Introduction
Hematopoietic stem cell transplantation (HSCT) is widely used for the cure of a variety of hematological malignant and non-malignant diseases sustaining the quality of life and the functional capacity of the patients. 1 , 2 – 3 Nevertheless, HSCT may also be associated with infection, respiratory, cardiovascular complications, poor nutritional performance, and loss of motor and respiratory muscle. 4 , 5 Fatigue is related to the side effects of the conditioning regimen and the reduction of physical activity levels resulting from pancytopenia and their complications. 6 During the conditioning period and until the engraftment, patients remain with restricted activities and in complete isolation. 7 Physiotherapy provides measures and tools to evaluate the functional capacity and can improve the muscle strength and aerobic capacity. 8 , 9 That support is fundamental for recovering functional deficits and earlier discharge. 10 The aim of this study was to evaluate the effects of hospital cardiorespiratory physical therapy protocol in keeping the functional capacity and its impact in the quality of life of the HSCT patients.
Method
This prospective and longitudinal study was developed at the HSCT Unit of the Clinics Hospital of University of Campinas, SP, Brazil, from January to December 2019. The project was approved by the ethics and research committee (CAAE no. 94927418.3.0000.5404).
Patients with hematological diseases and eligible for an autologous or allogeneic HSCT were invited to participate in the study. The patients elegible for an allogeneic HSCT were included if they had high or reduce dose allogeneic HSCT, with related HLA identical or haploidentical donors and graft source from bone marrow or peripheral blood. The conditioning regimens and GVHD prophylaxis were selected according to ongoing protocols at the University Hospital and patients were able to understand the proposed treatment and to sign the free informed consent.
The exclusion criteria were presence of neurological, cognitive and musculoskeletal disorders that might compromise the physical evaluation, hemodynamic instability, acute respiratory failure, sepsis and patients in contact isolation due to multidrug-resistant bacteria.
The presence of fever, gastro-intestinal tract abnormalities, dizziness or arterial pressure alteration was not exclusion criteria for the study. These conditions just delay the protocol application for a moment.
The functional evaluation, aerobic capacity and quality-of-life questionnaire were performed in two moments, pre-conditioning (initial evaluation), when patient was already hospitalized, and pre-discharge (final evaluation). The intervention proposed protocol was performed twice a week during hospitalization and included stretching, aerobic training, muscle strengthening of the upper limbs, and respiratory muscle. The following tools were applied to evaluate the functional and aerobic capacity: bilateral dynamometry (palmar grip strength), 11 Manovacuometry (maximum inspiratory pressure and maximum expiratory pressure) 12 and Ventilometry (measurements of tidal volume, minute volume and vital capacity) 13 to evaluated the peak expiratory flow “Peak Flow”, 14 and the 6-min walk test (6MWT). 15 The questionnaire SF-36 16 and the Visual Analog Scale (VAS) 17 were applied to evaluate the quality-of-life.
The intervention protocol is detailed in Table 1 and was initiated with global stretching followed by aerobic training in the portable ergometer cycle and muscle strengthening of the upper limbs with the use of an elastic band. The respiratory muscle training was also part of the protocol with the use of Power Breathe K5. The intervention exercises were performed according to Campanatti-Palhares Grando Protocol. 18 , 19 – 20
Table 1
Intervention protocol.
HRR: heart rate reserve.
| Stretches | Active-assisted stretching (upper, lower limbs and trunk). Total duration: 5 min (30 s for each muscle group). |
| Aerobic training | Cardiovascular and respiratory conditioning (using live up sports portable cycle ergometer). Duration: 20 min (minimum tolerable: 5 min ). Intensity: Heart rate of 60 to 80% of heart rate reserve [HRR= HR resting + 0.6 to 0.8 (maximum HR - resting HR)]. |
| Muscle strengthening of the upper limbs | Muscle strengthening of upper limbs with elastic band. Duration: 15 min (3 sets of 10 repetitions in each muscle group). |
| Strengthening of respiratory muscles | Respiratory muscle strengthening (performed with the Power Breathe K5 device). Automatic mode load, light level (training intensity of 50% of inspiratory pressure and initial expiratory) – 30 repetitions. |
Statistical analysis
All descriptive analysis and others were used in the IBM-SPSS (Statistical Package Social Sciences) version 24, considering p -value < 5%. The paired Student T-Test was applied, and when the assumptions were broken, it was used Independent T-Test.
