There is a growing interest in the role of exercise and physical activity in improving health outcomes and quality of life in individuals undergoing solid organ transplantation (SOT).1 Exercise training has been shown to be beneficial across several chronic disease groups that may lead to SOT2–5 and across organ groups posttransplant.6 However, guidelines for exercise training in SOT have not previously been published. The aim of this position statement is to provide evidence-based and expert-informed recommendations for exercise training pre- and posttransplant in adult and pediatric SOT populations and on the outcomes relevant to exercise training and physical function that should be evaluated in SOT.
Exercise refers to structured activity that is aimed at improving physical fitness or health, whereas physical activity is a broader term that encompasses any activity that requires skeletal muscle movement and increases energy expenditure.7 In addition to exercise, physical activity also includes leisure activities (eg, gardening, housework), active transportation (eg, walking to work/school or taking the stairs), and active play and sports.7 The focus of this position statement is in exercise, as the SOT literature to date has focused on structured, supervised exercise training and its effect on physical function and health outcomes. Exercise is further divided into subtypes, including aerobic training (large muscle groups, dynamic activities aimed at increasing heart rate), resistance training (activities aimed at loading isolated muscles or muscle groups to improve strength, muscular endurance, or power), flexibility (movements aimed at increasing range of motion and stretching the muscles and connective tissues), and balance training (movements aimed at challenging the vestibular, proprioceptive, and visual systems).8 Exercise training programs or “exercise prescriptions” are designed with a specific goal in mind (such as increasing aerobic capacity), and the program specifies the frequency, intensity, type, time, volume, and progression to meet this goal.8
Exercise (or aerobic) capacity is reduced in SOT candidates and recipients due to several contributing factors. In the pretransplant phase, exercise limitation can be mainly attributed to primary organ dysfunction, particularly in those with advanced heart or lung disease where circulatory or ventilatory limitations result in reduced aerobic capacity. Other factors such as anemia, deconditioning (which leads to maladaptation of skeletal muscle), muscle atrophy, weakness, malnutrition, and fatigue also contribute to exercise limitation across all types of SOT candidates, regardless of their underlying disease.9 Improvement in exercise capacity is observed posttransplant bacause of the alleviation of improved native organ function and symptoms; however, it has been shown that exercise capacity remains reduced to 40%–70% of predicted in the majority of adult and pediatric SOT recipients.9–11 Several factors can impact exercise capacity posttransplant, such as prolonged hospitalization, low physical activity levels, side effects of immunosuppressant medications (eg, corticosteroid-induced myopathy,12 mitochondrial dysfunction from calcineurin inhibitors13), ongoing skeletal muscle atrophy and weakness, and episodic illnesses (infections, rejection).14 Importantly, reduced exercise capacity and levels of physical activity in SOT candidates and recipients are key predictors of clinical outcomes before and after transplantation.15–18 However, exercise training can improve exercise capacity, and some transplant recipients reach very high levels of fitness.19,20 There are also several posttransplant complications that can be modified through exercise training, such as cardiovascular risk factors21 (hypertension, glucose dysregulation, overweight, or obesity), osteoporosis, muscle atrophy, and fatigue.22 Pretransplant exercise training improves exercise capacity of transplant candidates5 and has the potential to improve early posttransplant outcomes such as hospital length of stay.23 Despite the potential benefits of exercise training in SOT candidates and recipients, there is limited availability of dedicated transplant rehabilitation programs in Canada.24 Furthermore, a large proportion of adult and pediatric SOT recipients only engage in low levels of physical activity10,25–27 and face barriers to being physically active.25,26,28 There are currently no practice guidelines for exercise training before and after transplantation, which can limit the uptake of the research evidence into clinical practice. This position statement provides recommendations based on the current evidence and expert opinion and addresses the following questions:
- What is the evidence for exercise training in adults and pediatric SOT candidates and recipients?
- What type(s) of exercise training are recommended in the pretransplant phase?
- What type(s) of exercise training are recommended in the early and late posttransplant phases?
- What are the outcomes relevant to exercise and physical activity that should be measured pre- and posttransplant?
