Respiratory Failure
Conditions
Brief summary
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.
Interventions
OTHERLower SpO2 Target
SpO2 target 90% (range 88-92%)
OTHERIntermediate SpO2 Target
SpO2 target 94% (range 92-96%)
OTHERHigher SpO2 Target
SpO2 target 98% (range 96-100%)
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
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.
Intervention model description
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Receiving mechanical ventilation through an endotracheal tube or tracheostomy 3. Admitted to the study ICU or admission to the study ICU from the emergency department is planned
Exclusion criteria
1. Known pregnancy or beta hCG level greater than the laboratory upper limit of normal in a patient capable of becoming pregnant 2. Known to be a prisoner
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator-free Days (VFDs) to Study Day 28 | 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit Mortality (Exploratory Clinical Outcome) | 28 days | All-cause mortality prior to transfer out of the intensive care unit |
| 28-day, In-hospital Mortality (Secondary Outcome) | 28 days | All-cause mortality prior to discharge from the hospital, assessed at 28 days after enrollment (Secondary Outcome). |
| Vasopressor-free Days (Exploratory Clinical Outcome) | 28 days | Number of days alive and free from vasopressor receipt between the final receipt of vasopressors before 28 days and study day 28. |
| Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | 28 days | 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 |
| Intensive Care Unit-free Days (Exploratory Clinical Outcome) | 28 days | 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 |
| Hospital-free Days (Exploratory Clinical Outcome) | 28 days | Number of days alive and free from hospital admission to study day 28 |
| Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | 28 days | Presence of Stage II or greater AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Arrest (Exploratory Safety Outcome) | 28 days | Cardiac arrest with return of spontaneous circulation |
| Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | 28 days | 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. |
| Ischemic Stroke (Exploratory Safety Outcome) | 28 days | New ischemic stroke between enrollment and 28 days after enrollment as diagnosed by computed tomography, magnetic resonance imaging, or cerebral angiography. |
| Myocardial Infarction (Exploratory Safety Outcome) | 28 days | 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. |
| Ventricular Arrhythmia (Exploratory Safety Outcome) | 28 days | Documented ventricular arrhythmia |
| Atrial Arrhythmia (Exploratory Safety Outcome) | 28 days | Documented atrial arrhythmia |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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%) | 808 |
| 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%) | 859 |
| 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%) | 874 |
| Total | 2,541 |
Baseline characteristics
| Characteristic | Lower SpO2 Target | Intermediate SpO2 Target | Higher SpO2 Target | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years | 59 years | 59 years | 58 years |
| Overall Number of Participants | 808 Participants | 859 Participants | 874 Participants | 2541 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 11 Participants | 7 Participants | 28 Participants |
| Race (NIH/OMB) Black or African American | 121 Participants | 140 Participants | 136 Participants | 397 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 28 Participants | 38 Participants | 34 Participants | 100 Participants |
| Race (NIH/OMB) White | 649 Participants | 666 Participants | 695 Participants | 2010 Participants |
| Sex: Female, Male Female | 361 Participants | 385 Participants | 409 Participants | 1155 Participants |
| Sex: Female, Male Male | 447 Participants | 474 Participants | 465 Participants | 1386 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 285 / 808 | 296 / 859 | 297 / 874 |
| other Total, other adverse events | 1 / 808 | 0 / 859 | 0 / 874 |
| serious Total, serious adverse events | 0 / 808 | 0 / 859 | 0 / 874 |
Outcome results
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.
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lower SpO2 Target | Ventilator-free Days (VFDs) to Study Day 28 | 20 number of days |
| Intermediate SpO2 Target | Ventilator-free Days (VFDs) to Study Day 28 | 21 number of days |
| Higher SpO2 Target | Ventilator-free Days (VFDs) to Study Day 28 | 21 number of days |
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).
