What is the EPVent 2 Trial?

The EPVent2 Trial is a multi-national phase II study comparing two modes of mechanical ventilation to manage patients with ARDS.  Patients in this study are randomized 1:1 to either of the two study arms: patients in the EPVent group have their ventilator settings managed according to their esophageal pressure; patients in the control group are managed according to an alternative high PEEP strategy modeled after the control group of the OSCILLATE trial.  The trial accrued 200 patients from 14 centers between 2012 – 2017.

National Heart, Lung, And Blood Institute of the National Institutes of Health supports this research under Award Number UM 1 HL108724.  The trial is registered on ClinicalTrials.gov under NCT01681225.

The trial protocol paper is published through British Medical Journal Open Access, and available here: EPVent2 BMJ Open 2014.

 

What is esophageal pressure?

Lung inflation reflects transpulmonary pressure (PTP), the difference between pressures at the airway opening and the pleural space (PTP = airway pressure – pleural pressure).  Clinicians manage mechanical ventilation by monitoring and controlling airway pressure.  For example, PEEP levels are set to control airway pressures at end-expiration, and end-inspiratory plateau airway pressures are monitored to assess the potential for over distension.  Monitoring and controlling these pressures is intended to prevent further ventilator-induced lung injury.  This would seem to be a reasonable strategy to the extent that pleural pressure values are predictable or restricted to a narrow range.  However, there is evidence to suggest that pleural pressure ranges widely and unpredictably among patients with ARDS due to factors such as obesity or abdominal fluid accumulation that influence the mechanical behavior of the chest wall.  If there is a wide range of pleural pressure among individuals, it could significantly affect lung inflation produced by mechanical ventilation.  For example, a relatively high level of PEEP of 18 cmH2O could be too low in a patient with pleural pressure of 20 cmH2O, allowing repetitive collapse of airspaces with each expiration leading to atelectrauma, or too high in a patient with a pleural pressure of 5 cmH2O, causing over distension of the lungs at end-inflation.  Because airway pressure reflects the sum of pressures across the lung and chest wall, the portion of the applied pressure inflating the lung could vary widely depending on chest wall characteristics.  It is possible that inconsistency in the results of clinical trials of PEEP reflects a failure to individualize ventilator settings for pleural pressure in each patient.  We will test the hypothesis that high pleural pressure is important in the physiological dysfunction of a subset of patients with ARDS.

 

Pleural pressure has long been estimated in upright subjects by measuring esophageal pressure using an esophageal balloon-catheter.  It is well accepted that the respiratory changes in esophageal pressure are representative of changes in pleural pressure applied to the lung surface.  Furthermore, esophageal pressure is considered representative of an effective pleural pressure surrounding the lung, such that the difference between airway pressures and esophageal pressure is a valid estimate of PTP.  We propose a multi-centered prospective randomized trial to test the hypothesis that estimates of PTP derived from esophageal pressure can be used to change ventilator settings in patients with ARDS leading to improved patient outcome.

 

 

Inclusions

Exclusions

Process

Outcomes

 

 

 

 

Inclusions

1. Adult patients (age >16) admitted to Intensive care unit with moderate to severe acute respiratory distress syndrome (ARDS) as defined by the Berlin conference criteria:

a. 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.

c. Respiratory failure not fully explained by cardiac failure or fluid overload.

d. Intubation on mechanical ventilation and receiving PEEP ≥ 5 cmH2O.

2. Duration of ARDS ≤ 36 hours. ARDS onset defined as when the last criterion (a-d above) is met.

 

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Exclusions

Patients will be excluded from the study if they are known to have

  • Received mechanical ventilation more than 96 hours
  • Recently treated for bleeding varices, stricture, hematemesis, esophageal trauma, recent esophageal surgery or other contraindication for NG tube placement
  • Severe coagulopathy (platelet count < 5000 / microliter or INR > 4),
  • History of lung or liver transplantation,
  • Elevated intracranial pressure or conditions where hypercapnia-induced elevations in intracranial pressure should be avoided
  • Evidence of active air leak from the lung (including broncho-pleural fistula, pneumothorax, pneumomediastinum or air leak from an existing chest tube)
  • Participation in other intervention trials for ARDS, or sepsis within the past 30 days.
  • Neuromuscular disease that impairs ability to ventilate spontaneously, such as C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barre syndrome, and myasthenia gravis.
  • Severe chronic liver disease [Child-Pugh Score of ≥12].
  • Patients not committed to full support
  • 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 prior to enrollment (e.g. nitric oxide, ECMO, prone positioning, high frequency oscillation). This does not exclude if these therapies were used as the initial mode of ventilation.

 

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Process

EPV2 study flow

 

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Outcomes

Primary Efficacy Endpoint:

  • A composite outcome of mortality and time off the ventilator at 28-days.

Secondary Endpoints:

  • Ventilator free days to day 28 (VFD)
  • Hospital and ICU mortality to days 28 and 60
  • Hospital and ICU lengths of stay to days 28 and 60
  • Plasma biomarkers of lung injury on enrollment and days 3 and 7 after enrollment
  • 1-year survival
  • QOL (SF12), functional status (Barthel Index), and frailty (VES) assessed by phone follow up interview at 12 months

Safety Endpoints

  • Serious Adverse Events
  • Vasopressor requirements
  • Fluid balance
  • Incidence of broncho-pleural fistula
  • Acute Kidney Injury
  • Hospital and ICU mortality to day 28

 

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