The anticipated intervention could not be delivered due to low admission time

Chronic obstructive pulmonary disease (COPD) is highly prevalent and frequently punctuated by severe acute exacerbations (AECOPD), defined as a temporary worsening of symptoms which leads to hospitalisation. AECOPD result in physical inactivity, muscle weakness and decreased exercise capacity, which impacts negatively on patients' health status, and increases patients' susceptibility for new exacerbations and death. To date, light aerobic exercises, such as early mobilisation and low-intensity ambulation, have become part of standard of care during severe AECOPD. Nevertheless, additional strength training using neuromuscular electrical stimulation and functional exercises, which have been shown to prevent skeletal muscle dysfunction whilst inducing minimal stress in the ventilatory system, might be of added value to optimize patients' functional performance and symptoms during activities at discharge.

Therefore, this randomized controlled trial aims to evaluate the effectiveness of additional functional strength training and neuromuscular electrical stimulation on top of standard of care during hospitalisation for an AECOPD to enhance functional performance, symptoms of dyspnoea and fatigue during activities, and readmission rate.

Chronic obstructive pulmonary disease (COPD) is a progressive and life-threatening condition characterised by persistent respiratory symptoms and airflow limitation. It affects 384 million people, is one of the main causes of morbidity and the third cause of mortality worldwide, responsible for around 3 million deaths annually. Consequently, COPD results in significant and increasing health, economic and social burden. The trajectory of COPD is frequently punctuated by acute exacerbations (AECOPD), defined as episodes of acute worsening of respiratory symptoms that result in additional therapy.

Severe AECOPD lead to hospitalization and account for more than 70% of all COPD-related costs. AECOPD are associated with physical inactivity, quadriceps muscle weakness and decreased exercise capacity, which impacts negatively on patients' health status, and increases patients' susceptibility for exacerbations recurrence, hospitalisations and death. Therefore, minimising the negative sequelae of AECOPD and preventing rehospitalisation are fundamental treatment goals for individuals, families and health, economic and social systems.

People discharged from the hospital after an AECOPD benefit from participating in pulmonary rehabilitation, but uptake is generally low. By all means, however, it is important to maximize the patient's functional performance and minimize symptoms during activities by the time of discharge. During an AECOPD, patients experience increased dyspnoea. Consequently, exercise modalities with minimal ventilatory requirements are preferred. To date, light aerobic exercises, such as early mobilisation and low-intensity ambulation, have become part of the standard of care. Nevertheless, additional strength training using neuromuscular electrical stimulation (NMES) and functional exercises, which have been shown to prevent skeletal muscle dysfunction whilst inducing minimal stress in the ventilatory system, might be of added value to optimize patients' functional performance and symptoms at discharge.

The researchers hypothesise that adding functional strength training and NMES to the standard mobilisation practice during hospitalisation for an AECOPD will: i) preserve or enhance patients' functional performance; ii) reduce symptoms of dyspnoea and fatigue and iii) decrease the short-term readmission rate.

Therefore, this study aims to evaluate the impact of adding functional strength training and NMES to standard mobilisation practice during hospitalisation for an AECOPD on:

• functional performance (primary outcome);
• symptoms of dyspnoea and fatigue (secondary outcome);
• readmission rate (exploratory outcome).

Hospitalised patients with AECOPD will be recruited consecutively at the hospital "Ziekenhuis Oost-Limburg" (ZOL). Patients will be eligible if they are: i) hospitalised due to an AECOPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, ii) included within 48h of hospital admission and iii) able to provide informed consent. Exclusion criteria will include: i) need for mechanical ventilation or admission in the intensive care unit; ii) unstable cardiovascular disease; iii) hospitalization in the previous month; iv) significant musculoskeletal or neuromuscular impairment that precludes the performance of the tests or participation in the study; v) signs of cognitive impairment; vi) current neoplastic or immunological disease; vii) implantable electronic devices (e.g., pacemaker, implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy (CRT) device) and viii) sensitivity alterations.

A randomised controlled trial will be conducted. Researchers will provide patients with a brief explanation about the study, clarify any doubts and collect the informed consent. Patients will be assessed at 3 timepoints: within 48h of hospital admission (baseline assessment), at the day of discharge (post assessment) and 1 month after discharge (1-month follow-up). Additionally, patients' clinical records will be checked to assess for new AECOPD-related hospitalisations up to 6 months after discharge.

