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

Mechanical Ventilation Complication Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05536531
• Other study ID #: 52-c50
• Secondary ID: ID 210602003
• Status: Recruiting
• Phase: N/A
• Start date: July 11, 2022
• Est. completion date: February 28, 2023

Study information

• Verified date: July 2022
• Source: Pontificia Universidad Catolica de Chile
• Contact: Yorschua Jalil, PT, MSc
• Phone: 96691771
• Email: yfjalil[@]uc.cl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 32
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Consecutively admission to Christus ICU between March 2021 and December 2021.

2. Connected to invasive MV within the previous 24-48 hours

3. Deep sedation [non-cooperative state; Sedation-Agitation Scale (SAS) 1 or 2].

4. 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).

5. Written informed consent provided by patient/surrogate

Exclusion Criteria:

1. Age < 18 years

2. Pregnancy

3. Obesity (Body Mass Index >35 kg/m2)

4. Pre-existing Neuromuscular diseases (e.g., myasthenia Gravis, Guillain-Barré disease)

5. Diseases with systemic vascular involvement such as systemic lupus erythematosus.

6. Use of neuromuscular blockers

7. Technical obstacles to the implementation of NMES such as bone fractures or skin lesions (e.g., burns)

8. End-stage malignancy

9. Presence of cardiac pacemakers

10. Diagnosis of brain death.

Related Conditions & MeSH terms

• Asthenia
• Mechanical Ventilation Complication
• Muscle Weakness
• Paresis

Intervention

Device:
• Neuromuscular electrical stimulation (NMES)
Electrical stimulator (Electrostimulator TRAINFES 6 ADVANCED, Biomedical devices Spa, Santiago, Chile.) to administer NMES

Locations

Country	Name	City	State
Chile	Pontificia Universidad Católica de Chile	Santiago

Sponsors (1)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile

Country where clinical trial is conducted

Chile, 

References & Publications (5)

Dirks ML, Hansen D, Van Assche A, Dendale P, Van Loon LJ. Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients. Clin Sci (Lond). 2015 Mar;128(6):357-65. doi: 10.1042/CS20140447. — View Citation

Dres M, Dubé BP, Mayaux J, Delemazure J, Reuter D, Brochard L, Similowski T, Demoule A. Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients. Am J Respir Cri — View Citation

Goligher EC, Fan E, Herridge MS, Murray A, Vorona S, Brace D, Rittayamai N, Lanys A, Tomlinson G, Singh JM, Bolz SS, Rubenfeld GD, Kavanagh BP, Brochard LJ, Ferguson ND. Evolution of Diaphragm Thickness during Mechanical Ventilation. Impact of Inspiratory — View Citation

Routsi C, Gerovasili V, Vasileiadis I, Karatzanos E, Pitsolis T, Tripodaki E, Markaki V, Zervakis D, Nanas S. Electrical muscle stimulation prevents critical illness polyneuromyopathy: a randomized parallel intervention trial. Crit Care. 2010;14(2):R74. d — View Citation

Truong AD, Kho ME, Brower RG, Feldman DR, Colantuoni E, Needham DM. Effects of neuromuscular electrical stimulation on cytokines in peripheral blood for healthy participants: a prospective, single-blinded Study. Clin Physiol Funct Imaging. 2017 May;37(3): — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Diaphragmatic muscle structure (cemtimeters)	Diaphragmatic thickness measured with ultrasonography (Centimeters)	Change from begining (Day one) and at the end (Day three)
Secondary	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)
Secondary	Functional outcomes	Mechanical Ventilation time (Hours)	through Study completion, an average of 1 month as maximum during follow up
Secondary	Functional outcomes	ICU length of stay (Days)	through Study completion, an average of 2 month as maximum during follow up