This position statement is in line with the research priorities identified by a Canadian Institutes of Health Research-funded meeting held in Toronto in 2013, where participants identified the development and dissemination of “expert consensus guidelines,” a key step toward improving program development and implementation.1
MATERIALS AND METHODS
We followed the Standard Operation Procedures for developing position statements created by the Leading Clinical Practice Committee of the Canadian Society of Transplantation (CST). Before publication, this position statement was reviewed by the working group developed by the Leading Clinical Practice Committee, members of CST, as well as by the board of directors of CST. The search strategy was designed in MedLine and Pubmed to identify randomized controlled trials (RCTs) and systematic reviews of exercise interventions in solid organ (lung, heart, kidney, liver, and pancreas) transplant candidates and recipients but, when not available, all relevant study designs were reviewed. Key words included solid organ transplant, transplantation, candidates, recipients, lung, heart, liver, kidney, pancreas, exercise, physical activity, rehabilitation, and prehabilitation. Reference lists of relevant systematic reviews were also searched to identify additional studies.
In the section on exercise pretransplant in this study, we reviewed systematic reviews and studies of any design that examined the effectiveness of exercise training in SOT candidates. We also reviewed recent systematic reviews on exercise training in end-stage disease that may lead to transplantation (eg, liver cirrhosis, heart failure [HF] with left ventricular assist device [LVAD], and on extracorporeal membrane oxygenation [ECMO], as they may have included transplant candidates). Information from systematic reviews along with key studies for each organ group and expert opinion were used to provide recommendations.
For the section on exercise posttransplant in adults, we reviewed a recent systematic review and meta-analysis conducted by Janaudis-Ferreira et al,6 which included 29 RCTs examining the effects of exercise training in SOT recipients. Twenty-one of the 29 RCTs were unique studies and included a total of 736 SOT recipients (11 unique studies in kidney [n = 408]; 6 in heart [n = 198], 2 in lung [n = 50], 2 in liver [n = 80], and none in pancreas). These studies were designed to compare the effect of exercise intervention with nonexercise (control). We used Grading of Recommendations Assessment, Development, and Evaluation (The GRADE) approach of rating the quality of evidence to provide recommendations.29 The rating (high, moderate, low, or very low) reflects the confidence in the estimate of the effect to support a recommendation and considers the strengths and limitations of the body of evidence stemming from study design, risk of bias, imprecision, inconsistency, indirectness of results, and other considerations like publication bias. The GRADE approach was only used in this section due to the lack of RCTs comparing exercise to a nonexercise control in adult transplant candidates and in pediatric transplant candidates and recipients.
In pediatrics, there were no systematic reviews or RCTs in SOT candidates or recipients. Due to the lack of studies in this topic, in the pretransplant review, we identified systematic reviews and non-RCTs on exercise training in chronic conditions that lead to transplant in the pediatric population (eg, cystic fibrosis [CF], congenital heart disease, end-stage kidney disease on dialysis) to provide the reader with an overview of the evidence for exercise in these populations. In posttransplant, studies describing exercise intervention (any study design) in pediatric SOT recipients were reviewed. Recommendations were based on the best available evidence in each organ group and expert opinion.
For the outcome measure section, we reviewed a recent systematic review30 on outcome measures in RCTs of exercise interventions in SOT. We also reviewed studies that have examined the association between our outcomes of interest and important clinical endpoints in SOT adult and pediatric patients. We have provided recommendations on outcomes based on the current evidence from RCTs of exercise training and outcomes that are associated with important clinical end points as well as outcomes that are appropriate for clinical exercise prescription.
EXERCISE TRAINING IN THE PRETRANSPLANT PHASE
The overall goal of pretransplant rehabilitation programs is to optimize physical fitness and quality of life before transplant and to improve early posttransplant outcomes such as hospital length of stay and functional independence at hospital discharge.
