Introduction: After haematopoietic stem cell transplantation (HSCT), patients often experience complications such as respiratory difficulties, fatigue and decreased quality of life.
The aim of the study was to compare the effectiveness of different inspiratory muscle training (IMT) protocols on respiratory muscle strength and endurance, dyspnoea, maximal exercise capacity, diaphragmatic function, respiratory function parameters, peripheral muscle strength, fatigue, quality of life, oxidative stress parameters, muscle biomarkers and inflammatory biomarkers in HSCT recipients during the transplantation process.
Method: The study will include patients between 18-65 years of age, who are able to walk and understand the instructions, who do not have orthopedic, neurological or cardiac disorders and who will undergo haematopoietic stem cell transplantation. Patients with cognitive impairments; orthopedic or neurological diseases that may affect the evaluation of physical fitness tests; patients with comorbidities such as asthma, COPD will not be included in the study. In cases where the exercise group subjects' attendance to the training protocol is interrupted for 3 sessions or more consecutively, the voluntariness to participate in the research is lost during the research process, and clinical haemodynamic instability develops in the subjects, the participant will be excluded from the study. Patients in whom exercise training is contraindicated such as acute bleeding, haemoglobin value \<5 g/dl, platelet count ≤10000 mm3, high fever (body temperature \>38◦C), severe pain, confusion, dizziness, nausea and vomiting will not be included in the exercise.
It is planned as a prospective, randomised controlled and single blinded study. Triple blinding could not be performed due to the executive's evaluation and implementation of the study protocol. Patients included in the study will be randomly divided into 3 study groups of 15 people each. Stratified randomisation technique will be used. A total of 45 haematopoietic stem cell transplant patients will be included in the study. Patients will be evaluated 3 times: before exercise therapy (pre-HSCT), before and after starting the preparatory regime and after exercise therapy (post-HSCT). Primary assessment measures are dyspnoea, maximal exercise capacity, respiratory muscle strength and endurance, diaphragmatic respiration, oxidative stress parameters, inflammatory markers, muscle biomarkers, pulmonary function test. Secondary assessment measures were peripheral muscle strength, fatigue, depression, and quality of life.
The research arms consisted of a total of 45(15;15;15) people in 3 groups: 'standard inspiratory muscle training group', 'functional respiratory muscle training group' and 'control group' with 15 people in each group. All patients in the control and research groups will receive inspiratory muscle training for a total of 30 minutes twice a day, every weekday during the transplantation period, starting at the end of the session in which their initial assessment was made. Functional respiratory muscle training group will perform functional exercises simultaneously with inspiratory muscle training 3 days a week (Monday-Wednesday-Friday or Tuesday-Thursday-Saturday). All exercises will be supervised by a physiotherapist.
The most important originality of this study is that it is the first study to investigate the effects of functional respiratory muscle training on respiratory parameters, diaphragm function, peripheral muscle strength, maximum oxygen consumption, dyspnoea, fatigue, depression and quality of life in HSCT recipients. It is the first randomised controlled study to demonstrate the effect of inspiratory muscle training on diaphragmatic function in HSCT recipients and it is one of the rare studies in which exercise capacity will be evaluated by cardiopulmonary exercise test. It is also the first study to examine the relationship between inspiratory muscle training and muscle biomarkers and oxidative stress parameters in HSCT recipients.
H0: There is no difference in the effectiveness of different inspiratory muscle training protocols on maximal exercise capacity, respiratory muscle strength, respiratory muscle endurance, diaphragmatic function, oxidative stress parameters, muscle biomarkers, inflammatory biomarkers, dyspnoea, peripheral muscle strength, quality of life, fatigue, depression in haematopoietic stem cell transplant recipients.
H1: There is a difference in the effectiveness of different inspiratory muscle training protocols on maximal exercise capacity, respiratory muscle strength, respiratory muscle endurance, diaphragmatic function, oxidative stress parameters, muscle biomarkers, inflammatory biomarkers, dyspnoea, peripheral muscle strength, quality of life, fatigue, depression in haematopoietic stem cell transplant recipients.