Results
The median age was 50 years (20–71) and, the majority of, patients were male (65.5%); 58% patients have undergone an autologous HSCT and 35% identical related allogeneic HSCT. 24 (83%) out of 29 patients completed the study, making possible to address the two evaluations had been designed. 5 out of 29 patients were not evaluated. 5 due to clinical complications (3 died). Table 2 depicts the patients characteristics.
Table 2
Patients’ characteristics.
BMI: body mass index; AML: acute myeloid leukemia; NHL: non-Hodgkin lymphoma; LH: Hodgkin's lymphoma; ALL: acute lymphoblastic leukemia; CML: chronic myeloid leukemia. ⁎ one case was not evaluated because had early death.
| Characteristics | n = 29 |
| Gender: Male, n (%) | 19 (65.5) |
| Female | 10 (34.5) |
| Median age, (range), years | 50 (20–71) |
| Median weight, (range), Kg | 74 (50–115) |
| Median height, (range), m | 1.78 (1.53–1.9) |
| Median BMI, (range) | 26.47 (16.7–39) |
| Underlying disease, n (%) | |
| Multiple myeloma | 11 (38) |
| AML | 06 (20.5) |
| NHL | 06 (20.5) |
| HD | 02 (7) |
| ALL | 02 (7) |
| CML | 01 (3.5) |
| Sickle Cell Anemia | 01 (3.5) |
| Type of transplant, n (%) | |
| Autologous | 17 (58) |
| Identical related allogeneic | 10 (35) |
| Haploidentical allogeneic | 02 (7) |
| Conditioning, n (%) | |
| Busulfan + Cyclophosphamide | 13 (45) |
| Melphalan | 10 (35) |
| Busulfan + Fludarabine + Cyclophosphamide | 05 (17) |
| Fludarabine + Melphalan | 01 (3) |
| Doses: Myeloablative, n (%) | 26 (89.6) |
| Reduced intensity, n (%) | 3 (10.4) |
| Median day of hospitalization , (range) | 29 (13–57) |
| Median day of neutrophil engraftment (range) | 18 (10–45) |
| Median day of platelet engraftment (range) | 18 (9–43) |
| Median day of antibiotics during hospitalization , (range) | 2 (1–5) |
| Degree of mucositis, n (%) * | |
| 0-II | 16 (57) |
| III-IV | 12 (43) |
| Median of physiotherapeutic interventions , (range) | 3 (1–9) |
| Number of live patients discharged from hospital , n (%) | 26 (90) |
The median number of interventions per patient was 3 (1–9). All variables comparing the functional diagnosis before and after intervention were not statistically significant, but a significant decreasing in the right (29 versus 27, p ≤ 0.001) and left (27 versus 26, p ≤ 0.002) dynamometry were observed. Table 3 depicts the comparison of functional diagnosis before and after interventions.
Table 3
Comparison between functional diagnosis before and after interventions.
Kgf: kilogram strength; l/min: liters per minute; PE max: maximum expiratory pressure; PI max: maximum inspiratory pressure; cmH²O: centimeter of water; ipm: inspirations per minute; l: liters; ml: milliliters. ⁎ Paired T test.
| Variables | Initial evaluation ( n = 24) | Final evaluation ( n = 24) | p -value * |
| Average (SD) | Average (SD) | ||
| Right dynamometry, kgf | 29 (± 11) | 27 (± 9) | 0.001 |
| Left Dynamometry, kgf | 27 (± 10) | 26 (± 10) | 0.002 |
| Peak flow, l/min | 410 (± 146) | 378 (± 124) | 0.36 |
| PE max, cmH²O | 88 (± 29) | 86 (± 35) | 0.49 |
| PI Max, cmH²O | 84 (± 35) | 78 (± 35) | 0.25 |
| Respiratory rate, ipm | 15 (± 5) | 16 (± 5) | 0.34 |
| Volume per minute, l/min | 12086.38 (± 5326) | 13945.17 (± 3730) | 0.26 |
| Tidal volume, l | 0.82 (± 0.38) | 0.90 (± 0.35) | 0.64 |
| Vital capacity, ml | 3234.48 (± 913.0) | 3372.92 (± 921.7) | 0.34 |
All variables comparing the domains of SF-36 and 6 MWT before and after intervention were also not statically significant, but the 6MWT (386,2 versus 338,0, p ≤ 0.004) and walking/predicted distance (64 versus 56, p ≤ 0.003) had significant decreases. Table 4 depicts the comparison of the SF-36 domains and the 6 MWT before and after intervention.