A systematic review of exercise training in lung transplant candidates published in 20175 included 2 RCTs, 2 quasi-experimental studies, and 2 retrospective studies. Five of the 6 studies included patients with a variety of diagnoses, and 1 study only included people with chronic obstructive pulmonary disease.31
The exercise training programs in 4 studies consisted of combined aerobic training (treadmill walking and cycle ergometry) and resistance training (upper and/or lower limb exercises using free weights, machines, or body weight). One study compared continuous and interval aerobic training on a cycle ergometer31 and another used Nordic pole walking as the form of aerobic training.32 All exercise programs were supervised and took place in a hospital or institution setting.33
Most studies reported improvements in functional exercise capacity (measured by the 6-minute walk test [6MWT]) and health-related quality of life (HRQL). Only 1 study has evaluated the effect of pulmonary rehabilitation on posttransplant outcomes and reported that a greater 6-minute walk distance (6MWD) pretransplant was associated with shorter hospital length of stay.23 This was a retrospective study in which the key difference from other studies to date is that the rehabilitation program was offered for full duration of the pretransplant waiting period and there was no nonexercise (control) group.23 No studies to date have systematically defined and reported on adverse events during exercise training in lung transplant candidates, although some authors have indicated that no adverse events occurred during training.33
Following the systematic review by Hoffman et al,5 2 new studies in exercise training in lung transplant candidates have been published. Ochman et al,34 in a non-RCT, offered a 12-week Nordic walking program for lung transplant candidates. This study showed that this type of exercise was safe and feasible and that it improved functional exercise capacity, symptoms of dyspnea, and quality of life to a greater extent in the intervention group.34 A pre-post study by Singer et al35 delivered an 8-week home-based exercise program (walking + body weight exercises) plus nutritional support to 15 lung transplant candidates using an e-health application. The authors found the intervention to be acceptable to patients, safe, and capable of improving frailty scores.35
Early mobility and ambulation have been recently described in individuals on ECMO. In a systematic review including 9 studies of physiotherapy in awake people on ECMO, passive and active range of motion, bed mobility, sitting upright, and ambulation were found to be safe and feasible to conduct with a multidisciplinary team in place.36 The main risk of mobilizing patients on ECMO is risk of displacing the cannulae. As this is an emerging area of study, the evidence to date is of low quality, including only case reports and retrospective studies.36
Two small studies37,38 examined the effects of exercise training in heart transplant candidates. These studies included individuals with end-stage HF who were awaiting heart transplantation. Ben-Gal et al,37 in a non-RCT, offered an aerobic training (cycling and walking) to 6 heart transplant candidates (originally 12 patients had been recruited, but 6 dropped out for different reasons and became the comparison group) and found significant improvements in maximal and functional exercise capacity compared with the nonexercise group. A study by Dean et al38 delivered a 4-week resistance training to end-stage HF patients who were awaiting transplantation, and although their main outcome was vasoreactivity, the authors reported data on hand grip strength, but no improvement was seen in this outcome. No adverse events were reported in the studies of Ben-Gal et al or Dean et al.37,38
Exercise training has also been studied in people supported by LVAD either as bridge to transplantation or as a destination therapy.33,39 A meta-analysis of 4 studies comparing exercise training to control in LVAD found that exercise improved VO2 peak and quality of life.39 Of the 8 studies included in the systematic review, none reported any serious adverse events from exercise training.39
Current guidelines3,40 recommend exercise training as a significant nonpharmacologic intervention in patients with symptomatic HF, to improve functional capacity and quality of life.3,40 Cochrane reviews in 2004 (n = 29 studies) and 2014 (n = 33 studies) found that exercise training in people with HF improved VO2peak, exercise duration, work capacity, 6MWD, and quality of life,41,42 led to fewer hospital admissions,42 and showed a trend toward reduced long-term mortality in the exercise training group.42 It is important to note that people with advanced HF have been underrepresented in these exercise trials.
There are only 2 published studies43,44 that examined the effects of exercise specifically in kidney transplant candidates. Gross et al,43 in an RCT, offered an 8-week program of mindfulness-based stress reduction and yoga exercises to the intervention group and telephone-based support to the control group. The primary outcome of this study was anxiety measured by the State-Trait Anxiety Inventory; the authors found no reductions in anxiety in either of the groups.43 Exercise-related outcomes were not included in this study. McAdams-DeMarco et al,44 in a pre-post study, showed that a prehabilitation program for kidney transplant candidates was feasible and that by 2 months of pre-habilitation, participants improved their physical activity by 64%.44 The authors also reported that among 5 kidney transplant candidates who received transplantation during the study period, length of stay was shorter than age-, sex-, and race-matched controls.44
Although there is a limited number of studies on exercise training that are restricted solely to individuals listed for kidney transplant, there is a large body of literature on exercise training in people with end-stage kidney disease.4,45 In these studies, exercise training was delivered during dialysis or as an outpatient or home-based program on nondialysis days, and most provided supervised training programs. The majority of studies included aerobic training alone or in combination with resistance training. A few studies included resistance training alone, and 1 study used yoga as the form of the exercise.4,45 Positive effects were seen in aerobic capacity, muscle strength, mid-thigh muscle cross-sectional area, quality of life, and heart rate variability.4 The effects on walking capacity (eg, 6MWD) and blood pressure were not significant in dialysis patients. The systematic reviews did not report on adverse events from exercise.