Planned haematopoietic stem cell transplantation in the adult bone marrow transplant unit
Between the ages of 18-65
Under standard medical treatment, including immunosuppressives, antibiotics and other medications
Ability to walk, co-operate and be clinically stable
Cognitive disorders
Have orthopaedic or neurological diseases that may affect the assessment of physical fitness tests
Having comorbidities such as asthma, COPD
Conditions in which exercise training is contraindicated, such as acute bleeding, haemoglobin value <5 g/dl, platelet count ≤10000 mm3, high fever (body temperature >38◦C), severe pain, confusion, dizziness, nausea and vomiting
Parallel
Inspiratory Muscle Training
Other interventionInspiratory muscle training will be performed at 40% of MIP workload, 1 set of 8-10 diaphragmatic respirations for 15 minutes, with 5-10 seconds rest intervals between sets. 5 days a week, 2 sessions per day.
Functional Inspiratory Muscle Training
Other interventionThis study investigates the integration of functional inspiratory muscle training (IMT) with conventional physiotherapy. Patients will perform inspiratory muscle training using the threshold loading technique with the POWERbreathe IMT device, combined with functional exercises. The functional IMT protocol will be administered face-to-face, 3 days a week, for 30 minutes per session over a 6-week period. Resistance on the IMT device will be set to 40% of the patient's maximal inspiratory pressure (MIP) and adjusted weekly based on measured MIP values. Exercises will be categorized into three progressive difficulty levels (easy, medium, and hard), with each stage lasting 2 weeks. Patients will inhale through the POWERbreathe IMT device during exercise movements and exhale during the return phase, ensuring simultaneous respiratory muscle activation and functional training.
Sham Inspiratory Muscle Training
Other interventionControl group will be performed at 10% of the MIP workload, 1 set of 8-10 diaphragmatic breaths for 15 minutes, with 5-10 seconds rest intervals between sets. 2 sessions per day, 5 days a week.
Dyspnea Perception Measurement
Dyspnea perception will be assessed using the Modified Borg Scale and the Modified Medical Research Council (MMRC) Dyspnea Scale. Modified Borg Scale: A subjective scale to assess dyspnea at rest and/or during activity. The scale ranges from 0-10, where 0 indicates no dyspnea and 10 indicates very severe dyspnea, reflecting the participant's perceived breathlessness. Modified MMRC Dyspnea Scale: This scale evaluates dyspnea during daily activities. It is graded as follows: 0: No dyspnea except for severe activity. 1. Dyspnea during fast walking or uphill climbing. 2. Dyspnea causes slower movement or stops on flat ground. 3. Dyspnea causes stopping after walking 100 meters or a few minutes. 4. Dyspnea occurs during dressing or undressing, preventing leaving the house. Unit of Measure: Modified Borg Scale: 0-10 points MMRC Dyspnea Scale: Grade 0-4
Cardiopulmonary Function Measurement
Cardiopulmonary function will be assessed using the Cardiopulmonary Exercise Test (CPET) with the MES VO₂max Finder device (Poland), providing measurements of VO₂, VCO₂, VE, RER, and ventilatory threshold following ATS and ERS standards. Protocol: Pre-test Preparation: Avoid caffeine and vigorous exercise for 24 hours prior. Test Protocol: The Modified Bruce protocol with progressive increases in speed (2.7 to 8.8 km/h) and incline (0 to 20%) every 3 minutes. Vital Signs Monitoring: Heart rate, blood pressure, SpO₂, dyspnea, and fatigue monitored. Test Duration: 8-12 minutes, ending when two criteria are met (exhaustion, 90% max heart rate, RER ≥ 1.10, or blood lactate \> 8.0 mmol/L). Cooldown: 3-minute cooldown post-test. Gas exchange analyzed breath-by-breath, with calibration per ATS/ERS guidelines. Unit of Measure: VO₂: mL/min VCO₂: mL/min VE: L/min RER: Ratio Ventilatory Threshold: L/min
Respiratory Muscle Strength Measurement
Respiratory muscle strength will be assessed by measuring Maximum Inspiratory Pressure (MIP) and Maximum Expiratory Pressure (MEP) using the Micro Medical Micro RPM device (Rochester, UK), with measurements recorded in cmH₂O. MIP: Measured during maximal inspiration against a closed airway after full expiration. MEP: Measured during maximal expiration against a closed airway after full inspiration. Both MIP and MEP will be maintained for 1-3 seconds. Three measurements will be taken, and the best value will be recorded. Results will be expressed as a percentage of normal reference values adjusted for age and gender. Disposable, personalized mouthpieces and filters will be used to prevent infection, following ERS (2019) guidelines. Unit of Measure: MIP and MEP: cmH₂O, expressed as a percentage of normal reference values.
