Clinical trial NCT05536531: NMES Role to Prevent Respiratory Muscle Weakness in Critically Ill Patients and Its Association to Changes in Myokines.
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Muscle Weakness or Atrophy
Mechanical Ventilation Complication
Electrical Stimulations
Keywords: Neuromuscular electrical stimulation
Critical care
Lead sponsor: Pontificia Universidad Catolica de Chile
Sponsor class: OTHER
First posted: 2022-09-13
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Tracheal twitch pressure (centimeters of water)
timeFrame: Change from begining (Day one) and at the end (Day three)
measure: Change in Diaphragmatic thickness fraction (centimeter percentage change)
timeFrame: Change from begining (Day one) and at the end (Day three)
Secondary outcomes:
measure: IL-1 myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: IL-6 myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: Decorin myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: Myostatin myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: IL-15 myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: Brain derived neurotrophic Factor (BDNF) myokine
timeFrame: through Study, at begining (Day one) and at the end (Day three). Before and after intervención
measure: Change in Diaphragmatic muscle structure (cemtimeters)
timeFrame: Change from begining (Day one) and at the end (Day three)
measure: Change in peripheral muscle structure (centimeters)
timeFrame: Change from begining (Day one) and at the end (Day three)
measure: Functional outcomes
timeFrame: through Study completion, an average of 1 month as maximum during follow up
measure: Functional outcomes
timeFrame: through Study completion, an average of 2 month as maximum during follow up
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Pontificia Universidad Católica de Chile
Study officials:
affiliation: Facultad de Medicina, Pontificia Universidad Católica de Chile
name: Yorschua Jalil, PT, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dres M, Dube 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 Crit Care Med. 2017 Jan 1;195(1):57-66. doi: 10.1164/rccm.201602-0367OC.
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 Effort. Am J Respir Crit Care Med. 2015 Nov 1;192(9):1080-8. doi: 10.1164/rccm.201503-0620OC.
citation: 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.
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):255-262. doi: 10.1111/cpf.12290. Epub 2015 Oct 16.
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. doi: 10.1186/cc8987. Epub 2010 Apr 28.