Table 4
Comparison between the SF-36 domains and 6MWT before and after intervention.
6MWT: six-minute walk test; m: meters; %: percentage. ⁎ Paired T test.
| Variables | Pre-intervention ( n = 24) | Post-intervention ( n = 24) | p -value * |
| Mean (SD) | Mean (SD) | ||
| General SF-36 | 107.4 (± 21) | 108.1 (± 20) | 0.95 |
| Functional capacity | 59 (± 25) | 58 (± 27) | 0.44 |
| Physical aspects | 29 (± 33) | 21 (± 29) | 0.23 |
| Pain | 55 (± 30) | 53 (± 27) | 0.78 |
| General State | 66 (± 20) | 72 (± 21) | 0.09 |
| Mental health | 64 (± 24) | 68 (± 25) | 0.23 |
| Vitality | 62 (± 25) | 62 (± 27) | 0.99 |
| Social aspects | 60 (± 29) | 69 (± 30) | 0.07 |
| Emotional aspects | 45 (± 42) | 43 (± 45) | 0.76 |
| Walking distance in the 6MWT ´, m | 386.2 (± 74) | 338.0 (± 96) | 0.004 |
| Walking/predicted distance, % | 64 (± 17) | 56 (± 19) | 0.003 |
Discussion
Our study showed a reduction in bilateral palmar grip strength, post HSCT ( p < 0.0001 for the right hand and p = 0.002 for the left hand), which may characterize the decrease in overall muscle strength, even with the application of the proposed protocol. The decrease in muscle strength, often related only to physical inactivity, can also be related to adverse symptoms related to conditioning and low adherence to exercises and the physical therapy intervention protocol applied was not able to improve the strength. 7 , 21
Decreased tolerance to physical exercise after three weeks of HSCT, described by Morishita et al., 22 was also observed in our study that showed a decreasing in the walking distance evaluated by the 6MWT and walking/predicted distance, after HSCT. However, the perception of fatigue during exercise was similar before and after HSCT. These results might reflect the decrease in the cardiovascular and muscle conditioning, or low support, and the proposed protocol was not able to improve them. 23 Possibly, if the number of sessions were higher, increasing the intensity of the exercises, the results might be more evident. Fatigue and loss of strength in performing daily life activities are symptoms of functional deficit and those results can be related to the prognosis after HSCT. 24
The non-significant differences in the values of the pre- and post-HSCT evaluation may suggest that the physical therapy protocol can prevent the worsening of the functional capacity loss after HSCT because, there are data showing a significant reduction in the functional capacity after HSCT. 4 , 25 , 26 , 27
The patients in whom our proposed protocol was applied, no significant difference in the SF-36 domains before and after intervention was observed showing a preservation of quality-of-life. A tendency in a higher mean value of the domain “General State of Health” [pre 66 (SD± 20) and post 72 (SD± 21), p = 0.09)] was observed. This domain reflects the patients’ perception of their health, which is his/her perspective of improvement. 28
In addition, the exercises performed were not related to any adverse clinical effects. The presence of pancytopenia should not be a factor of contraindication to physical exercise. This activity can be performed safely, respecting the intensity tolerated by the patient, as stated by Morishita et al. 29
A potential risk associated with the intervention was a concern. To prevent those risks patients during the exercises were monitored in order to keep the heart rate in 60 to 80% of resting heart rate, peripheral oxygen saturation greater than or equal to 90%, and systolic blood pressure between 90 to 140 mm of mercury and diastolic blood pressure between 60 and 90 mm of mercury. 18 , 19 – 20 The median number of interventions per patient was 3 (1–9) reflecting the clinical condition complexity associated by the presence of fever, gastrointestinal discomfort, pain, blood pressure changes, platelet number less than 10,000/mm³ and hemoglobin below 8 g/blood deciliter which hampered a higher number of interventions sessions.
