Introduction
Hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative procedure for various hematologic malignancies. HSCT is classified into two types according to the donor, being either allogeneic or autologous [ 1 – 3 ]. Overall survival after HSCT has improved significantly over the past two decades due to improvements in pre-transplantation conditioning protocols and post-transplant immunosuppression. In the light of this increased survival rate, attention must be paid to potential complications associated with the transplantation [ 4 ].
HSCT is associated with several comorbidities such as pulmonary complications (PCs), infections, pain, fatigue, muscle weakness, decreased balance function, and graft-versus-host disease (GVHD), which directly affect the functional capacity and quality of life of HSCT patients [ 5 ]. The development of these complications may be attributed to the long period of physical inactivity and the direct toxicity from chemotherapy and radiation therapy in patients undergoing HSCT [ 6 – 8 ].
Many factors contribute to the development of PCs in about 40% to 60% of HSCT recipients [ 9 , 10 ]. These include the underlying disease, pre-transplant induction therapy, the type of HSCT, the time taken for the transplant, and activity restriction. The sedentary lifestyle of HSCT patients even before the transplantation, because of the chemotherapy and radiation therapy they receive, can result in the reduction of respiratory muscular strength (RMS), diaphragmatic excursion, and pulmonary volume, and in the accumulation of secretions in the airways [ 11 – 17 ]. Moreover, the combination of high-dose chemotherapy and total body irradiation (TBI) causes direct pulmonary toxicity and can result in radiation-induced lung injury or interstitial pneumonitis, which increases the incidence and severity of PCs and impairs cell-mediated and humoral immunity for up to 6 months, possibly extending to 12 months [ 18 , 19 ].
Pre-transplant physical therapy (PT) rehabilitation is essential since patients undergoing HSCT should meet a minimum level of physical performance status to be eligible for HSCT. There is growing evidence that PT is a promising additional pre- and post-HSCT intervention because of its positive multidimensional impacts on muscle strength, fitness, respiratory function, and quality of life [ 20 , 21 ].
Improving pre-transplantation cardiorespiratory fitness and muscle strength reduces the risks of pneumonia and atelectasis and improves post-transplantation aerobic capacity, especially in individuals with GVHD who require a long-term stay in a protective environment [ 22 – 24 ].
The rehabilitation of HSCT patients is challenging, both physically and emotionally. One of the basic PT goals for the patient after HSCT is to prevent pneumonia and improve pulmonary circulation. Chest physical therapy (CPT) is used to clear secretions, reduce pulmonary infection and improve pulmonary function (PF) [ 23 , 24 ]. The impact of CPT is not well defined, and therefore the aim of the present study was to evaluate the efficacy of CPT during the pre-transplant phase in patients waiting for HSCT by referring to spirometric values as well as RMS.
Material and methods
Design and sample
This randomized controlled trial design was conducted on patients scheduled for HSCT at the bone marrow transplant unit within the Cancer Institute. Sixty-eight patients scheduled for HSCT were recruited for the study during the period between June 2018 and December 2019. They were under the care of a hematologist and were waiting for a bone marrow transplant (BMT). Among these, 58 (85%) patients were eligible to participate in the study, and only 50 (73.5%) completed the final evaluation. Before engaging in the study, every patient was asked to sign a consent form. The research was designed following the Declaration of Helsinki criteria. The study proposal was approved by the Ethics Committee of the institution (P.T.REC/012/003367).
After obtaining written informed consent from, patients were scheduled for an appointment to complete baseline measurements (T0) and receive study arm assignment; this was timed to take place 3 weeks before HSCT. All eligible patients were informed about the study during their preparation visit 3 weeks before their admission for allogeneic HSCT. Equal randomization to the CPT (A) and control (B) groups was achieved in the simplest manner, by a manual drawing of numbers on opaque paper. Group A was subjected to CPT, which consisted of postural drainage, diaphragmatic breathing exercises, inspiratory muscle training using incentive spirometry, forced expiration (coughing, huffing), and mobilizing techniques (percussion, vibration, shaking) in addition to routine medical treatment. Group B was subjected to the same routine medical treatment only. Concealed allocation was achieved because the research assistant who carried out the randomization was not involved in any part of the study procedure. The assessment was done for all patients by an investigator who was blinded to the patient’s allocation and had no access to the patient’s information. Patients in both groups received standard physical therapy care during the inpatient waiting period, which focused on keeping patients as active as possible in terms of their daily living activities.
