Esra Pehlivan, Arif Balcı, Lütfiye Kılıç, Figen Kadakal. Abstract. Key words: Dyspnea, Muscle loss, Psychologic assessment.

Transcription

1 Article Preoperative Pulmonary Rehabilitation for Lung Transplant: Effects on Pulmonary Function, Exercise Capacity, and Quality of Life; First Results in Turkey Esra Pehlivan, Arif Balcı, Lütfiye Kılıç, Figen Kadakal Abstract Objectives: The frequency and success rates of lung transplant in patients with end-stage lung disease are increasing. In our study, we investigated the effects of preoperative pulmonary rehabilitation on pulmonary function, exercise capacity, and quality of life in patients who are candidates for lung transplant. Materials and Methods: This prospective study included 39 consecutive patients who were candidates for lung transplant. All patients underwent preoperative pulmonary rehabilitation for at least 3 weeks. Results: Our patient group included 25 male and 14 female patients with a mean age of 36 years (range, y). Although no significant improvement was shown in the forced expiratory volume in 1 second after pulmonary rehabilitation, significant improve - ments were observed in the Modified Medical Research Council dyspnea scores (P =.001) and 6-minute walk distance (P =.001). We also observed statistically significant improvements in the Short- Form 36 Quality of Life Questionnaire s physical function (P =.01) and emotional role (P =.02) sub - parameters. We also found a significant improvement in the Beck Depression Inventory score (P =.004). There was no correlation between Beck Depression Inventory scores before and after rehabilitation and 6-minute walk distance, Short-Form 36, and Modified Medical Research Council dyspnea scores. Conclusions: Our results suggest that preoperative pulmonary rehabilitation improves exercise capacity, reduces the sensation of dyspnea and muscle strength loss, and has a positive effect on the psychologic state of patients who are candidates for lung transplant. From the Pulmonary Rehabilitation Center, Medical Science University, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. Corresponding author: Esra Pehlivan, Department of Pulmonary Rehabilitation, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey Phone: ext fztesrakambur@yahoo.com Experimental and Clinical Transplantation (2018) 4: Key words: Dyspnea, Muscle loss, Psychologic assessment Introduction Lung transplant is the last treatment option for endstage lung disease patients for whom conservative treatments have failed. 1 A pulmonary rehabilitation (PR) program has an important role in this group of patients who have chronic lung diseases and complex medical histories. 2 Studies have shown positive effects of PR programs in patients who are on wait lists for transplant and have shown that postoperative outcomes are improved in patients who can obtain higher preoperative exercise capacity. 3 In chronic pulmonary diseases such as chronic obstructive pulmonary disease, bronchiectasis, and interstitial lung disease, the efficacy and reliability of exercise have been well-documented. 4-6 However, data are still scarce on the safety and efficacy of exercise in patients with end-stage lung disease who are transplant candidates. Evidence-based exercise training programs for pre- and postoperative stages of transplant have not yet been developed. Considering the exercise principles and recom mendations in the guidelines for the care of adults with chronic pulmonary disease, exercise training programs should be established to offer optimal health benefits for transplant candidates on wait lists. 7 Patients prepared for lung transplant are a select patient population with advanced chronic lung disease. These patients typically have ventilator limitations and disabilities and are at high risk of preand postoperative complications. Ideally, a PR program should be able to respond to patient s questions, explain the disease and treatment methods, make the patient understand the potential benefits and risks of the treatment, and prepare the patient for surgery both physically and mentally. 2,8 Copyright Başkent University 2018 Printed in Turkey. All Rights Reserved. DOi: /ect

2 456 Esra Pehlivan et al/experimental and Clinical Transplantation (2018) 4: Exp Clin Transplant Over the past 5 years, lung transplant has been actively taking place in Turkey. Unfortunately, there are few centers performing PR during the preoperative and postoperative transplant periods. Our unit is the first PR center in Turkey and the only one to offer preoperative and postoperative physiotherapy for lung transplant candidates. The implementation of a dedicated PR program for patients waiting for lung transplant is crucial for the continuity and success of the therapeutic pathway. In the present study, we aimed to investigate the effects of preoperative PR on pulmonary function, exercise capacity, and quality of life in patients who are candidates for lung transplant. To the best of our knowledge, this is the first study investigating PR for lung transplant