One limitation of our study is the heterogenicities related to underlying diseases, as well the type of HSCT. Nevertheless, 90% of the evaluated patients received a myeloablative conditioning making it a homogeneous population regarding outcome risks. Moreover, the sample size was not applied for obtaining adequate statistical power. Due that, our sample was not probabilistic and the enrolled eligible patients were consecutives and based on the availability for HSCT during the study period avoiding bias inclusion.
Conclusion
Cardiorespiratory rehabilitation can preserve functional capacity and quality-of life. We have not reported significant functional loss when was compared between the initial and final evaluation.
We conclude that is possible to perform safely hospital cardiorespiratory therapy protocol during the HSCT, even in pancytopenia conditions.
Conflicts of interest
The authors declare no conflicts of interest.
References
1. Passweg J.R., Baldomero H., Bader P., Bonini C., Cesaro S., Dreger P., et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40000 transplants annually. Bone Marrow Transplant. 2016;51:786–792. doi: 10.1038/bmt.2016.20.
2. Voltarelli J.C., Moraes D.A., Ribeiro A.A.F., Oliveira MC., Rodrigues M., Brum DG., et al. Brazilian consensus for hematopoietic stem cell transplantation for the treatment of autoimmune diseases. Br J Hematol Hemother. 2010;32(1):125–135.
3. Silla L.M.R., Dulley F., Saboya R., Paton E., Kerbauy F., Arantes AM., et al. Hematopoietic stem cell transplantation and acute myeloid leukemia: Brazilian guidelines. Br J Hematol Hemother. 2010;32(1):61–65.
4. Vasconcellos C.S., Martins M.E.C., Junior C.G., Aranha F.J.P., Souza C.A., Vigorito A.C. Functional evaluation indicates physical losses after hematopoietic stem cell transplantation. Br J Hematol Hemother. 2012;34(5):345–351. doi: 10.5581/1516-8484.20120090.
5. Bom E.A. State University of Campinas, Faculty of Medical Sciences; Campinas: 2011. Influence of Respiratory Physiotherapy on the Evolution of Respiratory Conditions of Patients in the Early Phase of Myeloablative Transplantation of Hematopoietic Progenitor Cells (PHCT) [Dissertation] p. 139.
6. Jafari H., Jannati Y., Nesheli H.M., Hassanpour S. Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation. J Res Med Sci. 2017;22(13) doi: 10.4103/1735-1995.199094.
7. Tonosaki A. The long-term effects after hematopoietic stem cell transplant on leg muscle strength, physical inactivity and fatigue. Eur J Oncol Nurs. 2012;4:475–482. doi: 10.1016/j.ejon.2011.11.005.
8. Mohammed J., Savani B.N., El-Jaeahri A., Vanderklish J., Cheville A.L., Hashmi S.K. Is there any role for physical therapy in chronic GvHD? Bone Marrow Transplant. 2018;53:22–28. doi: 10.1038/bmt.2017.155.
9. Trevisan M.E., Porto A.S., Pinheiro T.M. Influence of respiratory and lower limbs muscle training on functional performance of individuals with COPD. Physiother Res. 2010;17(3):209–213.
10. DeFor T.E., Burns L.F., Gold E.A., Weisdorf D.J. A Randomized trial of the effect of a walking regimen on the functional status of 100 adult allogeneic donor hematopoietic cell transplant patients. Biol Blood Marrow Transplant. 2007;1:948–955. doi: 10.1016/j.bbmt.2007.04.008.
11. Reis M.M., Arantes P.M.M. Measurement of handgrip strength: validity and reliability of the Saehan dynamometer. Physiother Res. 2011;18(2):176–181.
12. Caruso P., Albuquerque A.L, Santana P.V., Cardenas LZ., Ferreira JG., Prina E., et al. Diagnostic methods for evaluation of inspiratory and expiratory muscle strength. Br J Pulmonol. 2015;41(2):110–123. doi: 10.1590/S1806-37132015000004474.
13. Goldwasser R., Farias A., Freitas E.E., Saddy F., Amado V., Okamoto V. Weaning and interruption of mechanical ventilation. Br J Pulmonol. 2007;33(2):128–136.