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | 28-day, In-hospital Mortality (Secondary Outcome) | 281 Participants |
| Intermediate SpO2 Target | 28-day, In-hospital Mortality (Secondary Outcome) | 292 Participants |
| Higher SpO2 Target | 28-day, In-hospital Mortality (Secondary Outcome) | 290 Participants |
Secondary
Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome)
Presence of Stage II or greater AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | 230 Participants |
| Intermediate SpO2 Target | Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | 253 Participants |
| Higher SpO2 Target | Acute Kidney Injury (AKI) (Exploratory Organ Function Outcome) | 251 Participants |
Secondary
Hospital-free Days (Exploratory Clinical Outcome)
Number of days alive and free from hospital admission to study day 28
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lower SpO2 Target | Hospital-free Days (Exploratory Clinical Outcome) | 10 number of days |
| Intermediate SpO2 Target | Hospital-free Days (Exploratory Clinical Outcome) | 10 number of days |
| Higher SpO2 Target | Hospital-free Days (Exploratory Clinical Outcome) | 10 number of 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
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lower SpO2 Target | Intensive Care Unit-free Days (Exploratory Clinical Outcome) | 20 number of days |
| Intermediate SpO2 Target | Intensive Care Unit-free Days (Exploratory Clinical Outcome) | 19 number of days |
| Higher SpO2 Target | Intensive Care Unit-free Days (Exploratory Clinical Outcome) | 20 number of days |
Secondary
Intensive Care Unit Mortality (Exploratory Clinical Outcome)
All-cause mortality prior to transfer out of the intensive care unit
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Intensive Care Unit Mortality (Exploratory Clinical Outcome) | 244 Participants |
| Intermediate SpO2 Target | Intensive Care Unit Mortality (Exploratory Clinical Outcome) | 259 Participants |
| Higher SpO2 Target | Intensive Care Unit Mortality (Exploratory Clinical Outcome) | 249 Participants |
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
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lower SpO2 Target | Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | 28 number of days |
| Intermediate SpO2 Target | Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | 28 number of days |
| Higher SpO2 Target | Renal Replacement Therapy-free Days (Exploratory Clinical Outcome) | 0 number of 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.
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lower SpO2 Target | Vasopressor-free Days (Exploratory Clinical Outcome) | 25 number of days |
| Intermediate SpO2 Target | Vasopressor-free Days (Exploratory Clinical Outcome) | 25 number of days |
| Higher SpO2 Target | Vasopressor-free Days (Exploratory Clinical Outcome) | 25 number of days |
Other Pre-specified
Atrial Arrhythmia (Exploratory Safety Outcome)
Documented atrial arrhythmia
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Atrial Arrhythmia (Exploratory Safety Outcome) | 64 Participants |
| Intermediate SpO2 Target | Atrial Arrhythmia (Exploratory Safety Outcome) | 100 Participants |
| Higher SpO2 Target | Atrial Arrhythmia (Exploratory Safety Outcome) | 95 Participants |
Other Pre-specified
Cardiac Arrest (Exploratory Safety Outcome)
Cardiac arrest with return of spontaneous circulation
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Cardiac Arrest (Exploratory Safety Outcome) | 26 Participants |
| Intermediate SpO2 Target | Cardiac Arrest (Exploratory Safety Outcome) | 26 Participants |
| Higher SpO2 Target | Cardiac Arrest (Exploratory Safety Outcome) | 31 Participants |
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.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Ischemic Stroke (Exploratory Safety Outcome) | 12 Participants |
| Intermediate SpO2 Target | Ischemic Stroke (Exploratory Safety Outcome) | 17 Participants |
| Higher SpO2 Target | Ischemic Stroke (Exploratory Safety Outcome) | 16 Participants |
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.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Myocardial Infarction (Exploratory Safety Outcome) | 16 Participants |
| Intermediate SpO2 Target | Myocardial Infarction (Exploratory Safety Outcome) | 28 Participants |
| Higher SpO2 Target | Myocardial Infarction (Exploratory Safety Outcome) | 14 Participants |
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.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | 17 Participants |
| Intermediate SpO2 Target | Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | 24 Participants |
| Higher SpO2 Target | Pneumothorax or Pneumomediastinum (Exploratory Safety Outcome) | 36 Participants |
Other Pre-specified
Ventricular Arrhythmia (Exploratory Safety Outcome)
Documented ventricular arrhythmia
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lower SpO2 Target | Ventricular Arrhythmia (Exploratory Safety Outcome) | 20 Participants |
| Intermediate SpO2 Target | Ventricular Arrhythmia (Exploratory Safety Outcome) | 21 Participants |
| Higher SpO2 Target | Ventricular Arrhythmia (Exploratory Safety Outcome) | 20 Participants |