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
Authors:   , Jalil Contreras Yorschua Frederick 
Published: April 2024

Introduction: Critically ill patients hospitalized at Intensive Care Units (ICU) are characterized by an accelerated muscle wasting, particularly of respiratory muscles, occurring early due to mechanical ventilation (MV). Although active muscle activation may prevent these alterations, it is usually not available at early stages of care because of sedation, favoring a vicious circle. Neuromuscular electrical stimulation (NMES) represents an alternative to achieve muscle contraction in this setting, being able to prevent local muscle wasting, and according to some reports, has the potential to shorten MV time. It has been suggested that this potential benefit might be explained by systemic effects of NMES on distant muscles due to the release of myokines, a diverse range of chemokines secreted by myocytes during contraction. However, no studies have evaluated whether NMES applied to peripheral muscles (quadriceps) in critically ill patients can exert distant muscle effects over the diaphragm, and if such effects are associated to changes in myokine concentrations. Objective: To determine the effects of NMES applied to both quadriceps on myokine plasmatic concentrations, and on peripheral and respiratory muscle function and structure, in mechanical ventilated ICU patients when initiated at an early phase of their critical illness. Methods: Exploratory randomized controlled trial of NMES applied to both quadriceps, twice a day, for 3 days, in comparison to standard care (control group, CG). For myokine characterization (IL-6, BDNF, Myostatin and Decorin), blood samples were obtained at baseline (T0), at the end of the NMES session (T1), and 2 and 6 hours later (T2 and T6). This sampling was repeated on days 1 and 3. For the control group (CG) blood samples were obtained only at T0 and T6. An additional blood sample was also taken on Day 4 (T0) for both groups. Muscle characterization was performed at days 1 and 3 (T0 and T6 respectively). This consisted in ultrasonography of quadriceps muscle layer thickness (MLT), and diaphragmatic thickening fraction (TFdi), along with tracheal tube pressure derived from phrenic nerve magnetic stimulation (Ptr,tw), for diaphragmatic function. Results: 11 patients were randomized: 6 to CG and 5 to NMES. No differences were observed between groups at baseline. No significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) for quadriceps MLT change (p-value of 0.12). However, time as factor had a significant impact on MLT explained by a decrease from 1.92 ± 0.81 cm on day 1 to 1.63 ± 0.85 cm on day 3 in the CG, with a p-value of 0.003, while no change along time was observed in the NMES group (Change from 1.76 ± 0.62 cm on day 1 to 1.66 ± 0.61 cm on day 3, with a p-value of 0.51). Concerning diaphragmatic thickening fraction (TFdi), a significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) (p-value of 0.006). While in the CG there was an absolute TFdi decrease of 8.93% ± 6.4 (-32.6 ± 25.3 % of relative change) along time, in the NMES group TFdi increased 5.14± 6.55 % (+38.15 ± 58.6 % of relative change). Considering Twitch tracheal pressure (Ptr,tw), a significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) (p-value of 0.04). In the control group, Ptr,tw exhibited an absolute change of -1.43 ± 0.68 cmH20, corresponding to a relative decrease of 19.49% ± 16.98 from baseline values to day 3, while the NMES group experienced an absolute change of +2.5 ± 3.8 cmH2O, equivalent to a relative increase of 46.4 ± 45.6 %. Analyzing the raw plasmatic concentrations of myokines, no significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) for any of the myokine concentrations (Decorin, Myostatin, IL-6 and BDNF). Moreover, there were no significant changes observed either within or between groups at any time point. Conclusion: The preliminary data analysed supports the notion that peripheral NMES can preserve respiratory muscle function. It appears that this effect is not mediated by changes in any of the myokines included in the present study. Therefore, alternative mechanisms should be considered to explain how NMES may favour respiratory muscle preservation. The results observed on peripheral muscle layer thickness are yet unconclusive with the limited sample size analysed. Data from a larger number of patients is required to confirm these preliminary conclusions.