High-intensity Resistance Training in Post-exacerbation COPD

Background

Exacerbations of chronic obstructive pulmonary disease (COPD) represent critical events in the disease trajectory, significantly increasing mortality, hospital readmissions, and reducing quality of life. Following an exacerbation, affected individuals frequently experience higher symptoms and functional decline, which may be either reversible or not.

Individuals recovering from COPD exacerbations often face profound peripheral muscle weakness, particularly in the quadriceps. This is attributed to systemic inflammation, corticosteroid use, chronic inactivity, and nutritional deficits during acute phases.

Current international guidelines advocate for pulmonary rehabilitation (PR) during the post-acute recovery phase of COPD. These programmes integrate exercise training, self-management education, psychological support, and pharmacological optimization. PR programmes must be tailored to each participant's clinical conditions, comorbidities, and needs.

The ideal timing of PR initiation after an acute exacerbation of COPD remains debated. Some evidence shows that early rehabilitation involving endurance training during hospitalization did not reduce readmission rates nor improve long-term physical capacity, and was associated with increased mortality at 12 months, compared to delayed PR. Consequently, guidelines recommend starting PR within three weeks after discharge from acute hospital care to mitigate any risk associated with early initiation during the acute phase.

Regarding modality, the core component of PR programmes is moderate to high-intensity endurance training, recommended as the gold standard to improve exercise tolerance, functional capacity, and health-related quality of life in stable COPD. However, high-intensity endurance sessions may be hard to tolerate for individuals recovering from an exacerbation, who still experience severe symptoms and marked limitations in daily activities.

Alternative types of training that allow the muscles to be trained without triggering marked dyspnoea and fatigue have been investigated. Previous evidence describes lower cardiorespiratory stress induced by resistance training compared with endurance training in individuals with COPD.

In the context of COPD exacerbations, resistance training initiated early during hospitalization has been shown to effectively prevent muscle deterioration, promote anabolic balance, and counteract catabolic processes without exacerbating systemic inflammation. Individuals undergoing resistance training demonstrated significant improvements in quadriceps strength and six-minute walking distance (6MWD), highlighting its potential as a core component of early PR during COPD exacerbation.

Additional evidence indicates that adding resistance training to endurance training during the post-exacerbation phase produces significant increases in muscle strength while yielding comparable benefits in dyspnoea, exercise capacity, and quality of life.

Therefore, resistance training appears feasible and safe both in the acute and post-acute phases of a COPD exacerbation, but whether strength programmes may allow training for individuals unable to tolerate high-intensity endurance sessions remains unknown.

Among resistance training programmes, maximal strength training (MST) has the potential to most effectively improve lower limb function. MST consists of exercising at high loads and few repetitions, requiring participants to develop maximal rate of force mobilization during the concentric phase. Evidence in stable COPD indicates that MST is safe, feasible, and significantly improves quadriceps rate of force development, mechanical efficiency, and effort tolerance.

Currently, no clear guideline exists for the protocol to be used for participants in the initial rehabilitation phase after exacerbation. In clinical practice, during the early phase of the rehabilitation pathway, a high percentage of individuals (estimated between 40% and 50%) are unable to perform endurance training according to the gold standard for stable COPD (intensity at 70% of maximum watt at incremental test).

For this reason, MST could represent a valid alternative for individuals who are not able or not yet able to tolerate high-intensity endurance training after an exacerbation. Due to the lower respiratory involvement associated with this type of training, the investigators hypothesize higher tolerance, greater improvements in dyspnoea and lower limb muscular efficiency, and similar changes in effort tolerance.

Primary aim

The primary objective of this study is to compare the effects of an early MST programme versus a conventional high-intensity endurance training programme on dyspnoea reduction when initiated shortly after hospital discharge for a COPD exacerbation.