There are 4 published studies46–49 that examined the effects of exercise in liver transplant candidates. Limongi et al published 2 RCTs47,48 on a specific physiotherapy program that included inspiratory muscle training as well as upper limb and abdominal exercises. The outcomes of interest in these studies were maximal inspiratory and expiratory pressure, electromyography of diaphragm and rectus abdominus muscles, and quality of life measured by the Short Form-36 (SF-36). No difference between the intervention and control groups were found in either of these studies.47,48 Debette-Gratien et al,46 in a pre-post study, offered a 12-week supervised aerobic and resistance training to 13 liver transplant candidates and showed that their program was acceptable to patients and safe. They showed significant improvements in maximal and functional exercise capacity and muscle strength but not in quality of life.46 Finally, a recent pre-post study by Williams et al49 offered a 12-week home-based exercise to patients awaiting liver transplantation and showed that their program was safe, feasible, and improved functional exercise capacity at 6 and 12 weeks. Average daily step, lower limb function (measure by the Short Physical Performance Battery [SPPB]), and quality of life improved after 12 weeks. There was no difference in anxiety and depression after the training period.49
There is also emerging evidence on exercise training in people with liver cirrhosis, a common indication for liver transplantation. A systematic review and meta-analysis by Brustia et al2 included 4 RCTs of exercise or exercise plus nutrition therapy in patients with liver cirrhosis (total of 89 patients). Exercise training consisted of supervised aerobic training (treadmill walking and cycle ergometry) in all studies; 1 study also included “kinesiotherapy” consisting of exercises to improve muscle strength, balance, and co-ordination.2 The meta-analysis revealed no significant changes in aerobic capacity (VO2 peak), functional exercise capacity (6MWD), body mass index (BMI), or thigh circumference (surrogate measure of thigh muscle mass); likely because of the small number of studies included in the analysis. Regarding liver function, no changes were observed in Model for End-stage Liver Disease (MELD) or Child scores with exercise.2 One study showed an improvement in hepatic venous pressure gradient in the exercise plus nutrition therapy versus the control group.50 No adverse outcomes were noted across studies, except for 1 patient in 1 study who experienced mild bronchospasm.51
Sarcopenia is a hallmark feature of liver cirrhosis and is associated with increased risk of mortality and morbidity in liver transplant candidates.52 A recent review suggests that multimodal exercise training (aerobic, strength, and balance training) along with nutritional interventions may improve sarcopenia and frailty in liver transplant candidates.53 However, RCTs are needed to examine the effects of these interventions on muscle mass, strength and physical function, and the potential impact on clinical outcomes such as survival.53
Recommendations for Exercise in Adult SOT Candidates
- There are limited trials in exercise in the pretransplant phase that specifically included adult transplant candidates. Considering the existing evidence and the opinion of the expert panel, we made some specific recommendations that are described below.
- Exercise training in the pretransplant phase is safe and should consist of aerobic training or combined aerobic plus resistance training.
- There is insufficient evidence to provide guidelines on the dose of exercise (frequency, intensity, type, and time) to obtain benefits in the pretransplant phase.
- There is insufficient evidence for the program length or duration required to obtain benefits in the pretransplant phase.
- Exercise programs should be supervised and can be conducted in a hospital (inpatient or outpatient setting). There is some evidence for home-based programs, but larger trials are needed to confirm safety and effectiveness in this setting.
EXERCISE TRAINING IN THE POSTTRANSPLANT PHASE
The overall goal of the posttransplant rehabilitation programs is to help transplant recipients regain function, improve HRQL and participation in activities that they enjoy, as well as return to work and to their family and societal roles. Specific goals are to increase general mobility (early posttransplant) and to improve functional exercise capacity, muscle strength, HRQL, and outcomes related to cardiovascular disease and diabetes. The majority of the evidence for exercise training in transplant patients falls into the posttransplant phase and is described below by organ group and main outcome measures (maximal exercise capacity, muscle strength, and HRQL). This description is based on the findings of the systematic review by Janaudis-Ferreira et al.6 The specific timing posttransplant and characteristics of the exercise training offered in the RCTs of exercise post-SOT transplant6 are presented in Table 1. In general, the studies had low or unclear risk of bias.
