Outcome) | All-cause mortality prior to discharge from the hospital, assessed at 28 days after enrollment (Secondary Outcome). | 28 days |
| Intensive Care Unit Mortality (Exploratory Clinical Outcome) |
| Measure | Description | Time Frame |
|---|---|---|
| Atrial Arrhythmia (Exploratory Safety Outcome) | Documented atrial arrhythmia | 28 days |
| Ventricular Arrhythmia (Exploratory Safety Outcome) | Documented ventricular arrhythmia |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Matthew W Semler, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39784122 | Derived | Shapiro JC, Casey JD, Qian ET, Seitz KP, Wang L, Lloyd BD, Stollings JL, Freundlich RE, Self WH, Rice TW, Wanderer JP, Semler MW; Pragmatic Critical Care Research Group. Oxygen Targets for Mechanically Ventilated Adults with Sepsis: Secondary Analysis of the PILOT Trial. J Intensive Care Med. 2025 May;40(5):486-494. doi: 10.1177/08850666241299378. Epub 2025 Jan 9. | |
| 36278971 |
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The NIH's guidelines for data sharing will serve as the model for the approach we will follow for the proposed investigation;
http://grants.nih.gov/grants/policy/data\_sharing/data\_sharing\_guidance.htm
Even though the final dataset will be stripped of identifiers prior to release for sharing, the inherent link between the period in which the patient was admitted to the study ICU and group assignment in a cluster-crossover trial introduces a significant risk for deductive disclosure of subjects. Thus, we will make the data and associated documentation available to users only under a data sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.
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| ID | Title | Description |
|---|---|---|
| FG000 | Lower SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 90% (range 88-92%). Lower SpO2 Target: SpO2 target 90% (range 88-92%) |
| FG001 | Intermediate SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 94% (range 92-96%). Intermediate SpO2 Target: SpO2 target 94% (range 92-96%) |
| FG002 | Higher SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 98% (range 96-100%). Higher SpO2 Target: SpO2 target 98% (range 96-100%) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Lower SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 90% (range 88-92%). Lower SpO2 Target: SpO2 target 90% (range 88-92%) |
| BG001 | Intermediate SpO2 Target |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Ventilator-free Days (VFDs) to Study Day 28 | Number of days alive and free from invasive mechanical ventilation between the final liberation from invasive mechanical ventilation before 28 days and study day 28. Patients who continue to receive invasive mechanical ventilation at day 28 or have died prior to day 28 will receive zero VFDs. For patients who return to invasive mechanical ventilation and are subsequently liberated from invasive mechanical ventilation prior to day 28, VFDs will be counted from final liberation from mechanical ventilation. | Posted | Median | Inter-Quartile Range | number of days | 28 days |
|
enrollment to day 28
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lower SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 90% (range 88-92%). Lower SpO2 Target: SpO2 target 90% (range 88-92%) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Relative bradycardia | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chair of the Steering Committee | Pragmatic Critical Care Research Group | (615) 322-3412 | matthew.w.semler@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 10, 2022 | Nov 11, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012131 | Respiratory Insufficiency |
| ID | Term |
|---|---|
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
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In the PILOT trial, the entire study ICU will be assigned to a single SpO2 target (cluster-randomized) and the ICU will switch between lower, intermediate, and higher SpO2 targets every two months in a randomly generated sequence (cluster-crossover).
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Observer bias will be minimized by use of objective endpoints collected in duplicate by [1] study personnel blinded to group assignment and [2] automated data extraction from the electronic health record.
| Intermediate SpO2 Target |
| Other |
SpO2 target 94% (range 92-96%) |
|
| Higher SpO2 Target | Other | SpO2 target 98% (range 96-100%) |
|
All-cause mortality prior to transfer out of the intensive care unit
| 28 days |
| Vasopressor-free Days (Exploratory Clinical Outcome) | Number of days alive and free from vasopressor receipt between the final receipt of vasopressors before 28 days and study day 28. | 28 days |
| Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | Number of days alive and free from renal replacement therapy between the final receipt of renal replacement therapy before 28 days and study day 28 | 28 days |
| Intensive Care Unit-free Days (Exploratory Clinical Outcome) | Number of days alive and free from intensive care unit admission after the final transfer out of the intensive care unit before 28 days to study day 28 | 28 days |
| Hospital-free Days (Exploratory Clinical Outcome) | Number of days alive and free from hospital admission to study day 28 | 28 days |
| Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | Presence of Stage II or greater AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria | 28 days |
| 28 days |
| Cardiac Arrest (Exploratory Safety Outcome) | Cardiac arrest with return of spontaneous circulation | 28 days |
| Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | Pneumothorax or pneumomediastinum as defined by documentation in the electronic health record by treating clinicians or radiology of a pneumothorax on thoracic imaging or thoracic ultrasound. | 28 days |