Inclusion criteria
Patients (of both genders) were included in the study if they had been admitted to the HSCT unit, completed the induction therapy and were awaiting allogeneic HSCT. Additional inclusion criteria were: age range from 40 to 55 years, non-alcoholics, medically cleared to exercise by the transplant physician, and able to understand training instructions and follow the study protocol.
Exclusion criteria
Participants were excluded if they had one of the following: fever at the time of assessment, mucositis (grade IV or grade II–III with pain), post-HSCT complications that required hospitalization, or hemodynamic instability ( Figure 1 ).
Outcome measures
Measurements were obtained 3 weeks before HSCT (T0) as a baseline assessment, then at the end of treatment immediately before HSCT (T1) and the last assessment at 3 weeks after HSCT (T2).
Spirometry measures
Spirometry is a device that measures the rate at which the lung changes volume during forced breathing. Evaluations were conducted while the patient was in a sitting position, using a Helios 702 device (portable spirometer, Ambala, Haryana, India), following the guidelines for pulmonary function tests. The spirometry was calibrated on a regular daily basis. A disposable mouthpiece and bactericidal filter were coupled to the spirometer. Measurements with a nose clip were taken three times at 1-minute intervals.
The patient was instructed to inhale as deeply as possible, rest for 1 to 2 s and then exhale with maximum effort. The forced vital capacity (FVC), in which the patient inhales maximally and then exhales as rapidly and as completely as possible, the forced expiratory volume in 1 s (FEV1), which is the volume of air exhaled in the first second of the FVC maneuver, and the relation between FEV1 and FVC were measured [ 25 ].
During the spirometric measurements, patient effort and cooperation were required. Visual and verbal encouragement were given to the patients during the assessment. Air leaks, mouthpiece obstruction, and the Valsalva maneuver were avoided during the assessments. Measurement values were expressed in liters and the highest value was considered for analysis.
Respiratory muscle strength
To assess respiratory muscle strength (RMS), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were measured using a MicroMedical MicroRPM 01 (Respiratory Pressure Meter) according to American Thoracic Society and European Respiratory Society guidelines [ 26 ]. The device is a portable battery-operated non-invasive respiratory pressure meter with a clear digital display of the results.
Maximal inspiratory pressure
Maximal inspiratory pressure (MIP) is a composite of the pressure generated by the inspiratory muscles and the elastic recoil pressure of the lungs and chest wall. MIP was determined with empty lungs at residual volume (RV) by measuring upper airway pressure during a maximal voluntary inspiratory effort. Every patient was asked to expire to RV then perform the forceful inspiratory maneuver, sustaining it for 1 to 2 s. The best result from three tests was recorded and used for analysis as the value of inspiratory muscle strength, with a 1- or 2-minute rest and recovery period between efforts.
Maximal expiratory pressure
To measure MEP, every patient was asked to perform a maximal expiratory effort, sustaining it for 1 to 2 s. The best result from three tests was recorded and used for analysis as the value of expiratory muscle strength, with a 1- or 2-minute recovery period between efforts.
Intervention
Chest physical therapy (CPT)
Patients in group A were subjected to a supervised CPT program daily for 3 weeks before HSCT. The program consisted of postural drainage, diaphragmatic breathing exercises, coughing, huffing, percussion, shaking, and exercise training using an incentive spirometer in addition to routine medical treatment. The total duration of each CPT session ranged from 45 to 60 min according to patient tolerance. The choice of airway clearance method that was applied depended on two factors, patient preference and the individual response of the patient to treatment.
Postural drainage
Postural drainage (PD) involves placing the patient in different positions to clear secretions from the lower respiratory tract with the assistance of gravity. PD is effective when there is a large quantity of mucus with low viscosity. The time spent in each position was dependent on the quantity and viscosity of secretions [ 27 ].
Diaphragmatic breathing
Every patient in group A was asked to inhale maximally through the nose by directing airflow toward the epigastric region and then expire calmly through the mouth, with vibration applied by the therapist’s hand at the epigastric region at the end of inspiration and throughout the expiration. The frequency of breathing exercises was three series of ten repetitions, once per day [ 28 ].
