EPVent 2- A Phase II Study of Mechanical Ventilation Directed by Transpulmonary Pressures

Study Overview
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Brief Summary
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This phase II multi-centered, randomized controlled trial of mechanical ventilation directed by esophageal pressure measurement will test the primary hypothesis that using a strategy of maintaining a minimal but positive transpulmonary pressure (Ptp = airway pressure minus pleural pressure) throughout the ventilatory cycle will lead to an improvement in patient survival.

Detailed Description
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This phase II prospective randomized controlled trial of ventilation directed by esophageal pressure measurements will enroll 200 patients with moderate to severe ARDS by the Berlin conference definition in several academic medical centers in North America. The control group will be ventilated using an alternative high-PEEP strategy with PEEP and FiO2 set using to an empiric table. Plasma samples will be obtained at enrollment and days 3 and 7 and assessed for a variety of lung injury biomarkers to better assess the association between our intervention and the inflammation associated with mechanical ventilation and the development of ARDS. Hospital survivors will undergo a brief follow up phone survey to assess survival, functional status (Barthel Index), health-related QOL (Short Form 12), and frailty (VES) twelve months after enrollment. The study length will be six years with a six month start-up period followed by a planned 50 month enrollment and twelve month follow-up.

Official Title
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EPVent 2- A Phase II Study of Mechanical Ventilation Directed by Transpulmonary Pressures (EPVent2)

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Other: Esophageal-pressure guided mechanical ventilation
* Other: High PEEP mechanical ventilation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute onset of ARDS as defined by the Berlin Consensus Conference definitions: Hypoxemic respiratory failure with PaO2 / FIO2 ratio < 200 mmHg b) Bilateral alveolar/interstitial infiltrates on chest x-ray, with opacities not present for more than 7 days Respiratory failure not fully explained by cardiac failure or fluid overload Intubation on controlled ventilation and receiving PEEP ≥ 5 cm H2O Age 16 years or older Duration of ARDS 36 hours or less from meeting final Berlin criterion. Exclusion Criteria: Received mechanical ventilation more than 96 hours Recently treated or bleeding varices, esophageal stricture, hematemesis, esophageal trauma, recent esophageal surgery or other contraindication for nasogastric tube placement Severe coagulopathy (platelet count < 5000/microliter or INR > 4) History of lung transplantation Elevated intracranial pressure or conditions where hypercapnia-induced elevations in intracranial pressure should be avoided Evidence of active air leak from the lung not committed to full support Participation in other intervention trials for ARDS or for sepsis within the past 30 days. Neuromuscular disease that impairs ability to ventilate spontaneously Severe chronic liver disease, defined as Child-Pugh Score of ≥12 Treating clinician refusal, or unwillingness to commit to controlled ventilation for at least 24 hours Inability to get informed consent from the patient or surrogate. Use of rescue therapies for prior to enrollment (e.g. nitric oxide, ECMO, prone positioning, high frequency oscillation). This does not exclude cases where these therapies were used as the initial mode of ventilation

Ages Eligible for Study
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Minimum Age: 16 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPVent<br>The overall goals for the EPVent group (esophageal-pressure guided mechanical ventilation) are to employ an open-lung strategy that includes low tidal volumes and maintenance of a positive transpulmonary pressure at end-expiration [Ptpexp]. Fraction of inspired oxygen [FiO2] and transpulmonary pressure pressure during an expiratory hold will be changed to achieve values shown in one of the columns of a protocol-specified table to meet the oxygenation target. | Other: Esophageal-pressure guided mechanical ventilation<br> <br> * Other names: positive transpulmonary pressure at end-expiration;|
| Active Comparator: Control<br>The overall goals for the Control group are similar to those for the EPVent group: to employ an open-lung strategy that includes low tidal volumes using an alternative high positive end-expiratory pressure [PEEP] strategy. The control group PEEP and tidal volume will be managed without reference to the esophageal pressure measurements, and instead will follow an empiric high PEEP mechanical ventilation strategy. PEEP and FiO2 will be raised or lowered to achieve the oxygenation target level specified in a study table. | Other: High PEEP mechanical ventilation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite outcome of mortality and time off the ventilator at 28-days. | The trial will utilize a primary composite endpoint that incorporates death and days off the ventilator at 28 days 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. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator free days to day 28 | Number of calendar days breathing unassisted. | Day 28 | 
| mortality | Hospital and ICU mortality to day 60 | Day 60 | 
| lengths of stay | Hospital and ICU lengths of stay to days 28 and 60 | Day 60 | 
| biomarkers of lung injury | Plasma biomarkers of lung injury on enrollment and days 3 and 7 after enrollment | Day 7 | 
| Survival | Mortality to 1 year | 1 year | 
| Need for rescue therapy | Rescue measures will be chosen according to the practice at the clinical site, and may include repeated recruitment maneuvers, prone positioning, nitric oxide, epoprostenol sodium, airway pressure release ventilation, high frequency ventilation, or ECMO. | Day 28 | 
| Activities of daily living | Will assess via questionnaire (Barthel Index) done by phone at 1 year. Barthel Index scores range from 0-100, with 100 representing greatest independence of activities of daily living. | 1 year | 
| Self-reported health assessment | Will assess via questionnaire (12-Item Short-Form Health Survey [SF-12]) done by phone at 1 year. The SF-12 scores range from 0-100 points, with higher scores representing the highest level of health. | 1 year | 
| Frailty in patients age 65 and older | Will assess via questionnaire (Vulnerable Elders-13 Survey) done by phone at 1 year. VES scores range from 0-10 points, with higher scores representing greater risk. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, mechanical ventilation, ALI, esophageal pressure