Prone Positioning and Abdominal Binding on Lung and Muscle Protection in ARDS Patients During Spontaneous Breathing

Study Overview
=================
Brief Summary
-----------------
Ventilator-induced diaphragmatic dysfunction and intensive care unit (ICU)-acquired weakness are two consequences of prolonged mechanical ventilation and critical illness in patients with acute respiratory distress syndrome (ARDS). Both complicate the process of withdrawing mechanical ventilation, increase hospital mortality and cause chronic disability in survivors. During transition from controlled to spontaneous breathing, these complications of critical illness favor an abnormal respiratory pattern and recruit accessory respiratory muscles which may promote additional lung and muscle injury. The type of ventilatory support and positioning may affect the muscle dysfunction and patient-self-inflicted lung injury at spontaneous breathing onset. In that regard, ARDS patients with ventilator-induced diaphragmatic dysfunction and ICU-acquired weakness who are transitioning from controlled to partial ventilatory support probably present an abnormal respiratory pattern which exacerbates lung and muscle injury. Physiological-oriented ventilatory approaches based on prone positioning or semi recumbent positioning with abdominal binding at spontaneous breathing onset, could decrease lung and muscle injury by favoring a better neuromuscular efficiency, and preventing intense inspiratory efforts and high transpulmonary driving pressures, as well as high-magnitude pendelluft. In the current project, in addition to perform a multimodal description of the severity of ventilator-induced diaphragmatic dysfunction and ICU-acquired weakness in prolonged mechanically ventilated ARDS patients, prone positioning and supine plus abdominal binding at spontaneous breathing onset will be evaluated.

Detailed Description
-----------------
Study protocol will have three steps. The first step is a multimodal description to characterize ICU acquired weakness and ventilator-induced diaphragm dysfunction in prolonged mechanically ventilated ARDS patients at spontaneous breathing onset. The second step is a crossover clinical trial to test different ventilatory approaches oriented to improve physiological variables related to lung injury and diaphragm performance. The third step is a randomized controlled trial to test the effect of the previous ventilatory approaches on lung inflammatory response and biomarkers of lung and muscular injury. FIRST PHASE: A multimodal physiological description will be performed in assist-control ventilation at spontaneous breathing onset. At the study entry, the assessments will include conventional electromyography; electrical activity of the diaphragm; ultrasound of respiratory and non-respiratory muscles; respiratory flow; tidal volume; airway, esophageal and gastric pressures; and hemodynamic and electric impedance tomography monitoring at the end of 2-hours of spontaneous breathing period. SECOND PHASE: After the multimodal physiological description, a controlled randomized crossover trial will assign patients to three strategies of 2-hours period on pressure support ventilation mode: A.- Control group: supine at 45º, B.- Abdominal binding: supine at 45º plus abdominal binding, C.- Prone positioning (without abdominal banding). These strategies will be performed under standard positive end-expiratory pressure (PEEP) (ARDSNet strategy) and individualized PEEP (obtained at the lowest combination of collapse and overdistension according to electrical impedance tomography), applied in random order. Therefore, each patient will receive the six approaches, with washout periods of 15-minutes in assisted/controlled ventilation. THIRD PHASE: The day next to the crossover trial, each patient will be randomized to one of the three ventilatory strategies previously defined, A.- Control group: supine at 45º, B.- Abdominal binding: supine at 45º plus abdominal binding, C.- Prone positioning. These three strategies will be applied under standard PEEP (ARDSNet strategy). Between crossover and pilot randomized controlled trial, the patients will remain under moderate sedation in pressure support ventilation mode receiving an individualized PEEP level.