Cough and huff
A cough is a forced expiratory effort, and it is the most important component of the CPT program because it brings secretions present in the larger airways outside the respiratory tract. Huffing is not as forceful as a cough, and therefore the flow and intrapulmonary pressure are much lower compared to coughing. However, as it is done while the glottis is open, huffing can work better and be less tiring to the patient [ 29 ].
Chest percussion, vibration, shaking
Chest percussion, vibration, and shaking involve mechanical forces applied to the anterior, lateral, and posterior thorax in order to mobilize thick secretions with a higher viscosity. Chest percussion is the manual application of rhythmic clapping to the thorax cage with a frequency of about 3–6 Hz [ 30 ]. Chest vibration is a manual oscillatory movement that is applied during expiration, and chest shaking is a more forceful movement applied to the thorax cage throughout expiration. Each technique was applied for 10 to 20 min according to the patient’s tolerance [ 31 ].
Incentive spirometry
Incentive spirometry (IS) is the most widely used method for the prevention and treatment of respiratory problems in postsurgical patients, by maintaining the patency of airways at risk of closure. The patient is asked to take 10 slow maximal inspirations and to hold each breath for as long as possible. This routine is repeated every 2 h throughout the day [ 32 ].
Data analysis
Data were collected and analyzed first through exploratory analysis to verify central tendency and dispersion measures and to test data normality. This preliminary investigation aimed to define the statistical tests needed. IBM SPSS Statistics software (version 23.0) was used to analyze the data. Means and standard deviations were calculated, and qualitative data were expressed as percentages and frequencies. To test the normal distribution of the data the Shapiro-Wilk test was applied. Non-paired Student’s t -test was used to compare the variables FEV1, FVC, FEV1/FVC, MIP, and MEP between groups A and B. Repeated measures ANOVA tests followed by post hoc Scheffé tests for pairwise comparisons were used to test the treatment and time effects (T0, T1, T2) on the spirometric values (FEV1, FVC, FEV1/FVC) as well as respiratory muscle strength (MIP and MEP). All the statistical tests used were two-tailed, at a significance level of 5% [ 33 ].
Results
Demographic data and baseline clinical characteristics
The two groups were comparable before the beginning of the study in terms of their demographic data and baseline clinical characteristics, since all the initial demographic and clinical measures were similar in both groups. There were no statistically significant differences ( p > 0.05) between groups regarding gender distribution, smoking status, indications for SCT, age, height, weight, and BMI. In terms of their baseline clinical characteristics, there were no statistically significant differences between the groups in their spirometric mean values for FEV1, FVC, and FEV1/FVC, as well as respiratory muscle strength MIP and MEP ( p > 0.05, Table I ).
Table I
Demographic and baseline clinical characteristics in both groups
Values are mean ± SD, BMI – body mass index, † p-value compared between groups.
| Variable | Group A | Group B | P -value |
| Age [years] | 48.16 ±4.67 | 46.80 ±4.52 | 0.301 † |
| Height [cm] | 157.92 ±5.70 | 160.80 ±5.64 | 0.079 † |
| Weight [kg] | 71.32 ±11.75 | 76.08 ±11.95 | 0.162 † |
| BMI [kg/m 2 ] | 28.76 ±5.50 | 29.45 ±4.55 | 0.634 † |
| Sex, n (%): | |||
| Male | 12 (48) | 9 (36) | 0.395 † |
| Female | 13 (52) | 16 (64) | |
| Smoking status, n (%): | |||
| Non-smoker | 10 (40) | 13 (52) | 0.677 † |
| Ex-smoker | 13 (52) | 8 (32) | |
| Current smoker | 2 (8) | 4 (16) | |
| Indications for SCT, n (%): | |||
| Acute lymphoblastic leukemia | 8 (32) | 10 (40) | 0.811 † |
| Acute myeloid leukemia | 5 (20) | 3 (12) | |
| Myelodysplastic syndrome | 3 (12) | 2 (8) | |
| Chronic myeloid leukemia, | 2 (8) | 2 (8) | |
| Non-Hodgkin lymphoma | 1 (4) | 2 (8) | |
| Multiple myeloma | 2 (8) | 3 (12) | |
| Aplastic anemia | 4 (16) | 3 (12) | |
| FEV1_T0 | 2.93 ±0.55 | 2.97 ±0.41 | 0.773 † |
| FVC_ T0 | 4.17 ±0.46 | 4.12 ±0.53 | 0.735 † |
| FEV1/FVC_T0 | 0.71 ±0.15 | 0.73 ±0.16 | 0.570 † |
| MIP_T0 | 112.96 ±16.62 | 110.24 ±18.75 | 0.590 † |
| MEP_T0 | 136.00 ±25.39 | 144.86 ±23.81 | 0.218 † |
Pulmonary function
Repeated measures ANOVA were used to test treatment and time effects on the mean spirometric values within groups. The mean spirometric values of FEV1, FVC, and FEV1/FVC increased after 3 weeks of treatment with chest physical therapy for patients in group A at T1 compared with their baseline mean values at T0 ( p < 0.05).