After baseline assessment, patients will be randomly allocated (ratio 1:1) to either the experimental or standard of care group. Randomisation will be performed using a random number generator. Both groups will receive daily treatment until discharge. All treatment sessions will be performed by the experienced physiotherapist team in the hospital and/or by a trained member of the research team not involved in the assessments. Patients' symptoms, vital signs and peripheral oxygen saturations will be monitored in all sessions.

The standard of care group will receive the common treatment delivered at the hospital, i.e., routine medical treatment and daily sessions of approximately 15 minutes consisting of airway clearance techniques and breathing exercises upon indication, mobilization, and low-intensity daily walking/cycling exercise (5 to 10 minutes) according to patients' tolerance.

The experimental group will receive the standard of care plus functional strength training and quadriceps neuromuscular electrical stimulation. Functional strength training will include lower limb (e.g. rising from chair, heel rises) and upper limb (e.g. push-ups from the chair and against the wall) exercises for 15 min/day. Target levels of dyspnoea and/or perceived exertion will be 4 to 6 in the modified Borg scale. For NMES, electrodes will be placed longitudinally on the vastus intermedius and vastus medialis and a symmetric biphasic pulse waveform, with a pulse duration of 400ms, a frequency of 50Hz, in cycles of 8s of contraction and 20s of rest, will be used for 30min/day. The highest intensity tolerated by the patient will be used and intensity will be increased every time the patient feels comfortable with increasing the intensity. The device "Compex Pro Rehab" (CE-0473) will be used.

All the assessments will be performed by an experienced physiotherapist, blinded to the allocation group. All the measurements will be done at the hospital "Ziekenhuis Oost-Limburg".

Sociodemographic, anthropometric (i.e., height and weight to compute body mass index) and general clinical data, as well as prior spirometric measurement, will be collected from clinical records for patients' characterization. Functional performance (the primary outcome) will be measured with the 1-minute sit-to-stand test. Isometric quadriceps strength and handgrip strength will be assessed at right and left sides. Self-reported symptoms, functional status and impact of the disease will also be collected (modified British Medical Research Council dyspnoea questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue, London chest activities of daily living, COPD Assessment Test). Physical activity will be objectively quantified, as an exploratory outcome, with an Actigraph GT3X. Additionally, the number of new AECOPD-related hospitalisations up to 6 months after discharge will be retrieved from clinical records.

A sample size estimation based on preliminary data from an exploratory study was performed to detect a moderate effect size (f=0.2), with 80% power, 5% significance level and moderate correlation among repeated measure (r=0.5) on the 1-minute sit-to-stand test. Considering that in rehabilitation interventions during hospitalization drop-out rates are around 6% (25, 26), 30 patients with AECOPD per group will be needed.

Descriptive statistics (i.e., mean and standard deviation, median and interquartile range, and/or relative percentages) will be used to describe the sample. Data collected at the 3 timepoints will be compared between the standard of care and intervention groups using inferential statistics. Normality of the data distribution will be explored with histograms, Q-Q plots and Shapiro-Wilk or Kolmogorov-Smirnov tests. Independent t-tests for normally distributed data and Mann Whitney U-tests for ordinal and non-normally distributed data will be used to compare baseline measurements between the 2 groups. Chi-square or Fisher's Exact tests will be used for categorical data. Comparisons between groups and timepoints will be performed using a two-way mixed ANOVA for normally distributed data, or the Kruskal-Wallis test with Bonferroni-adjusted pairwise comparisons for the non-normally distributed data. All statistical analysis will be performed in the software Statistical Package for the Social Sciences (SPSS).

Inclusion Criteria:

• hospitalised due to an AECOPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria
• included within 48h of hospital admission
• able to provide informed consent
• dutch speaker

Exclusion Criteria:

• need for mechanical ventilation or admission in the intensive care unit
• unstable cardiovascular disease
• hospitalization in the previous month
• significant musculoskeletal or neuromuscular impairment that precludes the performance of the tests or participation in the study
• signs of cognitive impairment
• current neoplastic or immunological disease
• implantable electronic devices (e.g., pacemaker, implantable cardioverter defibrillator [ICD], cardiac resynchronization therapy [CRT] device)
• sensitivity alterations