Secondary aims

The secondary aims are to compare MST with high-intensity endurance training in terms of:

1. Functional capacity measured by 6MWD, and exercise tolerance 2. Fatigue reduction over time measured by the Fatigue Severity Scale 3. Muscle strength measured as maximum voluntary contraction of the quadriceps and 1-Repetition Maximum (1RM) on the leg press 4. Impact of the disease and quality of life

Only for non-dropout participants: 5. Peripheral muscle fatigue assessed through neuromuscular testing 6. Walking efficiency assessed by a dedicated treadmill test

Only after the last training session: 7. Satisfaction and acceptability of the training programmes

Material and Methods 1. Study protocol At enrolment, after providing informed consent, participants will be randomized per block of four by an external operator into two groups (1:1): one group will perform high-intensity resistance training (HIRT, experimental group) and the other conventional endurance training (HIET, control group). Both training programmes will include sessions 5 times/week, of exercises commonly used in respiratory rehabilitation, not involving additional risks compared to normal clinical practice. A senior physiotherapist will supervise all training sessions. 2. Intervention

The rehabilitation programme will consist, for the first 15 sessions, of:

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1. High-Intensity Resistance Training (HIRT) - Experimental Group Participants will perform high-intensity strength training with progressive workload increases and low-intensity endurance training without progression.

Strength training will be performed on a horizontal leg press:

• Four sets of five repetitions at 90-95% of 1RM

• Focus on concentric quadriceps contraction from 90° to full extension * Two-minute rest between sets * Load increased by 2.5 kg when participants exceed five repetitions Endurance training will consist of low-intensity cycling at 20% of maximum workload estimated from 6MWD. Intensity will remain unchanged throughout the study.

Possible side effects include delayed onset muscle soreness (DOMS), typically resolving within a short period.

HIRT will be performed in cycles of 2 days on and 1 day off. 2. High-Intensity Endurance Training (HIET) - Control Group

Participants will perform:

• Cycling at 70% of maximum workload estimated by 6MWD for 25 minutes

• Load increased by 10 watts when dyspnoea and fatigue are rated below 5 on the Borg scale * Three-minute warm-up and three-minute warm-down * Monitoring of heart rate, blood pressure, oxygen saturation, and symptoms at session end * Five sessions/week In addition, participants will perform low-intensity resistance training (20% 1RM), four sets of five repetitions on the same leg press, 6-7 days/week, with no progression.

After the 15-session programme, all participants will undergo T1 evaluation and continue with a combined programme (HIRT + HIET or HIET + HIRT) until discharge.

3\. Dropouts Withdrawal will be defined if participants cannot complete the first training session without adverse events or side effects.

Criteria:

\- HIRT group: at least 18/20 repetitions completed

\- HIET group: at least 20 minutes of cycling with ≤1-minute interruption Participants unable to complete the first session will be classified as dropouts and continue training at low intensity.

4\. Measures 4.1 Assessments at enrolment

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1. Anthropometric measurements (age, sex, BMI) 2. Comorbidities (CIRS scale) 3. Pulmonary function (spirometry) 4. Arterial blood gases in ambient air

• Distance walked on the Six-Minute Walk Test (6MWT) [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Fatigue Severity Scale (FSS) total score [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Maximal Voluntary Contraction (MVC) of isometric quadriceps voluntary strength. [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Lower Limb Strength Assessment with the 1-Repetition Maximum (1-RM) Test. [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Quadriceps muscle thickness (vastus lateralis) via ultrasound scanning [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Quadriceps pennation angle (vastus lateralis) via ultrasound scanning [Time frame: From randomization to the End of the program (up to 3 weeks)]
• Diaphragmatic thickness via ultrasound scanning [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Diaphragmatic excursion via ultrasound scanning [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Impact of the disease (COPD Assessment Test - CAT) [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Health-related Quality of Life (MRF-26 questionnaire) [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Maximal Voluntary Contraction (MVC) [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]
• Electrically stimulated resting force (Qtpot) [Time frame: From the date of randomization to the End of the program (up to 3 weeks)]