Follow-up of patients in group A at 3 weeks after HSCT (T2) revealed that their mean values of FEV1, FVC, and FEV1/FVC had decreased slightly compared with T1 ( p > 0.05) but was still significantly increased compared with the baseline (T0) measures ( p < 0.05). Regarding the control group, the mean values of FEV1, FVC, and FEV1/FVC had decreased markedly at both T1 and T2 compared with the baseline T0. On comparing the two groups at T1 and T2, the mean spirometric values of FEV1, FVC, and FEV1/FVC were improved significantly in group A more than in group B ( p < 0.05, Table II ).
Table II
Spirometric values (FEV1, FVC, FEV1/FVC) in both groups
* P-value compared within each group, † p-value compared between groups.
| Time of evaluation | Group A | Group B | P -value |
| FEV1: | |||
| T0 | 2.93 ± 0.55 | 2.97 ±0.41 | 0.773 † |
| T1 | 3.40 ±0.52 | 2.86 ±0.47 | 0.000 † |
| T | 3.34 ±0.60 | 2.80 ±0.44 | 0.001 † |
| P -value | < 0.001 * | 0.046 * | |
| FVC: | |||
| T0 | 4.17 ±0.46 | 4.12 ±0.53 | 0.735 † |
| T1 | 4.42 ±0.42 | 4.02 ±0.50 | 0.004 † |
| T2 | 4.29 ±0.44 | 3.86 ±0.61 | 0.007 † |
| P -value | 0.017 * | 0.062 * | |
| FEV1/FVC: | |||
| T0 | 0.71 ±0.15 | 0.73 ±0.16 | 0.570 † |
| T1 | 0.77 ±0.13 | 0.73 ±0.18 | 0.268 † |
| T2 | 0.79 ±0.16 | 0.75 ±0.18 | 0.377 † |
| P -value | 0.045 * | 0.758 * |
Respiratory muscle strength measures (MIP, MEP)
Table III shows the mean values of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) before treatment at T0 and after treatment at T1. Comparison of these measures indicates that they increased significantly after 3 weeks of treatment (T1) with chest physical therapy for patients in group A compared with their baseline mean values (T0), p < 0.05. Follow-up of patients in group A at 3 weeks after HSCT at T2 revealed that the mean values of MIP and MEP had decreased slightly compared with T1 ( p > 0.05) but were still significantly higher than the baseline (T0; p < 0.05). For the control group B, the mean values of MIP and MEP had decreased markedly at both T1 and T2 compared with the baseline (T0). Comparing both groups at T1 and T2, the mean values of MIP and MEP had both improved significantly more in group A than in group B ( p < 0.05).
Table III
Respiratory muscle strength (MIP, MEP) in both groups
* P-value compared within each group, † p-value compared between groups.
| Time of evaluation | Group A | Group B | P -value |
| MIP: | |||
| T0 | 112.96 ±16.62 | 110.24 ±18.75 | 0.590 † |
| T1 | 135.84 ±13.43 | 105.72 ±16.58 | 0.000 † |
| T2 | 132.20 ±16.07 | 103.60 ±15.35 | < 0.001 † |
| P -value | < 0.001 * | 0.082 * | |
| MEP: | |||
| T0 | 136.00 ±25.39 | 144.86 ±23.81 | 0.218 † |
| T1 | 152.44 ±19.14 | 134.84 ±24.33 | 0.007 † |
| T2 | 147.92 ±19.29 | 129.76 ±23.02 | 0.003 † |
| P -value | 0.001 * | < 0.001 * |
Discussion
Allo-HSCT survivors are unique patients who need special care due to the effects of chemotherapy and radiotherapy received before the transplant, which often result in various complex medical problems such as respiratory muscle weakness and functional capacity reduction. Weakness of expiratory muscles may cause inefficient gas exchange, powerless cough, and the accumulation of secretions, all of which may contribute to postoperative pulmonary complications such as atelectasis and pneumonia [ 34 ]. Chest physical therapy can be helpful not only in prevention but also in the treatment of respiratory dysfunctions in these unique patients [ 35 – 38 ].
