Precision Ventilation vs Standard Care for Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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The goal of this interventional study is to compare standard mechanical ventilation to a lung-stress oriented ventilation strategy in patients with Acute Respiratory Distress Syndrome (ARDS). Participants will be ventilated according to one of two different strategies. The main question the study hopes to answer is whether the personalized ventilation strategy helps improve survival.

Detailed Description
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ARDS is a devastating condition that places a heavy burden on public health resources. Recent changes in the practice of mechanical ventilation have improved survival in ARDS, but mortality remains unacceptably high. This application is for support of a phase III multi-centered, randomized controlled trial of mechanical ventilation, directed by driving pressure and esophageal manometry, in patients with moderate or severe ARDS. The primary hypothesis is that precise ventilator titration to maintain lung stress within 0-12 centimeters of water (cm H2O), the normal physiological range experienced during relaxed breathing, will improve 60-day mortality, compared to guided usual care. Specific Aim 1: To determine the effect on mortality of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS. • Hypothesis 1: The precision ventilation strategy will decrease 60-day mortality (primary trial endpoint). Specific Aim 2: To evaluate the effects on lung injury of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS. Hypothesis 2a: The precision ventilation strategy will improve clinical pulmonary recovery, defined using the composite endpoint alive and ventilator-free (AVF). Hypothesis 2b: The precision ventilation strategy will attenuate alveolar epithelial injury. Specific Aim 3: To evaluate the hemodynamic safety profile of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS. • Hypothesis 3: The precision ventilation strategy will decrease hemodynamic instability, measured as shock-free days through Day 28.

Official Title
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PREcision VENTilation to Attenuate Ventilator-Induced Lung Injury: A Phase 3 Multicenter Randomized Clinical Trial

Conditions
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Acute Respiratory Distress Syndrome, Respiratory Failure

Intervention / Treatment
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* Other: Precision ventilation
* Other: Guided usual care ventilation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Moderate or severe ARDS, defined as meeting all of the following (a-e): Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O Hypoxemia as characterized by: If arterial blood gas (ABG) available: the partial pressure of oxygen in the arterial blood (PaO2)/FiO2 ≤ 200 mm Hg, or, if ABG not available OR overt clinical deterioration in oxygenation since last ABG: SpO2/FiO2 ≤ 235 with SpO2 ≤ 97% (both conditions) on two representative assessments between 1 to 6 hours apart Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules Respiratory failure not fully explained by heart failure or fluid overload Onset within 1 week of clinical insult or new/worsening symptoms Early in ARDS course Within 48 hours since meeting last moderate-severe ARDS criterion (#2 above) Current invasive ventilation episode not more than 4 days duration Current severe hypoxemic episode (receipt of invasive ventilation, noninvasive ventilation, or high-flow nasal cannula) not more than 10 days duration Exclusion Criteria: Esophageal manometry used clinically Severe brain injury: including suspected elevated intracranial pressure, cerebral edema, or Glasgow coma score (GCS) ≤ 8 directly caused by severe brain injury (e.g., ischemia/hemorrhage). Gross barotrauma or chest tube inserted to treat barotrauma Esophageal varix or stricture; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy Severe coagulopathy (platelet < 5000/µL or international normalized ratio [INR] > 4) Extracorporeal membrane oxygenation or carbon dioxide (CO2) removal Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above) Chronic supplemental oxygen, pulmonary fibrosis, or lung transplant Refractory shock: norepinephrine-equivalent dose ≥ 0.4 µg/kg/min or simultaneous receipt of ≥ 3 vasopressors Severe liver disease, defined as Child-Pugh Class C ICU admission for burn injury Current ICU stay > 2 weeks or hospital stay (including subacute hospitalization) > 4 weeks Estimated mortality > 50% over 6 months due to underlying chronic medical condition Limitation on life-sustaining care, other than do-not-resuscitate Treating clinician refusal OR unwilling to use protocol-specified ventilator settings / modes Prisoner

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Precision ventilation<br>Ventilator support will be calibrated to maintain the range of lung stress typical of relaxed breathing in healthy adults. The ventilator management protocol takes into account pleural pressure, tidal volume and driving pressure, fraction of inspired oxygen (FiO2) and oxygen saturation (SpO2), and positive end-expiratory pressure (PEEP) titration. | Other: Precision ventilation<br>* The intervention arm prioritizes mitigation of ventilator-induced-lung-injury by individualizing support to patient-specific mechanics in an integrated approach to limit overdistension and atelectrauma. This is accomplished in this arm by titration of tidal volume to limitation of driving pressure at 12 centimeters of water (cmH2O) or less and using esophageal manometry to titrate PEEP to a transpulmonary pressure of 0 cmH2O with adjustments in respiratory rate to allow for permissive hypercapnia and FiO2 adjustments to assure adequate oxygenation.<br>|
| Active Comparator: Guided usual care<br>Ventilator support will be managed by the clinical team per usual care with select protocol-based guard rails to avoid practice extremes beyond the current body of evidence. PEEP titration will be performed by the clinical team within the limits set in. The allowable combinations of PEEP and FiO2 in the control arm reflect pre-intervention usual care observed at baseline in the recent large federally-funded multicenter ARDS trials. | Other: Guided usual care ventilation<br>* The comparison arm allows clinician discretion when titrating PEEP and tidal volume, while setting general targets for allowable PEEP/FiO2 combinations, target range for SpO2, and target range for tidal volume. This arm applies routine best-practice guidelines. This includes maintenance of tidal volumes of 6-8 cc/kg of ideal body weight, limiting plateau pressures to 30 cmH2O or less and application of PEEP-FiO2 combinations which include a wide range of typical usual care with esophageal manometry only for data collection and not clinical adjustment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 60-day mortality | All-cause, all-location mortality | 60 days from trial enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | All-cause, all-location mortality | 28 days from trial enrollment | 
| 6-month mortality | All-cause, all-location mortality | 6 months from trial enrollment | 
| A composite of alive and ventilator-free through 28 days | Alive and ventilator-free (AVF) is a composite outcome that incorporates survival and time to successful liberation from invasive mechanical ventilation among survivors in such a manner that death constitutes a more serious outcome. Every subject is compared to every other subject in the trial and assigned one number resulting from each comparison. Since mortality outcome is clinically more important, mortality takes precedence over days off the ventilator. The sum of scores for patients in the treatment group is compared to the sum of scores of subjects in the control group to form a test statistic by the Mann-Whitney technique. | 28 days from trial enrollment | 
| Time to successful liberation from invasive mechanical ventilation (IMV) through 60 days | Number of days from initiation of IMV until the patient is breathing for a period of at least 48 consecutive hours without invasive mechanical ventilation. | 60 days from trial enrollment | 
| Barotrauma through Day 28 | Any occurrence of pneumothorax, pneumomediastinum, subcutaneous emphysema, or chest tube insertion for barotrauma through Day 28 or until successful liberation from IMV, whichever occurs first. | 28 days from trial enrollment | 
| Pneumothorax through Day 28 | Any occurrence of pneumothorax through Day 28 or until successful liberation from IMV, whichever occurs first. | 28 days from trial enrollment | 
| Intensive care unit (ICU) length of stay through Day 60 | Number of days in the ICU from enrollment until the last transfer out of ICU, hospital discharge, death, or Day 60, whichever occurs first. | 60 days from trial enrollment | 
| Hospital length of stay through Day 60 | Number of days in the hospital from enrollment until hospital discharge, death, or Day 60, whichever occurs first. | 60 days from trial enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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critical care, critical illness, esophageal manometry, transpulmonary pressure, mechanical ventilation, lung stress