Maximal Exercise Capacity
Of the 2 RCTs in lung transplant recipients,54,55 only 154 assessed maximal exercise capacity (measured by VO2 peak). Langer et al54 offered an exercise program including aerobic as well as resistance training and showed an improvement in VO2 peak (% predicted) in the intervention group at 3 months and 1 year posttraining period. However, these improvements were not statistically significant different between groups. The authors in this study showed a statistically significant difference between the exercise and control groups in 6MWD at 3-month and 1-year follow-ups.54
Two RCTs54,55 assessed muscle strength in lung transplant recipients following an exercise training program. Langer et al54 assessed isometric quadriceps force and showed that after a training program consisting of aerobic and resistance exercises, quadriceps force improved to a greater extent in the intervention group compared with the control group immediately after the training program (3 mo). At 1-year follow-up, the improvement from the 3 months was still greater in the intervention group compared with the control.54 A study by Mitchell et al55 delivered lumbar extension resistance training and showed a greater magnitude of change in lumbar extensor strength in the intervention group.
Health-related Quality of Life
Only 1 RCT54 assessed HRQL (measured by the SF-36) in lung transplant recipients following an exercise training program. The authors found no between-group differences in any components of the SF-36 at 3-month follow-up, but there was a greater improvement in the intervention group in 2 subscales (physical functioning and role limitations due to physical functioning) at 1-year follow-up. The authors attributed the nondifference in HRQL at 3-month follow-up to the fact that all transplant recipients are likely to improve their self-perceived HRQL during the first 3 months after hospital discharge.54
Maximal Exercise Capacity
Six RCTs in heart transplant recipients56–61 assessed maximal exercise capacity (measured by VO2 peak). These studies showed that exercise training improves exercise capacity in heart transplant recipients. The exercise training programs included in these studies comprised of aerobic training (continuous or interval training on a treadmill or bicycle) and/or resistance training and lasted between 3 weeks and 6 months.56–61 Only 1 study62 examined the effects of aerobic training (in this case high-intensity interval training [HIIT]), long-term posttraining (5 y). This study found that even though patients in the intervention group were able to be physically active after the training period with more than 1 hour of daily activity at a moderate intensity, this volume of activity was not sufficient to maintain the higher achievements in VO2 peak 5 years posttransplant.62 This finding suggests that some intermittent structured exercise training period may be necessary to maintain the gains achieved after the initial period of training.
One RCT60 assessed muscle strength in heart transplant recipients after an exercise training. Nytrøen et al60 measured maximal quadriceps and hamstrings strength and showed that there was no change in maximal hamstrings strength in either the exercise or control groups. There was no change in maximal quadriceps strength between groups; however, there was a significant reduction in quadriceps strength in the control group after the training period.60 These findings were expected as this study offered HIIT on a treadmill with no resistance training component.
Health-related Quality of Life
Of the 12 RCTs in heart transplant recipients, 3 assessed HRQL60,62,63 (measured by the SF-36). Christensen et al63 showed that an 8-week HIIT program improved the mental health subscale of the SF-36 to a greater extent in the intervention group compared with the control group. No between-group differences were observed in other subscales of the SF-36. Nytrøen et al,60 who also delivered HIIT, showed a significant difference between groups in the general health subscale of the SF-36 but not in other subscales. Yardley et al62 who reported the 5-year outcomes of the study by Nytrøen et al60 observed statistically significant differences between groups in only 1 subscale of the SF-36; the “role limitations due to physical functioning” subscale.
Maximal Exercise Capacity
Five RCTs64–68 assessed aerobic capacity (measured by VO2 max) in kidney transplant recipients following an exercise program. All studies64,66–68 except for 165 demonstrated a greater improvement in VO2 peak after the training period in the intervention group compared with the control group. These studies included both aerobic and resistance training. The study by Karelis et al,65 in which no difference between groups in VO2 peak was observed, delivered a 16-week resistance training with no aerobic component included.