candidates in Turkey. Materials and Methods Between January 2013 and October 2016, 46 patients were admitted to the transplantation unit in Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital (Istanbul, Turkey). These patients were candidates for lung transplant due to end-stage lung disease and respiratory failure and were analyzed prospectively. Seven patients were excluded from the study because they did not complete the targeted PR program. The remaining 39 patients were included in the study. inclusion and exclusion criteria End-stage lung disease patients with planned transplants were included in our study. Exclusion criteria included cardiac disease preventing the patient from doing exercise, physical limitations (ie, musculoskeletal or neurologic disease), which prevented the patient from doing exercise, and serious cognitive and psychiatric disorders. Pulmonary function tests were conducted in the sitting position using the Sensor Medics model 2400 (Yorba Linda, CA, USA) and in accordance with American Thoracic Society guidelines. 9 Values for forced vital capacity and forced expiratory volume in 1 second were recorded. In addition, 6-minute walk test (6MWT) was conducted according to American Thoracic Society guidelines. 10 Heart rate, oxygen saturation, and modified Borg scale results were recorded. The severity of functional dyspnea was assessed using the Modified Medical Research Council Dyspnea Scale (mmrc). Increased mmrc levels of dyspnea are associated with increased mortality. 11 Muscle strength measurements were performed by using a digital dynamometer (Commander Muscle Tester, JTech Medical, Midvale, UT, USA) from the dominant extremity. Three measurements were made, and the best result was taken into consideration. The Short Form-36 (SF-36) was also used to assess the quality of life. The SF-36 includes 1 multi-item scale measuring each of 8 health concepts: (1) physical function, (2) role limitations because of physical health problems, (3) bodily pain, (4) social function, (5) general mental health (psychologic distress and psychologic well-being), (6) role limitations because of emotional problems, (7) vitality (energy/fatigue), and (8) general health perceptions. The contents of SF-36 items selected to measure these concepts are familiar to those who follow the health status assessment literature. 12 The Beck Depression Inventory (BDI) was used to evaluate the psychologic state. The BDI is a 21-item, self-reporting rating inventory that measures charac - teristic attitudes and symptoms of depression. 13 The supervised exercise program consisted of 2 days of group exercises under supervision of a physiotherapist and 3 days of exercise under no supervision at home, with a total of 5 days/week carried out for at least 8 weeks. Patient education was given at the beginning of the program. Within the education components, there was information about diseases, medications, and possible complications. In addition, patient respiratory exercises, respiratory control, dyspnea-coping methods, and bronchial hygiene techniques were taught. Aerobic and strengthening components were included in the exercise program. The patients performed 15-minute sets of stationary bike, treadmill walking, and arm ergometer workouts. The 6MWT and target heart rate method were used to identify the exercise intensity. Intensity was set to be at least 60% of the maximum heart rate. During the exercises, blood pressure, heart rate, saturation, and Borg Scale of Perceived Exertion scores were monitored. Strengthening exercises started with 30% of the load identified based on a maximum repeat calculation, and the load was increased according to the patient s tolerance. On the basis of variations in the overall condition of the patients, different

3 Esra Pehlivan et al/experimental and Clinical Transplantation (2018) 4: workloads and modifications were used while setting up the exercise program for each patient. For the home program, there were breathing exercises, strengthening exercises in simple workloads with TheraBand (TheraBand, Akron, OH, USA), and self-walking. So that patients could perform the exercises safely at home, patients and their relatives were trained on how to use the saturation and heart rate monitors with digital oximeter device and confidence intervals. In the study, control tests were performed at the beginning, at the end of week 4, and at the end of week 8. Written informed consent was obtained from each patient. The study protocol was approved by the Ethics Committee of Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki. Statistical analyses Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 15.0 software (SPSS Inc., Chicago, IL, USA). The Shapiro-Wilks test was used to determine normality of the variables. Any changes in the respiratory functions, mmrc, BDI, and some of the subscale items, including physical function, physical role, pain, vitality, and emotional role of SF-36, were compared using the Wilcoxon signed-rank test. Changes in the normally