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

Not Applicable

• Conditions: Respiratory Distress Syndrome, Adult
• Interventions: Procedure: No spontaneous breathing activity; Procedure: spontaneous breathing activity during APRV

• Registration Number: NCT04228471
• Lead Sponsor: University Hospital, Bonn

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-12-19
• Study First Submitted QC: 2020-01-13
• Study First Posted: 2020-01-14
• Study Start: 2020-02-08
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-08
• Last Update Posted: 2021-02-09
• Primary Completion: 2024-02
• Study Completion: 2024-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 840

Inclusion Criteria

1. Moderate to severe ARDS for ≤ 48 hours according to the Berlin definition will be defined by acute onset of:

   1. PaO2/FiO2 ≤ 200 mmHg (equivalent to ≤ 26.7 kPa) under invasive mechanical ventilation with PEEP ≥ 5 cmH2O
   2. Bilateral infiltrates documented by chest radiograph
   3. Not fully explained by cardiac failure or fluid overload (e.g. echocardiography)

2. Requirement for positive pressure ventilation via an endotracheal tube/ tracheotomy

3. Presence of informed consent according to local regulations

4. Age ≥ 18 years

5. Expected duration of mechanical ventilation > 48 hours at randomization

Exclusion Criteria

1. Need of extracorporeal lung support, high frequency oscillation and/or inhaled vasodilators for severe hypoxemia prior to inclusion
2. Woman known to be pregnant, lactating or having a positive or indeterminate pregnancy test
3. Neuromuscular disease that impairs ability to ventilate spontaneously
4. 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
5. Chronic kidney disease stage V (requirement of dialysis) according to the K/DOQI definition of chronic kidney disease
6. Massive diffuse alveolar haemorrhage
7. Recent lung transplant < 12 months
8. Morbid obesity defined as weight greater than 1 kg / cm
9. Burns > 70% total body surface
10. Suspected or known elevated intracranial pressure
11. Chronic liver disease (Child-Pugh grade C)
12. Ongoing chemotherapy and/or bone marrow transplantation within the last 3 months
13. Moribund patient not expected to survive 48 hours
14. Patients not expected to survive 90 days on the basis of the premorbid health status
15. Patient, surrogate, or physician not committed to full life support

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Controlled Mechanical Ventilation Group	No spontaneous breathing activity	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.
Spontaneous Breathing Group	spontaneous breathing activity during APRV	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.

Primary Outcome Measures

Name	Time	Method
All-cause mortality at study day 28 (D28)	All-cause mortality at D28 will be defined as number of patients who deceased at day 28.	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.
Number of Ventilator Free Days (VFD) until day 28 (D28)	Number of Ventilator Free Days will be measured until day 28.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Renal Support Free Days until study day 28 (D28)	Number of Renal Support Free Days will be measured until study day 28.	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.
Sequential Organ Failure Assessment (SOFA)	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.	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.
All-Cause Mortality Rate at study day 90 (D90)	All-cause mortality at D90 will be defined as number of patients who deceased at day 90.	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.
Number of Vasoactive Drug Free Days until study day 28 (D28)	Number of Vasoactive Drug Free Days will be measured until 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.

Trial Locations

Locations (1)

University Hospital Bonn, Department of Anesthesiology and Critical Care Medicine; 🇩🇪 Bonn, Germany