NMES Role to Prevent Respiratory Muscle Weakness in Critically Ill Patients and Its Association to Changes in Myokines.

Study Overview
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Brief Summary
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Particularly, muscle respiratory wasting will occur early (18 to 69 hours) in up to 60% of patients with mechanical ventilation (MV), leading rapidly to diaphragmatic weakness, which is associated with prolonged MV use, longer ICU and hospital stay, and higher mortality risk. Sepsis and muscle inactivity, derived from sedation and MV use, are key driver mechanisms for developing these consequences, which can be avoided through early physical activation. However, exercise is limited at the early stages of care, where sedation and MV are needed, delaying muscle activation. Neuromuscular electrical stimulation (NMES) represents an alternative to achieve early muscle contraction in non-cooperative patients, being able to prevent local muscle wasting and, according to some reports, has the potential to shorten the time on MV, suggesting a systemic effect through myokines, a diverse range of cytokines and chemokines secreted by myocytes during muscle contraction. However, no studies have evaluated whether NMES applied to peripheral muscles can exert distant muscle effects over the diaphragm, ameliorating its weakness and if this protective profile is associated with myokine's change in ICU patients. This proposal comprises a randomized controlled study of NMES applied twice daily, for three days, compared to standard care (no NMES). Thirty-two patients will be recruited in the first 48 hours after MV and randomly assigned to the control group or NMES group (16 subjects each). Muscle characterization of quadriceps and diaphragm will be performed at baseline (Day 1, before the first NMES session) and after the last NMES session (morning of day 4). Myokine measurements [IL-1, IL-6, IL-15, Brain-Derived Neurotrophic Factor (BDNF), Myostatin and Decorin], through blood serum obtained from peripheric blood samples, will be performed just before starting NMES (T0) at the end of the session (T0.5), and 2 and 6 hours later (T2 and T6). These myokine curves will be repeated on days 1 and 3 at the first NMES session of the day. The Control group will be assessed in the same way and timing, except that blood samples will be at T0 and T6. Additionally, functional outcomes such as MV time and ICU length of stay will be registered for all patients at ICU discharge. Standard care won´t be altered.

Detailed Description
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Critically ill patients hospitalized at Intensive Care Units (ICU) are characterized by an accelerated muscle wasting, which leads to general muscle weakness and loss of physical functions even after discharge. Particularly, muscle respiratory wasting will occur early (18 to 69 hours) in up to 60% of patients with mechanical ventilation (MV), leading rapidly to diaphragmatic weakness, which is associated with prolonged MV use, longer ICU and hospital stay and higher mortality risk. Sepsis and muscle inactivity, derived from sedation and MV use, are key driver mechanisms to developing these negative consequences, which can be avoided through early physical activation. However, exercise is limited at early stages of care, where sedation and MV are needed, delaying muscle activation and favoring a vicious circle. Neuromuscular electrical stimulation (NMES) represents an alternative to achieve early muscle contraction in non-cooperative patients, being able to prevent local muscle wasting and, according to some reports, has the potential to shorten the time on MV, suggesting a systemic effect through myokines, a diverse range of cytokines and chemokines secreted by myocytes during muscle contraction. These factors modulate the function and metabolism of distant organs and can promote muscle cell proliferation and growth in order to maintain muscle structure and function. However, no studies have evaluated whether NMES applied to peripheral muscles can exert distant muscle effects over the diaphragm, ameliorating its weakness, and if this protective profile is associated to myokine's change in critically ill patients. We hypothesize that in mechanical ventilated ICU patients NMES contributes to prevent respiratory muscle weakness when initiated at an early phase of their critical illness, and this effect is associated to acute changes in myokine profile, being able to facilitate discontinuation of MV and decrease ICU length of stay. This proposal comprises a randomized controlled study of NMES applied twice a day, for 3 days, in comparison to standard care (no NMES). Thirty-two patients will be recruited in the first 48 hours after connection to MV, and randomly assigned to either control group or stimulated group (16 subjects for each group). Muscle characterization of quadriceps and diaphragm (Structural ultrasonography evaluation of muscle thickness and tracheal twitch pressure assessment, derived from magnetic stimulation of phrenic nerve, for diaphragmatic strength) will be performed at baseline (Day 1, prior to the first NMES session) and after the last NMES session (morning of day 4). Myokine measurements (IL-1, IL-6, IL-15, BDNF, Myostatin and Decorin), through blood serum obtained from peripheric blood samples, will be performed at baseline 1 hour before NMES (T-1), just before starting NMES (T0), at the end of NMES session (T0.5), and 2 and 6 hours later (T2 and T6). This myokine curves will be repeated on days 1 and 3 at the first NMES session of the day. Control group will be assessed in the same way and timing, with the exception that blood samples will be performed at T0 and T6 of days 1 and 3. Additionally, functional outcomes such as MV time and ICU length of stay will be registered for all patients at ICU discharge. Standard care won´t be altered, performing passive mobilization according to ICU procedures in both groups.

