Study population

All consecutive patients admitted to the ICU of Nagoya University Hospital between March and September 2021 due to COVID-19 with length of stay (LOS) > 24 h in the ICU were evaluated for inclusion in this single-center, prospective, observational study according to the following eligibility criteria: age ≥ 18 years; positive for COVID-19 with respiratory failure requiring IMV. The details of our clinical setting and management of COVID-19 were reported previously11. The diagnosis of COVID-19 was confirmed by real-time polymerase chain reaction for SARS-CoV-2 from any specimen. Management strategies for COVID-19 requiring IMV in the ICU were centered on the “ABCDEF” bundle12, and patients requiring < 4 L of oxygen were transferred to the COVID-19 general ward. The exclusion criteria were patients who died in the ICU, those who were not intubated, and those who did not receive rehabilitation therapy in the ICU. The first stage of the rehabilitation therapy program performed by a multidisciplinary team critical care consisting of eight physical therapists wearing personal protective equipment consisted of positioning or range of motion exercises in patients with a Richmond agitation sedation scale score ≤  − 2. Patients whose condition stabilized proceeded to the second stage, which consisted of sitting on the edge of the bed, standing, transferring to a chair, and active muscle training until discharge from the ICU. A multidomain rehabilitation intervention was then applied on ICU discharge, which consisted of supervised rehabilitation therapy to improve strength, balance, mobility, and endurance. Patients who were transferred to the hospital immediately after discharge from the ICU did not undergo rehabilitation and functional assessments at hospital discharge on the COVID-19 general ward.

Data collection

The clinical details of the patients at presentation and their demographic information and biochemical data at ICU admission were obtained from electronic medical records, and details of management in the ICU were extracted from the ICU patient information system (Fortec ACSYS; Phillips, Tokyo, Japan). The 4C (Coronavirus Clinical Characterisation Consortium) Mortality Score, which uses eight variables—age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation on room air, Glasgow Coma Scale, blood urea nitrogen, and C-reactive protein—was calculated for each patient at the time of admission to the ICU, as described previously13. In addition, the worst Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, which were also calculated within 24 h after admission to the ICU, were used in the analyses. The clinical frailty scale, with scores ranging from 1 (very fit) to 9 (terminally ill), was used to assess the degree of frailty prior to ICU admission14.

Physical function

The physical function of each patient was evaluated at discharge from both the ICU and from hospital. Muscle strength was determined using 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 of 4 points)6,15. In addition, muscle strength was also assessed by measurement of handgrip strength with the patient performing two maximal isometric voluntary contractions of the hands for 3 s each for both hands with the elbow joint angle 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 analyses were performed using the greatest strength expressed as absolute value (in kg). Muscle weakness was defined as MRC sum score < 48 points, or handgrip strength < 11 kg for men and < 7 kg for women, respectively16. In addition, low handgrip strength was defined as handgrip strength < 28 kg for men and < 18 kg for women17. The grip and release test (GRT) and the foot tapping test (FTT), in which we measured the number of times the patient could flex and stretch their fingers in 10 s for each hand and tap the sole of the foot in 10 s for each foot 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, respectively18,19. The highest scores obtained for both GRT and FTT were used in the analyses.

Symptom burden

The self-administered Edmonton Symptom Assessment System (ESAS) questionnaire, a validated and reliable patient-reported outcome measures tool assessing the severity of nine common symptoms (anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being), was used to assess each patient’s symptoms at discharge from the ICU and from hospital. The patients rated each symptom on an 11-point numeric scale with scores ranging from 0 (absence of symptom) to 10 (worst possible symptom)20. The ESAS scores were classified according to severity as follows: 0, no symptoms; 1–3, mild; 4–6, moderate; and 7–10, severe21.

Clinical outcomes

Clinical outcomes, including LOS in the ICU, unplanned ICU readmission, and the location of hospital discharge were included in the analysis. The ICU mobility scale score, an 11-point ordinal scale ranging from 0 (lying/passive exercises in bed) to 10 (independent ambulation), was calculated at the time of discharge from the ICU and hospital. The number of days taken to first mobilization (defined as ICU mobility scale score ≥ 3, i.e., sitting on the edge of the bed or higher) was assessed22. The Barthel Index routinely recorded in the nursing and rehabilitation summaries was used as a measure of activities of daily living (ADL) at the time of hospital discharge.

All patients were followed up prospectively at approximately 6 months after ICU discharge by mail-based surveys with the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire and the EuroQol Visual Analogue Scale (EQ-VAS) as indices of QOL23. The EQ-5D-5L summary index was calculated based on responses related to five health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which was rated on a 5-point scale from 1 (best) to 5 (worst). The responses were translated using Japanese value sets into the EQ-5D-5L summary index, ranging from − 0.025 (worst) to 1 (best)24. EQ-VAS was used to record the patient’s self-rated health on a scale ranging from 0 (worst) to 100 (best).

Statistical analysis

Continuous variables are expressed as the median and interquartile range (IQR), and categorical variables are expressed as numbers and percentages. As there was no established cutoff value for prolonged IMV in COVID-19 patients, the cohort was divided into the short IMV group and prolonged IMV group according to the median duration of IMV. Differences between groups were evaluated by the Mann–Whitney U test for continuous variables and Fisher’s exact test for dichotomous variables. Within-group differences in physical function and symptom burden between ICU discharge and hospital discharge were evaluated by Wilcoxon’s signed-rank test. The primary outcome was MRC sum score at ICU discharge.

Statistical analyses were performed using SPSS version 23.0 (IBM Corporation, 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

The 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 all participants were informed that they were free to opt out of participation in the study at any time.

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