O’Connor et al69 reported the long-term outcomes of the 12-week resistance or aerobic training program that was originally described in the study by Greenwood et al.64 The authors demonstrated a significant difference in relative VO2 peak between the aerobic group and control group at 9-month follow-up but not between the resistance training group and control group.69
Four studies64,67,68,70 assessed quadriceps muscle strength in kidney transplant recipients following an exercise training program, and 3 studies64,67 demonstrated greater gains in quadriceps muscle strength in the intervention group compared with the control group. Of note, compared with the control group, Greenwood et al64 found a greater improvement in isometric quadriceps force in the group that received resistance training but not in the group that performed aerobic training. In contrast, Painter et al67 found a significantly higher improvement in quadriceps force in the intervention group even though resistance exercises were not included.
Five studies64,65,67,68,71 assessed HRQL (measured by either the SF-36 or the World Health Organization Five Well-Being Index) in kidney transplant recipients following an exercise training program. Of those, 3 studies65,67,71 found a greater improvement in HRQL in the intervention group compared with the control group after the training period. More specifically, these studies found a greater improvement in the intervention group in the physical,67 vitality, and general health subscales of the SF-3671 and in the general scores of the World Health Organization Five Well-Being Index.65
Maximal Exercise Capacity
Only 1 study72 assessed maximal exercise capacity (measured by VO2 peak) in liver transplant recipients following an exercise training program. This study delivered a 24-week intervention of resistance and aerobic exercise training at a moderate-to-high intensity and showed a greater improvement in VO2 peak in the intervention group (15% increase) compared with the control group (7% increase in VO2 peak).72
One study72 assessed muscle strength in 8 different movements (hip extension, elbow flexion/extension, shoulder flexion/extension, shoulder abduction, and knee flexion/extension) in liver transplant recipients following an exercise training program. Greater improvements were observed in hip extension and elbow flexion in the intervention compared with the control group.72
Health-related Quality of Life
Only the study by Moya-Nájera et al72 assessed HRQL (measured by the SF-36) in liver transplant recipients after an exercise training program. All 8 subscales were improved at the end of the training period in the intervention group, while only 4 increased in the control group. However, statistically significant differences were only observed in the physical functioning and vitality subscales.72
Safety of Exercise Training Posttransplant
Information on safety were clearly noted in a few RCTs that examined the effects of exercise post-SOT,55,58,60,64,65,68 and only 255,60 reported some adverse events. Nytrøen et al60 reported that 1 patient in the control group had a myocardial infarction and Mitchell et al55 reported a nonstatistically significant increase in rejection episodes in the exercise group.
Recommendations for Exercise in Adult SOT Recipients
- There is high quality of evidence that exercise training improves maximal exercise capacity, lower extremity muscle strength, and HRQL in lung, heart, kidney, and liver recipients (GRADE Recommendation Tables 2–4).
- Exercise training in the posttransplant phase is safe and should consist of aerobic training or combined aerobic plus resistance training. To obtain benefits early or late posttransplant, exercise training should be of a moderate-to-vigorous intensity level, 3–5 times a week for a minimum of 8 weeks.
- Early posttransplant (1–6 mo) and/or in case of medical instability, exercise programs should be supervised and can be offered in an outpatient setting or at home.
- Late posttransplant (>6 mo), structured exercise programs, or physical activities can be unsupervised and offered at home or in private fitness centers.
EXERCISE TRAINING IN PEDIATRIC SOT CANDIDATES AND RECIPIENTS
As in the adult SOT population, limitations to exercise capacity, muscle weakness, and low physical activity levels are documented in children with end-stage organ failure and posttransplant.26,73–75 While there is a paucity of exercise training studies specific to children listed for transplant, there is evidence from some studies in pediatric chronic disease conditions, such as CF and end-stage kidney disease. In the posttransplant phase, there is some evidence for the positive impact of exercise training on physical fitness and quality of life in children,74,76 but the studies are of lower quality with a lack of randomization and small sample sizes that limit their generalizability. The literature indicates that pediatric transplant recipients have low physical activity levels,77 which may result in lost opportunities for social and physical development, as well as important health benefits.78,79 Despite their complex medical needs, children posttransplant may benefit from regular participation in age-appropriate exercise, which may have a positive impact on their physical fitness and HRQL.80
Exercise Training in the Pretransplant Phase in the Pediatric Population
There is limited evidence for the impact of exercise training in pediatric heart or lung transplant candidates. In pediatric heart transplant candidates (infants <1 y and children between 1 and 10 y) who are bridged to transplant with a ventricular assist device, early mobility and inpatient rehabilitation have been shown to be feasible and safe and result in improved functional capacity during the pretransplant waiting period.77,81,82 However, the level of evidence in these publications is low (case reports77,81 and small, uncontrolled study82); hence, the results must be interpreted with caution.