Respiratory Muscle Endurance Measurement
Respiratory muscle endurance will be assessed using the Powerbreath Plus MR (HaB International Ltd., Southam, England), an inspiratory muscle training device employing a constant threshold load technique. The resistance of the device will be set at 60% of the participant's Maximum Inspiratory Pressure (MIP) value. During the test: The device will be placed in the participant's mouth, and the nose will be closed with a clip. The participant will be instructed to breathe through the device for a maximum of 10 minutes. Participants will be informed before the test that they can remove the device and stop the test if they feel excessive shortness of breath or discomfort. The time the participant is able to continue the test will be recorded in seconds. Unit of Measure: The unit of measure for this outcome is seconds for the duration the participant can continue the test.
Peripheral Muscle Strength Measurement
Peripheral muscle strength will be assessed using a portable manual muscle strength measuring device (Model 01165, Lafayette, IN, USA) and a Jamar Hydraulic Hand Dynamometer (Jamar, Nottinghamshire, UK). The muscles assessed include: Upper extremity: Shoulder abductor, shoulder flexor, elbow flexor, and elbow extensor. Lower extremity: Hip flexor and knee extensor. Grip strength will be measured in a sitting position with the elbow flexed at 90° and wrist neutral. Three measurements will be taken for each side (right and left), and the best value recorded in kilograms (kg) for grip strength and Newton-meters (Nm) for knee extensor strength. The measurements will be interpreted using reference equations from Andrews et al. Unit of Measure: Grip strength: kg Knee extensor strength: Nm Minimal Clinical Significance: Knee extensor strength: 17.2 Nm Grip strength: 6.25 kg
Fatigue Perception Measurement
Fatigue perception will be assessed using the Turkish adaptation of the Fatigue Severity Scale (FSS). The self-administered scale consists of nine items that evaluate the severity of fatigue experienced by the participant. Each item is rated on a 7-point scale, where 1 indicates "strongly disagree" and 7 indicates "strongly agree." The total score can range from a minimum of 9 to a maximum of 63. A total score of 36 or above indicates severe fatigue according to the criteria established by Armutlu et al. (2007). The scale provides a reliable assessment of the participant's perceived fatigue severity, allowing for the evaluation of changes over time.
Depression Measurement
Depression will be assessed using the 21-item self-administered Beck Depression Inventory (BDI), developed by Beck et al. The scale consists of 21 items that assess depression-specific conditions. Each item is scored on a 4-point scale, where scores range from 0 to 3. A higher score indicates a higher level of depression. The total score on the inventory can range from 0 (no depression) to 63 (severe depression). A score above 17 is accepted as indicative of the presence of depression. The unit of measure for this outcome is the total score, reported in points.
Quality of Life Measurement
Quality of life will be assessed using the Turkish adaptation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, Version 3.0). The Turkish version has been proven to be reliable and valid for use with patients. The questionnaire consists of 30 items, designed to evaluate the quality of life of cancer patients. It comprises nine subscales, which include: Five functional scales: Physical, role, cognitive, emotional, and social functioning. One global health and quality of life scale. Three symptom scales: Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, loss of appetite, constipation, diarrhoea, and financial difficulties. Additionally, the questionnaire includes items assessing the financial impact of the disease and its treatment. The unit of measure for this outcome is the total score, reported in points, derived from responses to the individual items within the subscales.
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Ceren Derya Gültekin
Lead sponsor
Istinye University
Sponsor institution