Performing chest physical therapy before transplantation should be an essential part of the pre-transplant rehabilitation process. There is a gap in the literature regarding the precise role of CPT pre-HSCT and its impact on PF and RMS before and after HSCT. Therefore, the present study was carried out to investigate the safety, feasibility, and effects of pre-transplant CPT on PF and RMS before and after HSCT.
The findings of the present study revealed that the mean spirometric values of FEV1, FVC, and FEV1/FVC, as well as MIP and MEP, all improved significantly more in the CPT group than in the control group after 3 weeks of treatment at T1, immediately before HSCT.
Follow-up of the intervention group at 3 weeks after HSCT (T2) revealed that the mean values of FEV1, FVC, and FEV1/FVC, as well as MIP and MEP, had decreased a little compared with T1 but were still significantly increased in comparison with the baseline measures at T0, and compared with the control group ( p < 0.05). These results suggest that a CPT protocol applied before the transplant can improve PF and RMS before HSCT, as well as preventing a significant decrease of them after HSCT. Improvements in PF in the CPT group might be attributed to the CPT program, which was used to improve their ventilation efficiency and prevent lung infection by improving alveolar ventilation, venous return, and lymph waste, and decreasing dead space ventilation [ 39 ].
Suesada et al . (2007) found a significant reduction in MIP in patients who did not undergo respiratory exercises within 5 days of hospitalization [ 40 ]. Furthermore, other previous studies have also observed ventilation-related diaphragmatic dysfunction and a decrease in contractile fiber units due to disuse after only 12 h of mechanical ventilation [ 41 – 43 ].
Using incentive spirometry as a component of the CPT program might increase RMS and endurance. The increase in RMS may be due to increased recruitment of motor units. IS also improves the efficiency of ventilation, gives visual feedback for diaphragmatic training, maintains positive pressure in the airways, and increases perfused alveoli. While performing breathing exercises with IS, the patient should mobilize a large tidal volume with a low respiratory rate to improve muscle strength via an increased inspiration/expiration ratio. The maximum inspiration the patient took while using IS may increase the transpulmonary pressure and pulmonary volume, additionally, the rest at the end of inspiration keeping up this increase and ensuring alveolar stability [ 44 , 45 ]. Exercises using IS have many benefits; they are simple, cheap, safe, and have no known side effects. Another benefit is that once the patient is educated on how to use the method, no further supervision is needed [ 46 ].
Some studies have found that IS improves pulmonary functions (VC, FEV1, PEFR, and MVV), as it reduces the resistance to airflow by increasing lung volume, improving deep diaphragmatic breathing, and improving the expansion of collapsed areas [ 47 ]. Feedback respiratory training can improve respiratory function, exercise capacity, dyspnea perception and quality of life, and is especially motivating for children [ 48 ].
Bom et al . administered a pulmonary rehabilitation protocol that included inspiratory muscle training immediately after HSCT and continuing over a seven-day treatment period, and reported improvement in RMS [ 49 ]. In the current study, PF and RMS improved significantly after a CPT program that was applied for 3 weeks before the transplant, with large treatment effects seen after HSCT.
There are some limitations to the current study including sample size, local site recruitment, and the absence of a control group that did not receive any intervention; also, the type of conditioning regimen was not considered, the time that the participants spent out of bed and the hospitalization duration were not assessed, and follow-up assessment after discharge was lacking. The study did not include measurements of immune outcome. Another limitation was that the physiotherapist was not blinded to the study groups.
In conclusion, the current study highlights the positive impact of a 3-week CPT protocol applied before transplantation in improving pre-transplant pulmonary function and respiratory muscle strength and preventing their post-transplant reduction in allo-HSCT recipients. CPT is recommended to be applied during the pre-transplant waiting period, not merely to prevent the decline in pulmonary function and respiratory muscle force but also to increase gains in these measures.
Acknowledgments
This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R168), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
Conflict of interest
The authors declare no conflict of interest.