distributed 6MWD and some of the SF-36 subparameters were analyzed using paired sample t test. P <.05 was considered statistically significant. Results Of the 39 patients in our study, 25 were males (64%) and 14 were females (36%). The mean age was ± years (range, y). The mean body mass index was ± 4.49 kg/m 2. All patients were candidates for transplant due to end-stage lung disease. Demographic characteristics of the patients, diagnoses, ejection fraction, and systolic pulmonary artery pressure are presented in Table 1. Table 2 shows functional parameters (6MWD, mmrc) after PR program and change from baseline. Significant improvements were observed in 6MWD (P =.001) and mmrc dyspnea scores (P =.001). With no statistical difference, there was a slight decrease in the mean results of lung functions. There were no statistically significant differences in quadriceps femoris (QF) (P =.95) and biceps muscle strength (P =.32). table 1. Demographic Characteristics and Diagnoses Results, No. (%) or Means ± SD Sex Male 64 (25) Female 36 (14) Age, y ± Body mass index, kg/m ± 4.49 Diagnosis Bronchiectasis 41 (16) Emphysema 5 (2) Silicosis 15 (6) ILD 12 (5) Sarcoidosis 5 (2) COPD 10 (4) Cystic fibrosis 10 (4) Ejection fraction, % 53.78±5.83 spap, mmhg 41.60±11.55 Abbreviations: COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; SD, standard deviation; spap, systolic pulmonary artery pressure table 2. Functional Parameters After Pulmonary Rehabilitation and Change From Baseline Before PR After PR P Value (means ± SD) (means ± SD) 6MWD, m ± ± mmrc 3.91 ± ± Measured FEV 1, L 0.80 ± ± Predicted FEV 1, % ± ± Measured FVC, L 1.27 ± ± Predicted FVC, % ± ± QF Muscle strength, lb ± ± Biceps muscle strength, lb ± ± Abbreviations: 6MWD, 6-minute walking distance; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; mmrc, Modified Medical Research Council; PR, pulmonary rehabilitation; QF, quadriceps muscle; SD, standard deviation table 3. Beck Depression Inventory and SF-36 Quality of Life Scores After Pulmonary Rehabilitation and Change From Baseline Before PR After PR P Value (means ± SD) (means ± SD) BDI ± ± SF-36 Physical function ± ± Physical role ± ± Pain ± ± General health ± ± Energy/vitality ± ± Social function ± ± Emotional role ± ± Mental health ± ± Abbreviations: BDI, Beck depression inventory; PR, pulmonary rehabilitation; SF-36, Short-Form 36; SD, standard deviation The BDI and SF-36 quality of life scores of patients are shown in Table 3. A significant improvement was observed in BDI scores after PR (P =.004).

4 458 Esra Pehlivan et al/experimental and Clinical Transplantation (2018) 4: Exp Clin Transplant Statistically significant improvements in the SF-36 Quality of Life Questionnaire were also shown for physical function (P =.01) and emotional role (P =.02) subparameters. We found no correlations between BDI scores before and after PR and 6DWD, SF36, and mmrc (Table 4). table 4. Correlation of Depression, Exercise Capacity, Quality of Life, and Dyspnea Discussion Δ6MWD ΔSF-36 (PF) ΔSF-36 (ER) ΔmMRC ΔBDI r = r = r = r = P =.43 P =.55 P =.16 P =.71 Abbreviations: BDI, Beck depression inventory; ER, emotional role; mmrc, Modified Medical Research Council; PF, physical function; SF-36, Short- Form 36 Pulmonary rehabilitation has been proven to be a valid, reliable, and useful application for patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease. 14 In most surgical procedures, including volume reduction and lung transplant, PR has potential benefits before and after surgery. 15 Although PR is an indispensable component that increases the success rate of lung transplant, there is no guideline for PR to be applied to transplant candidates. Mostly, there is a long waiting period for end-stage lung disease patients who are transplant candidates. 16 In several studies, PR has been found to be helpful in minimizing physical and psychologic losses of patients. 17,18 In the present study, we also examined the effects of preoperative physiotherapy on lung transplant candidates. This study is the first and most comprehensive study conducted in Turkey on PR in lung transplant patients. The implementation of preoperative PR in a patient group at a terminal stage and with a high potential for additional cardiovascular diseases raises concerns about bringing an additional load on the system. On the basis of clinical experiences, however, it is clear that this patient population benefits from PR. 19 In our study, we included a risky patient group with a low ejection fraction and high systolic pulmonary artery pressure. However, we observed no complications during exercise while observing significant improvements in exercise capacity and dyspnea scores. Furthermore, the cardiovascular outcomes of exercise training in solid-organ transplant candidates have not yet been proven. The present observations in the literature are with small-scale, short-term studies. 