Acute Respiratory Distress Syndrome, Respiratory Failure
Conditions
Keywords
critical care, critical illness, esophageal manometry, transpulmonary pressure, mechanical ventilation, lung stress
Brief summary
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
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 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 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 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 ARDS. • Hypothesis 3: The precision ventilation strategy will decrease hemodynamic instability, measured as shock-free days through Day 14.
Interventions
OTHERPrecision ventilation
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.
OTHERGuided usual care ventilation
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.
Sponsors
Beth Israel Deaconess Medical Center
NYU Langone Health
Massachusetts General Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Study team and leadership will be blinded to all analyses throughout the study. Unblinded statistician will perform analyses for the Data and Safety Monitoring Board (DSMB) and be sequestered from the remainder of the team.
Intervention model description
Participants will be randomized to the intervention arm or control arm. Participants in the intervention group (precision ventilation), will have mechanical ventilation using settings directed by the amount of air pressure in the chest and lungs, using esophageal manometry. The treating clinical team is not masked to esophageal and transpulmonary pressure values and can view these data throughout the period of protocol-directed ventilation. Participants in the control group (guided usual care), will have ventilator support (low tidal volume mechanical ventilation) managed by the clinical team per usual care. The treating clinical team is masked to esophageal and transpulmonary pressure values and cannot view or be informed of these data at any time during the period of protocol-directed ventilation. An esophageal catheter will be inserted strictly for monitoring of respiratory mechanics by study staff, but values will not be used to titrate the ventilator.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Ventilator-dependent ARDS, with all of the following (a-e): 1. Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 8 cm H2O or FiO2 ≥ 0.5 2. Hypoxemia as characterized by: • If arterial blood gas (ABG) available: the partial pressure of oxygen in the arterial blood (PaO2)/FiO2 ≤ 300 mm Hg, or, • if ABG not available OR overt clinical deterioration in oxygenation since last ABG: SpO2/FiO2 ≤ 316 with SpO2 ≤ 97% (both conditions) on two representative assessments between 1 to 6 hours apart. • If patient is positioned prone or receiving inhaled pulmonary vasodilator at time of screening: Qualifying PaO2/FiO2 or SpO2/FiO2 (as defined above) that was recorded within the 6 hours immediately prior to initiating either of these therapies may be used for eligibility determination. • If PEEP has been increased by \> 5 cm H2O within the last 12 hours immediately prior to screening: Qualifying PaO2/FiO2 or SpO2/FiO2 (as defined above) prior to PEEP increase may be used for eligibility determination if recorded within this 12-hour window. 3. Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules 4. Respiratory failure not fully explained by heart failure or fluid overload 5. Onset within 1 week of clinical insult or new/worsening symptoms 3. Early in ARDS course * Full criteria for ARDS (#2 above) first met within previous 3 days * 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
1. Esophageal manometry already in use clinically 2. 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 or hemorrhage) 3. Gross barotrauma or chest tube inserted to treat barotrauma (note: chest tube inserted strictly for drainage of pleural effusion is not an exclusion) 4. Esophageal pathology that, in judgement of the site investigator, significantly increases risk of esophageal catheter placement, including high-risk esophageal varices, recent oropharyngeal or gastroesophageal surgery; or past esophagectomy 5. Ongoing severe coagulopathy (platelet \< 5000/μL or INR \> 4) 6. Extracorporeal membrane oxygenation (ECMO) or CO2 removal (ECCO2R) 7. Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above) 8. Any of the following severe chronic lung diseases: cystic fibrosis, acute bronchiectasis exacerbation, acute exacerbation of a chronic interstitial lung disease (ILD), chronic pulmonary hypertension (PH) on PH-targeted vasoactive medication, or lung transplant 9. End-stage chronic cirrhosis with Child-Pugh Class C (Section 12.3) 10. ICU admission for burn injury 11. Current ICU stay \> 2 weeks or acute care hospital stay \> 4 weeks 12. Moribund patient not expected to survive 24 hours as assessed by the study physician; if cardiopulmonary resuscitation (CPR) was provided, assessment for moribund status must occur at least 6 hours after CPR was completed 13. Current limitation on life-sustaining care (other than do-not-resuscitate), or expectation by clinical team that a limitation on life-sustained care will be adopted within next 24 hours. 14. Treating clinician refusal or unwilling to use protocol-specified ventilator settings/modes 15. Prisoner 16. Previous enrollment in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 60-day mortality | 60 days from randomization | All-cause, all-location mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 28-day mortality | 28 days from randomization | All-cause, all-location mortality |
| Alive and ventilator-free through 28 days | 28 days from randomization | A composite outcome that incorporates survival for the defined follow-up interval and time to successful liberation from invasive mechanical ventilation (IMV) among survivors. |
| Alive and Respiratory Support-Free | 28 days from randomization | A composite outcome that incorporates survival for the defined follow-up interval and time to successful liberation from advanced respiratory support among survivors. Advanced respiratory support is defined in Section 1.2. This outcome will be formulated as a win ratio and separately as a time-to-event competing risk endpoint. |
| Barotrauma through Day 14 | 14 days from randomization | Any occurrence of pneumothorax, pneumomediastinum, subcutaneous emphysema, or chest tube insertion for barotrauma through Day 14 or until successful liberation from IMV, whichever occurs first. |
Countries
United States
Contacts
CONTACTValerie Goodspeed, MPH
CONTACTNancy Ringwood, RN
PRINCIPAL_INVESTIGATORDaniel Talmor, MD MPH
Beth Israel Deaconess Medical Center
Outcome results
None listed