There have been several studies in children with CF; a primary indication for pediatric lung transplant. A recent systematic review of exercise training in CF83 included 7 studies (randomized or quasi-RCTs) exclusively in children and adolescents with CF (mean age ranges between 10 and 15 y). None of the studies specifically included individuals listed for lung transplant, and there was a broad range of disease severity among the study subjects. The majority of studies included aerobic training or aerobic plus resistance training. One study examined anaerobic (high intensity) training, and another study included inspiratory muscle training in addition to aerobic and resistance training. The length of the training programs varied widely from 2 weeks, to a large RCT of 24 months. Most studies had unclear risk of bias due to lack of reporting. Hospital- or institutional-based exercise programs had very high adherence rates (>90%), and 3 studies indicated that there were no adverse events during exercise training. Studies also showed that aerobic training was effective in improving aerobic capacity (VO2 peak or shuttle walk distance), and resistance training resulted in improved muscle strength. Combined training (aerobic plus resistance training) may, therefore, be most applicable to the pediatric CF population.
Studies of exercise training in children and adolescents (mean age range 11–16 y) with congenital heart disease (with or without surgery) have been summarized in systematic reviews.84,85 The exercise training programs included either aerobic training alone or combined aerobic and resistance training and demonstrated an improvement in aerobic capacity (VO2 peak). In the nonsurgical population, exercise did not result in any adverse effects, but this was not reported in studies of postsurgical population. No studies examined the effects of exercise training on prognostic outcomes, such as hospitalizations or survival. These results, however, cannot be directly extrapolated to heart transplant candidates as most studies include children with repaired versus palliated defects or children with a higher level of cardiovascular function than those waiting for transplant.
There is very limited evidence for exercise training in pediatric kidney or liver transplant candidates, with no exercise intervention studies in children preliver transplant and small studies on exercise training in children with end-stage kidney disease. Three studies have examined exercise training in children on dialysis: 2 using intradialytic exercise76,86 and 1 using a community-based exercise program.87 The mean age of the participants in these studies ranged from 12.6 to 15.6 years. The community-based program, which included aerobic training, resistance exercises, and active games, had a very high dropout rate with only 5 out of 20 children completing the program. Intradialytic exercise consisted of 1-hour sessions of cycling and resistance exercises and was done twice weekly. Out of the 21 patients who were enrolled, 9 were not able to adhere to the program due to various reasons. Therefore, the barriers to exercise training in this population need to be addressed to improve feasibility.
Exercise Training in the Posttransplant Phase in the Pediatric Population
There are a few small, nonrandomized trials examining exercise training in children following thoracic transplants. In children post-heart or lung transplant (mean age of 13 ± 3 years), a 12-week nonrandomized trial of home- or hospital-based exercise program that included aerobic, resistance, and flexibility components, resulted in increased 6MWD, proximal muscle strength (shoulder and hip), and flexibility in both groups.88 There were no significant differences between the 2 delivery modes on any of the study outcomes. In pediatric heart transplant recipients (mean age 14.7 ± 5 y), a 12-week home-based exercise program of combined aerobic and resistance training showed improvements in aerobic capacity (VO2peak) and muscle strength.89 A unique case study described an adolescent who underwent cardiac transplant at 13.6 years old and retransplant at 16.2 years old and participated in structure aerobic training after each transplant.90 Following each transplant, aerobic training resulted in improved VO2 peak; and 1 year after retransplant, VO2 peak was higher than baseline (before the first transplant).90
To the best of our knowledge, there are no exercise intervention studies specific to children post-liver transplant. A study conducted in children on dialysis and post-kidney transplant (n = 44; mean age 15.1 ± 3.4 y) utilized pedometers as a motivational intervention to increase physical activity levels over a 12-week period.73 Although the improvement in steps per day did not reach significance, the change in steps per day was associated with improvements in 6MWD and self-reported physical function (based on the pediatric quality-of-life inventory [PedsQL]).73
A study was conducted in a mixed population of pediatric SOT recipients (16 thoracic and 3 abdominal transplant; mean age of 14.5 ± 2.7 y) using the World Transplant Games as an incentive to improve physical fitness.91 This study had a control group that consisted of SOT recipients (n = 14) who were not intending to participate in the Games. A home-based program of aerobic, strength, and flexibility exercises was provided, and participants took part in group-based sport training days with coaches. Between-group comparisons revealed improvements in the Progressive Aerobic Cardiovascular Endurance Run (PACER) and push-ups test in the training group. The training group also showed an improvement in physical activity level during the training period, compared with baseline. This suggest that the Games could be used as an incentive to motivate SOT recipients to engage in a structured, goal-based training program and also improve their level of physical activity.