References
1 Del Campo L , León NG , Palacios DC , Lagana C , Tagarro D . Abdominal complications following hematopoietic stem cell transplantation . Radiographics 2014 ; 34 : 396 – 412 . 24617687 10.1148/rg.342135046
2 Costa V , McGregor M , Laneuville P , Brophy JM . The cost-effectiveness of stem cell transplantations from unrelated donors in adult patients with acute leukemia . Value Heal 2007 ; 10 : 247 – 55 . 10.1111/j.1524-4733.2007.00180.x 17645679
3 Singh AK , McGuirk JP . Allogeneic stem cell transplantation: a historical and scientific overview . Cancer Res 2016 ; 76 : 6445 – 51 . 27784742 10.1158/0008-5472.CAN-16-1311
4 Guilcher GM , Hematopoietic stem cell transplantation in children and adolescents . Pediatr Rev 2016 ; 37 : 135 – 44 . 27037099 10.1542/pir.2015-0044
5 Remberger M , Ackefors M , Berglund S , et al . Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study . Biol Blood Marrow Transplant 2011 ; 17 : 1688 – 97 . 21620989 10.1016/j.bbmt.2011.05.001
6 Yafawi JZD , Shehada ES , Soubani AO . Pulmonary complications following hematopoietic stem cell transplantation . In: Hematopoietic Stem Cells: New Research . Montgomery WG , Burton HI (eds.) . Nova Science Publishers, Inc . 2012 ; 1 – 49 .
7 Khurshid I , Anderson LC . Non-infectious pulmonary complications after bone marrow transplantation . Postgrad Med J 2002 ; 78 : 257 – 62 . 12151565 10.1136/pmj.78.919.257 PMC1742355
8 Yanik G , Kitko C . Management of noninfectious lung injury following hematopoietic cell transplantation . Curr Opin Oncol 2013 ; 25 : 187 – 94 . 23340330 10.1097/CCO.0b013e32835dc8a5
9 Afessa B , Litzow MR , Tefferi A . Bronchiolitis obliterans and other late-onset non-infectious pulmonary complications in hematopoietic stem cell transplantation . Bone Marrow Transplant 2001 ; 28 : 425 – 34 . 11593314 10.1038/sj.bmt.1703142
10 Wah TM , Moss HA , Robertson RJH , Barnard DL . Pulmonary complications following bone marrow transplantation . Br J Radiol 2003 ; 76 : 373 – 9 . 12814922 10.1259/bjr/66835905
11 Hagemeister FB . Treatment of relapsed aggressive lymphomas: regimens with and without high-dose therapy and stem cell rescue . Cancer Chemother Pharmacol 2002 ; 49 Suppl 1 : S13 – 20 . 12042984 10.1007/s00280-002-0447-1
12 Dimeo FC , Tilmann MH , Bertz H , Kanz L , Mertelsmann R , Keul J . Aerobic exercise in the rehabilitation of cancer patients after high dose chemotherapy and autologous peripheral stem cell transplantation . Cancer 1997 ; 79 : 1717 – 22 . 9128987
13 Berry DA , Ueno NT , Johnson MM , et al . High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials . J Clin Oncol 2011 ; 29 : 3224 – 31 . 21768454 10.1200/JCO.2010.32.5936 PMC4322116
14 Demirer T , Buckner CD , Appelbaum FR , et al . Busulfan, cyclophosphamide and fractionated total body irradiation for autologous or syngeneic marrow transplantation for acute and chronic myelogenous leukemia: phase I dose-escalation of busulfan based on targeted plasma levels . Bone Marrow Transplant 1996 ; 17 : 491 – 5 . 8722344
15 Pedrazzoli P , Ledermann JA , Lotz JP , et al . High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. On behalf of the European Group for Blood and Marrow Transplantation (EBMT) Solid Tumors Working Party . Ann Oncol 2006 ; 17 : 1479 – 88 . 16547069 10.1093/annonc/mdl044
16 Chi AK , Soubani AO , White AC , Miller KB . An update on pulmonary complications of hematopoietic stem cell transplantation . Chest 2013 ; 144 : 1913 – 22 . 24297123 10.1378/chest.12-1708
17 Teasell R , Dittmer DK . Complications of immobilization and bed rest. Part 2: other complications . Can Fam Physician 1993 ; 39 : 1440 – 6 . 8324412 PMC2379609
