Table of Contents
Study cohorts
This single-center, retrospective observational, case–control study was performed in patients ≥ 18 years old admitted to the ICU of Nagoya University Hospital due to COVID-19 with respiratory failure requiring IMV between January and April 2022 (EMS therapy group) and age-matched controls admitted between March and September 2021 (historical control group) with length of stay > 24 h in the ICU. Patients who died in the ICU, who were not intubated, and who did not receive rehabilitation therapy in the ICU were excluded.
In all patients, COVID-19 diagnosis was confirmed by real-time polymerase chain reaction (PCR) for SARS-CoV-2 from any specimen. Our clinical setting and management of COVID-19 were reported previously5,18. Management of COVID-19 requiring IMV in the ICU was based on the “ABCDEF (Assess & manage pain, Both spontaneous awakening trials and spontaneous breathing trials, Choice of sedation and analgesia, Delirium assessment & management, Early mobilization and exercise, and Family engagement)” bundle19. Patients requiring < 4 L of O2 were transferred to the general COVID-19 ward. Rehabilitation therapy was performed by a multidisciplinary critical care team. The first stage of rehabilitation performed in patients with Richmond Agitation Sedation Scale (RASS) score ≤ − 2 consisted of positioning or range of motion exercises. In patients whose condition stabilized, rehabilitation proceeded to the second stage consisting of sitting on the edge of the bed, standing, transferring to a chair, and active muscle training until discharge from the ICU.
Electrical muscle stimulation
EMS therapy was incorporated into the rehabilitation program in all patients in the EMS therapy group once they had progressed beyond the initial very acute phase after discontinuing neuromuscular blockade. Patients with skin lesions, cardiac pacemakers, infection or trauma of the extremities, those who were unable to walk before hospital admission, and those who could not speak Japanese were excluded from the EMS therapy group. EMS was applied to the bilateral upper and lower limb muscles (biceps brachii, quadriceps femoris, and gastrocnemius muscles: middle of the upper arm and approximately 2 cm above the cubital fossa for biceps brachii, approximately 5 cm below the inguinal fold and 3 cm above the upper patella border for the quadriceps femoris, and approximately 3 cm below the popliteal fossa and immediately above the proximal end of the Achilles tendon for the gastrocnemius muscles) with a stimulator (Solius; Minato Medical Science, Osaka, Japan) using self-adhesive surface electrodes (40 × 80 mm). The EMS intervention included as part of the standard rehabilitation therapy for patients with respiratory or circulatory failure and postoperative patients in the ICU in our institution was reported previously20,21,22. We applied EMS with a variable-frequency train that began with high-frequency bursts (200 Hz), followed by low-frequency stimulation (20 Hz), and EMS was applied as a symmetrical biphasic square wave with 0.4-s pulses of direct current followed by a 0.6-s pause. Pulse groups consisting of 10 impulse trains were delivered to unilateral muscle groups at 10-s intervals during the session, and the output current was adjusted to ensure visible muscle contraction. EMS was applied by trained physiotherapists for 30 min per day, 6 days per week, for up to 2 weeks until the discharge from the ICU. We set the discontinuation criteria during the EMS session as follows: (1) change in systolic blood pressure > ± 20 mmHg; (2) increase in heart rate > + 20 beats/min; (3) development of sustained ventricular arrhythmia, atrial fibrillation, and paroxysmal supraventricular tachycardia; (4) decrease in blood oxygen saturation > − 4%.
Data collection
The Coronavirus Clinical Characterisation Consortium Mortality Score was calculated for each patient on admission to the ICU23. The worst Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, both of which were also calculated within 24 h after ICU admission, were used in the analyses. The clinical frailty scale was used to assess the degree of frailty prior to ICU admission, with scores ranging from 1 (very fit) to 9 (terminally ill)24.
Physical function and clinical outcomes
Physical function was evaluated in each patient at the time of discharge from the ICU. Muscle strength was determined based on the Medical Research Council (MRC) sum score, which assesses the strength of each muscle group in the upper and lower limbs with scores for each muscle group ranging from 0 to 5 and higher scores indicating greater muscle strength (total score range: 0 = worst to 60 = best, minimal clinically important difference 4 points)3,25; MRC sum score < 48 points was taken as the definition of muscle weakness26. Handgrip strength was also measured to assess muscle strength with the patient performing two maximal isometric voluntary contractions of each hand for 3 s with the elbow joint fixed at 90° flexion in the supine position using a Jamar dynamometer set to the second handle position (DHD-1 Digital Hand Dynamometer; Saehan Corporation, Seoul, South Korea). The greatest strength expressed as an absolute value (kg) was used in the analyses. The grip and release test and foot tapping test, involving measurement of the number of times the patient could flex and stretch the fingers of each hand in 10 s and tap the sole of each foot in 10 s while keeping the heel in contact with the floor and with the knees at 90° flexion, were performed with the patient in the supine position to evaluate upper and lower peripheral extremity motor function, respectively27,28. The analyses were performed using the highest scores obtained for both grip and release test and foot tapping test.
Clinical outcomes, including length of stay in the ICU, unplanned readmission to the ICU, and the location of hospital discharge (i.e., home or to another department/institution/ward/facility), were included in the analysis. At ICU discharge, we calculated the ICU mobility scale score for each patient determined on an 11-point ordinal scale ranging from 0 (lying/passive exercises in bed) to 10 (independent ambulation). The time taken to first mobilization (defined as ICU mobility scale score ≥ 3, i.e., sitting on the edge of the bed or higher) was assessed29.
Statistical analysis
Continuous variables are expressed as the median and interquartile range (IQR), and categorical variables are expressed as numbers and percentages. Differences between groups were evaluated by the Mann–Whitney U test for continuous variables and Fisher’s exact test for dichotomous variables. The primary outcome was MRC sum score at ICU discharge.
Statistical analyses were performed using SPSS version 23.0 (IBM Corp., Armonk, NY) and R version 3.2.1 (R Foundation for Statistical Computing, Vienna, Austria). In all analyses, a two-tailed P < 0.05 was taken to indicate statistical significance.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of Nagoya University Hospital, and was performed in accordance with the tenets of the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. Informed patient consent was obtained, and the patients agreed to reveal their facial photos for academic purposes. All participants were informed that they were free to opt out of participation in the study at any time.