20 In addition, little is known about physical activity profiles of lung transplant candidates. In a previous study, Wickerson and associates 21 compared the physical activity levels on rehabilitation versus free days and found that patients with advanced interstitial lung disease were highly inactive on free days, indicating a significant difference in physical activity and functional scores compared with rehabilitation days. In our study, all patients showed positive improvements in 6MWT and physical activity scores. In lung disease patients at the terminal stage, the main goal of PR is not to improve pulmonary function parameters. With the systemic effects of exercising, particularly on peripheral muscle strength, fatigue and dyspnea decrease and quality of life improves. 8, 22 Consistent with the previous findings, no improvements in pulmonary functions were observed in our study. We also observed a slight decrease in the mean of lung function results without statistical importance. This may mean that lung disease continues to progress despite rehabilitation. In addition, there was a highly significant improve - ment in dyspnea scores. This result shows that dyspnea is also affected by different parameters from respiratory functions. In another study, Manzetti and associates 23 found no significant differences in cardiopulmonary exercise testing at the end of a PR program among transplant candidates; however, there was an increase in the 6MWT distance. This finding indicates that 6MWT is safe to perform on transplant candidates. In their National Emphysema Treatment Trial (NETT), Ries and associates 24 reported significant impro vements in the peak workload, 6MWT distance, quality of life, and dyspnea scores in 1218 patients with severe emphysema. In the present study, we similarly observed a highly statistically significant improvement in the 6MWT distance. There are studies showing that QF muscle strength may be a predictor of mortality in chronic respiratory patients. 25 Skeletal muscle weakness is shown in lung transplant candidates. Reduced muscle mass and reductions in QF strength are consistently observed in the pretransplant period, and these reductions have been shown to persist up to 3 years into the posttransplant period. 26 In a study from Maury and colleagues, patients with muscle

5 Esra Pehlivan et al/experimental and Clinical Transplantation (2018) 4: weakness before transplant showed a decrease in muscle strength after transplant. 27 A review from Langer suggested that QF muscle strength decreases progressively in the preoperative period. 28 No increase in muscle strength was observed in our study. At the same time, there was no decline. It is possible to interpret this as a result of the PR program slowing down muscle strength loss. The SF-36 Quality of Life Questionnaire is a multipurpose, short-form health survey that is applied in many populations, both with disease and healthy, and has been used in many transplant studies. 29 Florian and associates 17 showed that PR applied in transplant candidates on wait lists had a positive effect on exercise capacity and quality of life, as assessed by the SF-36. In our study, there were improvements in the physical function and emotional role subparameters of SF-36. In contrast to our clinical experience, not observing improvements in all SF-36 subparameters could bring about the need to establish special quality of life questionnaires for transplant candidates. Furthermore, psychologic problems are seen in many patients on transplant wait lists. 30 Another benefit of preoperative PR is that, for individuals who are immobilized for a long time or who are unable to go outside, it provides an opportunity to interact with other patients, to socialize, and to establish a close relationship with health professionals. 19 In the present study, improved depression scores also support the benefit of preoperative PR. In addition, a positive change in BDI is independent of exercise capacity, quality of life, and amount of dyspnea. Study limitations One of the limitations of this study is the lack of a randomized-controlled trial design due to fewer transplant cases than in the international community and the small sample size. In addition, 7 patients underwent transplant before completing the planned PR procedure; therefore, their data could not be used, leading to reduction in the number of our patients. It is also difficult to conduct a prospective randomized study with this patient population. Pulmonary rehabilitation is a clinically meaningful and useful application in the preoperative lung transplant period. It is not ethical to withhold applying PR to a group of patients at the initiative of researchers. Another limitation is that we were unable to obtain postoperative follow-up outcomes. Some of the patients included in the study died before transplant, and some are still on wait lists for transplant. In conclusion, results of our study seem to be consistent with the hypothesis that PR, which is included in standard treatment programs at lung transplant centers, was useful, reliable, and effective in our cohort. 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