18 Gratwohl A , Baldomero H , Demirer T , et al . Hematopoietic stem cell transplantation for solid tumors in Europe . Ann Oncol 2004 ; 15 : 653 – 60 . 15033675 10.1093/annonc/mdh142
19 Roychowdhury M , Pambuccian SE , Aslan DL , et al . Pulmonary complications after bone marrow transplantation: an autopsy study from a large transplantation center . Arch Pathol Lab Med 2005 ; 129 : 366 – 71 . 15737032 10.5858/2005-129-366-PCABMT
20 Dimeo F , Fetscher S , Lange W , Mertelsmann R , Keul J . Effects of aerobic exercise on the physical performance and incidence of treatment-related complications after high-dose chemotherapy . Blood 1997 ; 90 : 3390 – 4 . 9345021
21 Wiskemann J , Huber G . Physical exercise as adjuvant therapy for patients undergoing hematopoietic stem cell transplantation . Bone Marrow Transplant 2008 ; 41 : 321 – 9 . 18026154 10.1038/sj.bmt.1705917
22 Baumann FT , Kraut L , Schüle K , Bloch W , Fauser AA . A controlled randomized study examining the effects of exercise therapy on patients undergoing hematopoietic stem cell transplantation . Bone Marrow Transplant 2010 ; 45 : 355 – 62 . 19597418 10.1038/bmt.2009.163
23 Mohammed J , Aljurf M , Althumayri A , et al . Physical therapy pathway and protocol for patients undergoing hematopoietic stem cell transplantation: recommendations from The Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) Group . Hematol Oncol Stem Cell Ther 2019 ; 12 : 127 – 32 . 30653940 10.1016/j.hemonc.2018.12.003
24 Danaher EH , Ferrans C , Verlen E , et al . Fatigue and physical activity in patients undergoing hematopoietic stem cell transplant . Oncol Nurs Forum 2006 ; 33 : 614 – 24 . 16676017 10.1188/06.ONF.614-624
25 Barreiro T , Perillo I . An approach to interpreting spirometry . Am Fam Physician 2004 ; 69 : 1107 – 15 . 15023009
26 Graham BL , Steenbruggen I , Barjaktarevic IZ , et al . Standardization of spirometry 2019 update an official American Thoracic Society and European Respiratory Society technical statement . Am J Respir Crit Care Med 2019 ; 200 : 70 – 88 . 10.1164/rccm.201908-1590ST PMC6794117 31613151
27 Van Der Schans CP . Conventional chest physical therapy for obstructive lung disease . Respir Care 2007 ; 52 : 1198 – 206 . 17716386
28 Bom EA , de Souza CV , Thiesen RA da S , Miranda ECM , de Souza CA . Evaluation of respiratory conditions in the early phase of hematopoietic stem cell transplantation . Rev Bras Hematol Hemoter 2012 ; 34 : 188 – 92 . 23049417 10.5581/1516-8484.20120047 PMC3459632
29 Gursli S , Sandvik L , Bakkeheim E , Skrede B , Stuge B . Evaluation of a novel technique in airway clearance therapy – Specific Cough Technique (SCT) in cystic fibrosis: a pilot study of a series of N-of-1 randomized controlled trials . SAGE Open Med 2017 ; 5 : 205031211769750 . 10.1177/2050312117697505 PMC5433674 28540046
30 Warnock L , Gates A . Cochrane Library Cochrane Database of Systematic Reviews Chest physiotherapy compared to no chest physiotherapy for cystic fibrosis . Cochrane Database Syst Rev 2015 ; 2015 : CD001401 . 26688006 10.1002/14651858.CD001401.pub3 PMC6768986
31 Li SK , Silva YR . Investigation of the frequency and force of chest vibration performed by physiotherapists . Physiother Can 2008 ; 60 : 341 – 8 . 20145766 10.3138/physio.60.4.341 PMC2792789
32 Liu CJ , Tsai WC , Chu CC , Muo CH , Chung WS . Is incentive spirometry beneficial for patients with lung cancer receiving video-assisted thoracic surgery? BMC Pulm Med 2019 ; 19 : 121 . 31286923 10.1186/s12890-019-0885-8 PMC6615301
