Improving Our Understanding of Respiratory Muscle Training to Facilitate Weaning From Mechanical Ventilation in the ICU

Study Overview
=================
Brief Summary
-----------------
Mechanical ventilation is a life-saving treatment frequently applied in intensive care unit (ICU). Nonetheless, by putting at rest the respiratory muscles, it can lead to respiratory muscle weakness and atrophy, which are accompanied by prolonged duration of mechanical ventilation, difficult weaning and increased ICU mortality. Despite a strong theoretical rationale and some evidence supporting the use of inspiratory muscle training (IMT) to address respiratory muscle weakness and atrophy, the optimal approach to IMT remains largely uncertain. In fact, mechanistic studies evaluating physiological adaptations that occur in respiratory muscles of mechanically ventilated patients in response to different training regimens have not been conducted so far. The aim of this study is to comprehensively investigate changes in respiratory muscle function in response to three different conditions that patients will be exposed to during their period of weaning from mechanical ventilation.

Detailed Description
-----------------
A majority of mechanically ventilated patients develop respiratory muscle weakness during critical illness. The potential value of implementing rehabilitative interventions for respiratory muscle conditioning are supported by observations showing that respiratory muscle weakness is associated with prolonged duration of mechanical ventilation, difficult weaning, and increased ICU mortality. Despite a strong theoretical rationale and some evidence supporting its use, mechanistic studies evaluating physiological adaptations that occur in respiratory muscles of mechanically ventilated patients in response to different training regimens have not been performed so far. Consequently, the characterization of IMT modalities and of the optimal approach to IMT remain largely uncertain. To date, the great part of the studies on the topic employed an external mechanical threshold device to perform trainings, in general adopting loads ranging between 10-50% of maximal inspiratory strength (i.e. maximal inspiratory pressure (PImax)). Intermittent spontaneous breathing periods (e.g. using partially assisted or spontaneous modes of ventilation) are also frequently applied as an activating stimulus to the respiratory muscles during periods of mechanical ventilation. A tapered flow resistive load (TFRL) device (POWERbreathe KH2, HaB International, UK) has been already tested and implemented at University Hospital Leuven as a way of loading respiratory muscles in ICU patients. The TFRL approach represents a potential more optimal way of loading the respiratory muscles in patients on prolonged mechanical ventilation. Such a loading approach allows higher inspiratory tidal volumes to be reached and higher work and power generation during trainings, by adapting to changes in length-tension characteristics of the inspiratory muscles during inspiration. With regards to training modalities, high-intensity IMT modalities by applying loads ranging between 30 and 50 %PImax, have not yet been proven to be associated with better improvements in respiratory muscle strength compared to low-intensity (sham) IMT modalities at loads not exceeding 10 %PImax. On the other hand, no studies are available that assessed changes in respiratory muscle function beyond assessments of respiratory muscle strength in response to training. Additionally, no training studies have tried to quantify the intrinsic loading of the patients (i.e. elastic and resistive resistances of the chest wall and the lungs) that muscles are exposed to in between periods of additional loading applied during IMT sessions. The aim of this study is to comprehensively investigate changes in respiratory muscle function in response to three different conditions that difficult to wean patients will be exposed to during their weaning period. The complementary quantification of the entity of loading that respiratory muscles are bearing during assisted, spontaneous and resistive breathing would provide important novel insights on the optimization of IMT stimulus in different patients on prolonged mechanical ventilation.

Official Title
-----------------
Improving Our Understanding of Respiratory Muscle Training to Facilitate Weaning From Mechanical Ventilation in the ICU

Conditions
-----------------
Weaning Failure

Intervention / Treatment
-----------------
* Other: Procedure: Usual Care (UC)
* Other: Procedure: UC + HI-IMT
* Other: Procedure: UC + LI-IMT (sham IMT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Difficult and prolonged weaning patients Adequate oxygenation Febrile temperature < 38ºC Hemodynamic stability Stable blood pressure No or minimal vasopressors No myocardial ischemia Adequate hemoglobin and mentation Resolution of disease acute phase Able to follow simple verbal commands related to IMT Mechanically ventilated via a tracheostomy or endotracheal tube Exclusion Criteria: Pre-existing neuromuscular disease Agitation Hemodynamically instable (arrhythmia, decompensated heart failure, coronary insufficiency) Hemoptysis Diaphoresis Spinal cord injury above T8 Use of any type of home MV support prior to hospitalization Skeletal pathology that impairs chest wall movements Poor general prognosis or fatal outcome