Official Title
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Role of Neuromuscular Electrical Stimulation to Prevent Respiratory Muscle Weakness in Critically Ill Patients and Its Association to Changes in Myokines Profile. A Randomized Clinical Trial.

Conditions
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Muscle Weakness or Atrophy, Mechanical Ventilation Complication, Electrical Stimulations

Intervention / Treatment
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* Device: Neuromuscular electrical stimulation (NMES)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consecutively admission to Christus ICU between March 2021 and December 2021. Connected to invasive MV within the previous 24-48 hours Deep sedation [non-cooperative state; Sedation-Agitation Scale (SAS) 1 or 2]. ICU-acquired weakness risk (One of the following risk factors: the need for invasive MV, sepsis, hyperglycemia, APACHE II admission score >13 pts, use of corticosteroids, and/or muscle inactivity due to deep sedation). Written informed consent provided by patient/surrogate Exclusion Criteria: Age < 18 years Pregnancy Obesity (Body Mass Index >35 kg/m2) Pre-existing Neuromuscular diseases (e.g., myasthenia Gravis, Guillain-Barré disease) Diseases with systemic vascular involvement such as systemic lupus erythematosus. Use of neuromuscular blockers Technical obstacles to the implementation of NMES such as bone fractures or skin lesions (e.g., burns) End-stage malignancy Presence of cardiac pacemakers Diagnosis of brain death.

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: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NMES group<br>NMES will be implemented simultaneously on quadriceps femoris muscles of both lower limbs using an electrical stimulator (TRAINFES 6 ADVANCED, Biomedical devices Spa, Santiago, Chile). Four rubber surface electrodes will be placed over motor points. However, since the electrodes will cover big proportion of muscle surface, anatomical distribution of the belly muscle plus visible contraction of it will be considered for correct setting. The stimulation will be delivered by biphasic current, symmetric (compensated) impulses of 45-50 Hz frequency, 400 μsec pulse duration. With a stimulus duration of 25 minutes, and an on-off programming of 5 seconds on (including 0.8 second rise time, 3.4 seconds of plateau and 0.8 second of fall time) and 5 seconds off, at current intensities able to cause maximal visible contractions. The session duration will be 30 minutes and will be applied twice a day. | Device: Neuromuscular electrical stimulation (NMES)<br>* Electrical stimulator (Electrostimulator TRAINFES 6 ADVANCED, Biomedical devices Spa, Santiago, Chile.) to administer NMES<br>* Other names: Standard Care;|
| No Intervention: Control<br>Sham NMES will not be provided. Standard care won´t be altered and passive mobilization will be performed according to routine ICU procedures. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tracheal twitch pressure (centimeters of water) | Sub Maximal diaphragmatic strength measured trough tracheal twitch pressure derived from magnetic stimulation of phrenic nerve. | Change from begining (Day one) and at the end (Day three) | 
| Change in Diaphragmatic thickness fraction (centimeter percentage change) | Diaphragmatic function derived from ultrasonography measurement of diaphragmatic muscle thickness between inspiration and expiration (during twitch manoeuvre) | Change from begining (Day one) and at the end (Day three) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IL-1 myokine | IL-1 Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| IL-6 myokine | IL-6 Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| Decorin myokine | Decorin Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| Myostatin myokine | Myostatin Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| IL-15 myokine | IL-15 Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| Brain derived neurotrophic Factor (BDNF) myokine | BDNF Measured in peripheral blood samples (pg/dL) | through Study, at begining (Day one) and at the end (Day three). Before and after intervención | 
| Change in Diaphragmatic muscle structure (cemtimeters) | Diaphragmatic thickness measured with ultrasonography (Centimeters) | Change from begining (Day one) and at the end (Day three) | 
| Change in peripheral muscle structure (centimeters) | Muscle layer thickness of vastus intermedius and rectus femoris of the quadriceps, measured with ultrasonography (Centimeters) | Change from begining (Day one) and at the end (Day three) | 
| Functional outcomes | Mechanical Ventilation time (Hours) | through Study completion, an average of 1 month as maximum during follow up | 
| Functional outcomes | ICU length of stay (Days) | through Study completion, an average of 2 month as maximum during follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromuscular electrical stimulation, Critical care