33 Mishra P , Pandey CM , Singh U , Gupta A , Sahu C , Keshri A . Descriptive statistics and normality tests for statistical data . Ann Card Anaesth 2019 ; 22 : 67 – 72 . 30648682 10.4103/aca.ACA_157_18 PMC6350423
34 Sutbeyaz ST , Koseoglu F , Inan L , Coskun O . Respiratory muscle training improves cardiopulmonary function and exercise tolerance in subjects with sub-acute stroke: a randomized controlled trial . Clin Rehabil 2010 ; 24 : 240 – 50 . 20156979 10.1177/0269215509358932
35 James MC . Physical therapy for patients after bone marrow transplantation . Phys Ther 1987 ; 67 : 946 – 52 . 3295900 10.1093/ptj/67.6.946
36 Dimeo F , Fetscher S , Lange W , Mertelsmann R , Keul J . Effects of aerobic exercise on the physical performance and incidence of treatment-related complications after high-dose chemotherapy . Blood 1997 ; 90 : 3390 – 4 . 9345021
37 White AC , Terrin N , Miller KB , Ryan HF . Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation . Chest 2005 ; 128 : 145 – 52 . 16002928 10.1378/chest.128.1.145
38 Kovalszki A , Schumaker GL , Klein A , Terrin N , White AC . Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation . Bone Marrow Transplant 2008 ; 41 : 965 – 9 . 18264142 10.1038/bmt.2008.15
39 Scherer TA , Spengler CM , Owassapian D , Imhof E , Boutellier U . Respiratory muscle endurance training in chronic obstructive pulmonary disease: impact on exercise capacity, dyspnea and quality of life . Am J Respir Crit Care Med 2000 ; 162 : 1709 – 14 . 11069801 10.1164/ajrccm.162.5.9912026
40 Suesada MM , Martins MA , Carvalho CRF . Effect of short-term hospitalization on functional capacity in patients not restricted to bed . Am J Phys Med Rehabil 2007 ; 86 : 455 – 62 . 17515684 10.1097/PHM.0b013e31805b7566
41 Vassilakopoulos T , Petrof BJ . Ventilator-induced diaphragmatic dysfunction . Am J Respir Crit Care Med 2004 ; 169 : 336 – 41 . 14739134 10.1164/rccm.200304-489CP
42 Chang AT , Boots RJ , Brown MG , Paratz P , Hodges PW . Reduced inspiratory muscle endurance following successful weaning from prolonged mechanical ventilation . Chest 2005 ; 128 : 553 – 9 . 16100137 10.1378/chest.128.2.553
43 Gayan-Ramirez G , Decramer M . Effects of mechanical ventilation on diaphragm function and biology . Eur Respir J 2002 ; 20 : 1579 – 86 . 12503720 10.1183/09031936.02.00063102
44 Thorms C , Ispeth H , Sawyert R . Improved pulmonary function and exercise tolerance with inspiratory muscle conditioning in patients with cystic fibrosis . Chest J 1993 ; 104 : 1490 – 7 . 10.1378/chest.104.5.1490 8222813
45 Paiva DN , Assmann LB , Bordin DF , et al . Inspiratory muscle training with threshold or incentive spirometry: which is the most effective? Rev Port Pneumol (2006) 2015 ; 21 : 76 – 81 . 25926370 10.1016/j.rppnen.2014.05.005
46 So MW , Heo HM , Koo BS , et al . Efficacy of incentive spirometer exercise on pulmonary functions of patients with ankylosing spondylitis stabilized by tumor necrosis factor inhibitor therapy . J Rheumatol 2012 ; 39 : 1854 – 8 . 22859343 10.3899/jrheum.120137
47 El-Refaey B , Abd-El Maksoudb G , Ali O . Efficacy of feedback respiratory training on respiratory muscle strength and quality of life in children with spastic cerebral palsy: a randomized controlled trial . Bull Faculty Phys Ther 2017 ; 22 : 46 – 52 .
48 Fattah SA , Monim MTA , Aziz EA , et al . Chest physical therapy and its effects on lung functions in mechanically ventilated critically ill infants . Egypt J Neonatol 2001 ; 2 : 177 – 84 .
49 Bom EA , de Souza CV , Thiesen RA , Miranda EC , de Souza CA , Evaluation of respiratory conditions in an early phase of hematopoietic stem cell transplantation . Rev Bras Hematol Hemoter 2012 ; 34 : 188 – 92 . 23049417 10.5581/1516-8484.20120047 PMC3459632