| Ischemic Stroke (Exploratory Safety Outcome) | New ischemic stroke between enrollment and 28 days after enrollment as diagnosed by computed tomography, magnetic resonance imaging, or cerebral angiography. | 28 days |
| Myocardial Infarction (Exploratory Safety Outcome) | New myocardial infarction between enrollment and 28 days after enrollment, defined as detection of a rise in cardiac troponin values with at least one value above the 99th percentile and clinical evidence of acute myocardial ischemia. | 28 days |
| Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays MA, Stollings JL, Buell KG, Brems JH, Qian ET, Seitz KP, Wang L, Lindsell CJ, Freundlich RE, Wanderer JP, Han JH, Bernard GR, Self WH, Rice TW; PILOT Investigators and the Pragmatic Critical Care Research Group. Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation. N Engl J Med. 2022 Nov 10;387(19):1759-1769. doi: 10.1056/NEJMoa2208415. Epub 2022 Oct 24. |
| 34711597 | Derived | Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays M, Roth M, Stollings J, Brems J, Buell KG, Wang L, Lindsell CJ, Freundlich RE, Wanderer JP, Bernard GR, Self WH, Rice TW; PILOT Investigators and the Pragmatic Critical Care Research Group. Protocol and statistical analysis plan for the Pragmatic Investigation of optimaL Oxygen Targets (PILOT) clinical trial. BMJ Open. 2021 Oct 28;11(10):e052013. doi: 10.1136/bmjopen-2021-052013. |
During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 94% (range 92-96%). Intermediate SpO2 Target: SpO2 target 94% (range 92-96%) |
| BG002 | Higher SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 98% (range 96-100%). Higher SpO2 Target: SpO2 target 98% (range 96-100%) |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Overall Number of Participants | Count of Participants | Participants |
|
| Overall Number of Participants | Count of Participants | Participants |
|
| Overall Number of Participants | Count of Participants | Participants |
|
| OG001 |
| Intermediate SpO2 Target |
During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 94% (range 92-96%). Intermediate SpO2 Target: SpO2 target 94% (range 92-96%) |
| OG002 | Higher SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 98% (range 96-100%). Higher SpO2 Target: SpO2 target 98% (range 96-100%) |
|
|
| Secondary | 28-day, In-hospital Mortality (Secondary Outcome) | All-cause mortality prior to discharge from the hospital, assessed at 28 days after enrollment (Secondary Outcome). | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Secondary | Intensive Care Unit Mortality (Exploratory Clinical Outcome) | All-cause mortality prior to transfer out of the intensive care unit | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Secondary | Vasopressor-free Days (Exploratory Clinical Outcome) | Number of days alive and free from vasopressor receipt between the final receipt of vasopressors before 28 days and study day 28. | Posted | Median | Inter-Quartile Range | number of days | 28 days |
|
|
|
| Secondary | Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | Number of days alive and free from renal replacement therapy between the final receipt of renal replacement therapy before 28 days and study day 28 | Posted | Median | Inter-Quartile Range | number of days | 28 days |
|
|
|
| Secondary | Intensive Care Unit-free Days (Exploratory Clinical Outcome) | Number of days alive and free from intensive care unit admission after the final transfer out of the intensive care unit before 28 days to study day 28 | Posted | Median | Inter-Quartile Range | number of days | 28 days |
|
|
|
| Secondary | Hospital-free Days (Exploratory Clinical Outcome) | Number of days alive and free from hospital admission to study day 28 | Posted | Median | Inter-Quartile Range | number of days | 28 days |
|
|
|
| Secondary | Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | Presence of Stage II or greater AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Other Pre-specified | Atrial Arrhythmia (Exploratory Safety Outcome) | Documented atrial arrhythmia | Posted | Count of Participants | Participants | 28 days |
|
|
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| Other Pre-specified | Ventricular Arrhythmia (Exploratory Safety Outcome) | Documented ventricular arrhythmia | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Other Pre-specified | Cardiac Arrest (Exploratory Safety Outcome) | Cardiac arrest with return of spontaneous circulation | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Other Pre-specified | Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | Pneumothorax or pneumomediastinum as defined by documentation in the electronic health record by treating clinicians or radiology of a pneumothorax on thoracic imaging or thoracic ultrasound. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Other Pre-specified | Ischemic Stroke (Exploratory Safety Outcome) | New ischemic stroke between enrollment and 28 days after enrollment as diagnosed by computed tomography, magnetic resonance imaging, or cerebral angiography. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Other Pre-specified | Myocardial Infarction (Exploratory Safety Outcome) | New myocardial infarction between enrollment and 28 days after enrollment, defined as detection of a rise in cardiac troponin values with at least one value above the 99th percentile and clinical evidence of acute myocardial ischemia. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| 285 |
| 808 |
| 0 |
| 808 |
| 1 |
| 808 |
| EG001 | Intermediate SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 94% (range 92-96%). Intermediate SpO2 Target: SpO2 target 94% (range 92-96%) | 296 | 859 | 0 | 859 | 0 | 859 |
| EG002 | Higher SpO2 Target | During invasive mechanical ventilation in a study location, the fraction of inspired oxygen will be titrated to target an arterial oxygen saturation of 98% (range 96-100%). Higher SpO2 Target: SpO2 target 98% (range 96-100%) | 297 | 874 | 0 | 874 | 0 | 874 |
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