Official Title
-----------------
Effect of Prone Positioning and Abdominal Binding on Lung and Muscle Protection in ARDS Patients With ICU-acquired Weakness Transitioning From Controlled to Spontaneous Breathing

Conditions
-----------------
Acute Respiratory Distress Syndrome, Mechanical Ventilation Complication, ICU Acquired Weakness

Intervention / Treatment
-----------------
* Procedure: Prone Positioning
* Procedure: Abdominal Binding
* Procedure: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult ARDS patients with moderate-severe ARDS on controlled protective mechanical ventilation for more than 3 days Stable hemodynamics Level of consciousness enough to initiate spontaneous breathing Exclusion Criteria: Unstable hemodynamics Tracheostomy Abnormal level of consciousness Central nervous system injury Esophageal varices Pregnancy Contraindications for installation of electrical impedance tomography or ultrasound assessments

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Three phase-study: Multimodal physiological description Randomized crossover trial Pilot randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Control Group<br>ARDS patients at spontaneous breathing onset on pressure support ventilation mode in supine position at 45º degrees, performed under standard PEEP according to ARDSNet strategy and individualized PEEP applied in random order. | Procedure: Control<br>* ARDS patients at spontaneous breathing onset on pressure support ventilation mode in supine position at 45º degrees, performed under standard PEEP according to ARDSNet strategy and individualized PEEP applied in random order.<br>|
| Experimental: Prone Positioning<br>ARDS patients at spontaneous breathing onset on pressure support ventilation mode in prone position, performed under standard PEEP according to ARDSNet strategy and individualized PEEP applied in random order. | Procedure: Prone Positioning<br>* Prone positioning will be performed according to ICU local protocol with trained provider teams.<br>|
| Experimental: Abdominal Binding<br>ARDS patients at spontaneous breathing onset on pressure support ventilation mode in supine position at 45º degrees using an abdominal binder with the binder's upper edge below the costal margin to allow rib-cage movement, performed under standard PEEP according to ARDSNet strategy and individualized PEEP applied in random order. | Procedure: Abdominal Binding<br>* An abdominal binder will be used in semi-recumbent position (supine at 45º). The degree of abdominal compression will be defined as an increase in end-expiration gastric pressure of 5 cm of water during steady-state breathing; this level of abdominal compression has demonstrated to optimize lung function and neuromuscular efficiency in healthy subjects and athletes with cervical spinal cord injury.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Second Phase) High-Magnitude Pendelluft | Frequency of high-magnitude pendelluft monitored by electrical impedance tomography | Two hours on each ventilatory strategy during phase 2 (day 2 of the protocol) | 
| (Third Phase) Change in Inflammatory Biomarkers Measured by ELISA (IL-6, IL-8, TNF-α, IFN-γ, IL-18, IL-1β, Caspase-1, RAGE, Angiopoietin-1 and 2) and change in oxidative stress related biomarkers (F2 isoprostane) | ELISA-based detection of inflammatory biomarkers (absolute and ratios) and oxidative stress related biomarkers (absolute and ratios) measured in plasma and in exhaled breath condensate | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) | 
| (Third Phase) Change in Regional Lung Inflammation | Regional lung inflammation will be evaluated with dynamic positron emission tomography/computed tomography of fluoro-2-deoxy-D-glucose (18F-FDG) net uptake rate | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) | 
| (Third Phase) Change in Fast-Twitch Skeletal Muscle Troponin I Measured by ELISA | ELISA-based detection of fast-twitch skeletal muscle troponin I measured in plasma | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Second Phase) Respiratory Mechanics Variables | Esophageal pressure swing, transdiaphragmatic pressure and transpulmonary driving pressure measured by a esophageal/gastric catheter | Two hours on each ventilatory strategy during phase 2 (day 2 of the protocol) | 
| (Third Phase) Change in High-Magnitude Pendelluft | Frequency of high-magnitude pendelluft monitored by electrical impedance tomography | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) | 
| (Third Phase) Change in Respiratory Mechanics Variables | Esophageal pressure swing, transdiaphragmatic pressure and transpulmonary driving pressure measured by a esophageal/gastric catheter | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) | 
| (Third Phase) Change in Neuromechanical Coupling of Diaphragm | Change in neuromechanical coupling of diaphragm, which corresponds to the ratio between transdiaphragmatic pressure and electrical activity of the diaphragm measured by a esophageal/gastric catheter | At baseline and after 24 hours of each ventilatory strategy during phase 3 (day 3 of the protocol) |