Early PReserved SPONtaneous Breathing Activity in Mechanically Ventilated Patients With ARDS (PReSPON)

Study Overview
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Brief Summary
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The potential benefits of preserved early spontaneous breathing activity during mechanical ventilation are an increased aeration of dependent lung regions, less need for sedation, improved cardiac filling, and better matching of pulmonary ventilation and perfusion and thus oxygenation. Two small randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) reported less time on mechanical ventilation and in the intensive care unit (ICU) with preserved early spontaneous breathing activity during Airway Pressure Release Ventilation (APRV). Debate exists over the net effects of preserved early spontaneous breathing activity with regard to ventilator-associated lung injury (VALI). In fact, by taking advantage of the potential improvement in oxygenation and recruitment at lower inflation pressures associated with APRV, physicians could possibly reduce potentially harmful levels of inspired oxygen, tidal volume, and positive end-expiratory pressure (PEEP). However, spontaneous breathing during mechanical ventilation has the potential to generate less positive pleural pressures that may add to the alveolar stretch applied from the ventilator and contribute to the risk of VALI. This has led to an ongoing controversy whether an initial period of controlled mechanical ventilation with deep sedation and neuromuscular blockade or preserved early spontaneous breathing activity during mechanical ventilation is advantageous with respect to outcomes in ARDS patients. A RCT investigating the effects of early spontaneous breathing activity on mortality in moderate to severe ARDS has been highly recommended in the research agenda for intensive care medicine. The objective of this study is to evaluate the efficacy and safety of preserved spontaneous breathing activity during APRV in the early phase of moderate to severe ARDS.

Official Title
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Early PReserved SPONtaneous Breathing Activity in Mechanically Ventilated Patients With Acute Respiratory Distress Syndrome - The PReSPON Randomized Controlled Trial

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Procedure: spontaneous breathing activity during APRV
* Procedure: No spontaneous breathing activity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate to severe ARDS for ≤ 48 hours according to the Berlin definition will be defined by acute onset of: PaO2/FiO2 ≤ 200 mmHg (equivalent to ≤ 26.7 kPa) under invasive mechanical ventilation with PEEP ≥ 5 cmH2O Bilateral infiltrates documented by chest radiograph Not fully explained by cardiac failure or fluid overload (e.g. echocardiography) Requirement for positive pressure ventilation via an endotracheal tube/ tracheotomy Presence of informed consent according to local regulations Age ≥ 18 years Expected duration of mechanical ventilation > 48 hours at randomization Exclusion Criteria: Need of extracorporeal lung support, high frequency oscillation and/or inhaled vasodilators for severe hypoxemia prior to inclusion Woman known to be pregnant, lactating or having a positive or indeterminate pregnancy test Neuromuscular disease that impairs ability to ventilate spontaneously Severe chronic respiratory disease (e.g. COPD, pulmonary fibrosis, and other chronic diseases of the lung, chest wall or neuromuscular system) requiring home oxygen therapy or mechanical ventilation (non-invasive ventilation or via tracheotomy) except for Continuous Positive Airway Pressure (CPAP) or non-invasive Biphasic Positive Airway Pressure (BiPAP) used solely for sleep-disordered breathing Chronic kidney disease stage V (requirement of dialysis) according to the K/DOQI definition of chronic kidney disease Massive diffuse alveolar haemorrhage Recent lung transplant < 12 months Morbid obesity defined as weight greater than 1 kg / cm Burns > 70% total body surface Suspected or known elevated intracranial pressure Chronic liver disease (Child-Pugh grade C) Ongoing chemotherapy and/or bone marrow transplantation within the last 3 months Moribund patient not expected to survive 48 hours Patients not expected to survive 90 days on the basis of the premorbid health status Patient, surrogate, or physician not committed to full life support

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spontaneous Breathing Group<br>Spontaneous breathing activity will be allowed during APRV within one hour after randomization throughout the first 48 hours. After 48 hours, standard routine care should be provided in both groups, although we suggest moderate sedation while spontaneous breathing is maintained with APRV, pressure support ventilation (PSV), or other assisting ventilator modes. Weaning off mechanical ventilation will be performed after 48 hours according to a protocol using spontaneous breathing trials. | Procedure: spontaneous breathing activity during APRV<br>* Allowing spontaneous breathing activity with APRV throughout the first 48 hours.<br>|
| Experimental: Controlled Mechanical Ventilation Group<br>Pressure controlled mechanical ventilation will be applied throughout the first 48 hours. After 48 hours, standard routine care should be provided in both groups, although we suggest moderate sedation while spontaneous breathing is maintained with APRV, pressure support ventilation (PSV), or other assisting ventilator modes. Weaning off mechanical ventilation will be performed after 48 hours according to a protocol using spontaneous breathing trials. | Procedure: No spontaneous breathing activity<br>* No spontaneous breathing activity will be allowed with pressure controlled ventilation throughout the first 48 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality at study day 28 (D28) | All-cause mortality at D28 will be defined as number of patients deceased at D28 divided by number of all patients. In case of missing survival status in more than 1% of the patients, additional analyses will be carried out using multiple imputation or estimating-equation methods. The date of death will be recorded for all patients who die. Up to D28, the patient's location at the time of death (ICU or hospital) will also be recorded. | All-cause mortality at D28 will be defined as number of patients who deceased at day 28. | 
| Number of Ventilator Free Days (VFD) until day 28 (D28) | Number of VFDs until D28 are defined as number of days alive and completely off the ventilator until day 28. A patient will be reported as ventilator free after two consecutive calendar days of unassisted spontaneous breathing (UAB). UAB is defined as: Spontaneously breathing with face mask, nasal prong oxygen or room air T-piece breathing Tracheostomy breathing CPAP ≤5 cmH2O without pressure support or another mode of assisted mechanical ventilation Use of CPAP or BIPAP solely for sleep apnoea management Patients still on positive pressure ventilation/receiving assisted breathing who are transferred to another hospital or healthcare facility prior to D28 will be followed up to assess the VFD outcome at D28. | Number of Ventilator Free Days will be measured until day 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Mortality Rate at study day 90 (D90) | All-cause mortality at D90 is defined as number of patients deceased at D90 divided by number of all patients. Patients with missing survival status will be counted as non-survivor. | All-cause mortality at D90 will be defined as number of patients who deceased at day 90. | 
| Number of Vasoactive Drug Free Days until study day 28 (D28) | Number vasoactive drug free days are defined as number of days alive and completely off the vasoactive drugs until D28. Any vasoactive support given to the patient will be recorded in the e-CRF. Vasoactive support includes: catecholamine and non-catecholamine vasopressors, inotropes and vasodilating agents. | Number of Vasoactive Drug Free Days will be measured until D28. | 
| Number of Renal Support Free Days until study day 28 (D28) | Number of Renal Support Free Days are defined as number of days alive and completely off the renal support until day 28. Any renal support given to the patient will be recorded on a specific page in the e-CRF. | Number of Renal Support Free Days will be measured until study day 28. | 
| Sequential Organ Failure Assessment (SOFA) | Organ failure status will be assessed using the mean SOFA score, which assesses six organ systems: respiration, coagulation, liver, cardiovascular, central nervous system and renal function. A patient will be defined as being free of organ failure when the SOFA score is zero. | The score will be assessed pre-randomization on study day 1 (D1) and daily up to study day 7 (D7) and while the patient is in the ICU until D28. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Airway Pressure Release Ventilation, Bilevel Continuous Positive Airway Pressure, Biphasic Continuous Positive Airway Pressure, Mechanical Ventilation, Ventilator-Induced Lung Injury, Spontaneous Breathing