14. Burge P.S. Peak flow measurement. Thorax. 1992;47:903. doi: 10.1136/thx.47.11.903.
15. American thoracic society committee on proficiency standards for clinical pulmonary function laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respirat Crit Care Med. 2002;166(1):111–117. doi: 10.1164/ajrccm.166.1.at1102.
16. Ciconelli R.M., Ferraz M.B., Santos W., Quaresma M.R. Translation into Portuguese and validation of the generic quality of life assessment questionnaire SF36 (Brazil SF-36) Br J Rheumatol. 1999;39(3):143–150.
17. Martinez J.E., Grassi D.C., Marques L.G. Analysis of the applicability of three pain assessment instruments in different care units: outpatient, infirmary and urgency. Br J Rheumatol. 2011;51(4):299–308.
18. Battisti A., Oliveira D.S., Kessler E.C.H., et al. Comparison of static stretching, of 15 or 30 s , in the extensibility of hamstrings. ConScientiae Health. 2012;11(4):566–572.
19. Abad C.C.C., Silva R.S., Mostarda C., Silva I.C.M., Irigoyen M.C. Effect of aerobic and resisted exercise on autonomic control and hemodynamic variables of healthy young people. Br J Phys Educ Sport. 2010;24(4):535–544.
20. Campanatti-Palhares L., Simoncini T.C., da Silva Augusto PG., Masi Galhardo FD., Pereira MG., Vian BS., et al. Effects of a physiotherapeutic protocol in respiratory function, aerobic capacity and quality of life after kidney transplantation. Transplant Proc. 2018;50:750–753. doi: 10.1016/j.transproceed.2018.02.045.
21. Mohammed J., AlGhamdi A., Hashmi S.K. Full-body physical therapy evaluation for pre- and posthematopoietic cell transplant patients and the need for a modifiedrehabilitation musculoskeletal specific grading system for chronic graft-versus-host disease. Bone Marrow Transplant. 2018;53:625–627. doi: 10.1038/s41409-017-0075-3.
22. Morishita S., Wakasugi T., Tanaka T., Harada T., Kaida K., Ikegame K., et al. Changes in Borg scale for resistance training and test of exercise tolerance in patients undergoing allogeneic hematopoietic stem cell transplantation. Support Care Cancer. 2018;26:3217–3223. doi: 10.1007/s00520-018-4168-3.
23. Persoon S., Kersten M.J., Buffart L.M., Vander Slagmolen G., Baars JW., Visser O., et al. Health-related physical fitness in patients with multiple myeloma or lymphoma recently treated with autologous stem cell transplantation. J Sci Med Sport. 2017;20:116–122. doi: 10.1016/j.jsams.2016.01.006.
24. Jones L.W., Devlin S.M., Maloy M.A., Wood WA., Tuohy S., Espiritu N., et al. Prognostic importance of pretransplant functional capacity after allogeneic hematopoietic cell transplantation. Oncologist. 2015;20:1290–1297. doi: 10.1634/theoncologist.2015-0200.
25. Abo S., Ritchie D., Denehy L., Panek-Hudson Y., Irving L., Granger L. A hospital and home-based exercise program to address functional decline in people following allogeneic stem cell transplantation. Support Care Cancer. 2018;26:1727–1736. doi: 10.1007/s00520-017-4016-x.
26. Öberg A., Genberg M., Malinovschi A., Hedenström H., Frisk P. Exercise capacity in young adults after hematopoietic cell transplantation in childhood. Am J Transplant. 2018;18:417–423. doi: 10.1111/ajt.14456.
27. Somerfield M.R., Rizzo J.D. Can a modest exercise program really improve physical functioning and quality of life among recipients of hematopoietic SCT? Bone Marrow Transplant. 2010;45:217–218. doi: 10.1038/bmt.2009.164.
28. Ferreira V.S.B. State University of Campinas, Faculty of Medical Sciences; Campinas: 2019. Evaluation of the Quality of Life of Patients with Extraperitoneal Rectal Cancer Submitted to Neoadjuvant Therapy, Using the SF-36 Instrument [Dissertation] p. 85.
29. Morishita S., Kaida K., Setogawa K., Kajihara K., Ishii S., Ikegame K., et al. Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation. Eur J Cancer Care (Engl) 2013;22:289–299. doi: 10.1111/ecc.12027.