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, three arms parallel group randomized controlled trial with 1:1:1 allocation ratio
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Usual Care (UC)<br>Intermittent spontaneous breathing periods | Other: Procedure: Usual Care (UC)<br>* Intermittent spontaneous breathing periods<br>|
| Experimental: UC + High-intensity inspiratory muscle training (HI-IMT)<br> | Other: Procedure: UC + HI-IMT<br>* UC + Supervised daily sessions of training including 4 sets of 6-10 full vital capacity breaths against an external load using a tapered flow resistive device (POWERbreathe KH2, HaB International, UK). The maximum tolerable resistance allowing patients to inhale at least 70% of their inspiratory vital capacity will be chosen and progressively increased throughout the training period.<br>|
| Experimental: UC + Low-intensity inspiratory muscle training (LI-IMT) (sham IMT)<br> | Other: Procedure: UC + LI-IMT (sham IMT)<br>* UC + superrvised daily sessions of training including 4 sets of 6-10 breaths at the lowest external imposable load with the tapered flow resistive device (POWERbreathe KH2, HaB International, UK) (i.e. 3 cmH2O).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Inspiratory Pressure (PImax) | Using a unidirectional valve which will be connected to the patient's tracheostomy tube or endotracheal tube for an uninterrupted period of 25 seconds. | Maximal duration of IMT treatment: 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diaphragm mobility, thickness and thickening fraction by ultrasounds | Assessment by diaphragm ultrasounds | Maximal duration of IMT treatment: 28 days | 
| Change in contractile material and structural alteration of sternocleidomastoid muscle | By analyzing muscle microbiopsies using Hematoxylin & Eosin (H&E) staining. | Maximal duration of IMT treatment: 28 days | 
| Change in fiber proportion of sternocleidomastoid muscle fibers | By analyzing muscle microbiopsies with immunostaining of the myosin heavy chain. | Maximal duration of IMT treatment: 28 days | 
| Change in size of sternocleidomastoid muscle fibers | By analyzing muscle microbiopsies with immunostaining of the myosin heavy chain. | Maximal duration of IMT treatment: 28 days | 
| Change in amount of satellite cells of sternocleidomastoid muscle | By analyzing muscle microbiopsies with Pax7 immunostaining | Maximal duration of IMT treatment: 28 days | 
| Change in amount of fibrotic tissue of sternocleidomastoid muscle | By analyzing muscle microbiopsies with Masson staining | Maximal duration of IMT treatment: 28 days | 
| Change of gene expression of atrophy/hypertrophy related pathways of sternocleidomastoid muscle | By analyzing muscle microbiopsies with RT2 profiler PCR array skeletal muscle, Qiagen | Maximal duration of IMT treatment: 28 days | 
| Change in cell proliferation of sternocleidomastoid muscle | By analyzing muscle microbiopsies cell proliferation assays | Maximal duration of IMT treatment: 28 days | 
| Change in cell differentiation of sternocleidomastoid muscle | By analyzing muscle microbiopsies cell differentiation assays | Maximal duration of IMT treatment: 28 days | 
| Change in Blood Flow Index (BFI) of extra-diaphragmatic respiratory muscles | Measured by near-infrared spectroscopy in combination with injections of the tracer indocyanine green dye (ICG), with optodes transcutaneously positioned on the scalene, sternocleidomastoid and upper rectus abdominis muscles. | Maximal duration of IMT treatment: 28 days | 
| Change in Tissue Oxygenation Index (TOI) of ex of extra-diaphragmatic respiratory muscles | Measured by near-infrared spectroscopy with optodes transcutaneously positioned on the scalene, sternocleidomastoid and upper rectus abdominis muscles | Maximal duration of IMT treatment: 28 days | 
| Change in signal amplitude of diaphragm electromyography | Diaphragm electromyography will be collected with an esophageal electrode catheter | Maximal duration of IMT treatment: 28 days | 
| Change in signal amplitude of electromyography of extra-diaphragmatic respiratory muscles | Electromyography of scalene, sternocleidomastoid, parasternal intercostal and rectus abdominis muscles will be collected through surface electromyography electrodes | Maximal duration of IMT treatment: 28 days | 
| Esophageal and gastric pressure | Using a multifunction nasogastric catheter | Maximal duration of IMT treatment: 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ICU acquired muscle weakness, IMT, Weaning outcomes, Maximal inspiratory pressure, Diaphragm EMG, Surface EMG, Diaphragm ultrasounds, Microbiopsies, Difficult to wean patients, Respiratory muscles