Recommendations for Exercise in Pediatric SOT Candidates and Recipients
- Randomized trials of exercise training pre- and post-SOT transplant in children are needed. As the population is small, multicenter trials are needed to include a larger and representative sample. Considering the existing evidence, the expert panel made some specific recommendations that are described below.
- Pre- and posttransplant exercise training should include a combination of aerobic, resistance, and flexibility activities. Due to the lack of evidence, specific recommendations regarding the level of supervision, type of exercise (aerobic, resistance, combined), training parameters (frequency, intensity, type, time, volume, and progression), or length of the exercise program cannot be provided.
- Exercise programs should be individualized based on underlying pathology, the age of the child, level of experience, and developmental status. Individual barriers and motivators to exercise and physical activity need to be addressed to optimize program adherence.
- Engagement in physical activity (eg, recreational activities, sports) should be emphasized.
- Motor skill development should be monitored and interventions to address motor deficits need to be provided to support physical activity both pre- and post-SOT.
OUTCOMES FOR EXERCISE AND PHYSICAL ACTIVITY IN SOT
Based on a systematic review of RCTs of exercise training SOT recipients, the most common outcome domains included in the published studies are aerobic capacity (VO2peak), muscle strength, body composition, and quality of life.30 This review also identified that most studies focus on outcomes related to body structure and function (ie, physiological impairments), and there were few outcomes related to the domains of activity or participation according to the International Classification of Functioning, Disability and Health (http://www.who.int/classifications/icf/en/). Clinically, outcome measures are used for patient evaluation and assessment to determine baseline level of function, develop an exercise training program, and track changes over time. We have provided recommendations on outcomes based on the current evidence from RCTs of exercise training, outcomes that are associated with important clinical end points in SOT patients or outcomes that are appropriate for clinical exercise prescription.
Aerobic capacity, which refers to the body’s ability to extract and utilize oxygen for energy or work, is the most commonly measured outcome domain in RCTs of exercise training in SOT recipients.30 In clinical practice, aerobic exercise training programs can be individually prescribed and evaluated using tests of aerobic capacity. The cardiopulmonary exercise test (CPET, conducted on a cycle ergometer or treadmill) is the gold-standard test for the measurement of peak aerobic capacity (ie, VO2peak). VO2peak is also an important marker of mortality in transplant recipients.92,93 However, the CPET is not widely available in all clinical setting as it requires technical expertise, specialized equipment, and medical supervision.8
The 6MWT, a self-paced, submaximal functional exercise test, is also used as a measure of aerobic capacity in adult SOT populations94 and an essential component of lung transplant candidacy evaluation in adults and pediatrics.95,96 6MWD has moderate correlations with VO2peak in advanced HF,97 end-stage lung disease,98 heart transplant recipients,99,100 and is a predictor of pre- and posttransplant mortality across SOT candidates.95,101,102
Both the CPET and 6MWT are also used in pediatric SOT populations. In addition, the PACER is a field test for children that has been used in pediatric transplant recipients.10,75 Other submaximal exercise tests or field walking tests (eg, incremental shuttle walk test) have not been well studied in SOT.
Muscle strength refers to the force or tension generating capacity of a muscle8 and can be measured in several ways using a variety of instruments and procedures.103 Muscle weakness has been shown to persist from the pretransplant to posttransplant phase across organ groups.104–108 Several exercise trials include measures of upper and lower body muscle strength as a primary or secondary outcome, most commonly quadriceps (knee extensor) strength for the lower limb and handgrip strength for upper limb. Handgrip strength is also used as an indicator of overall muscle strength and has published normative values, allowing for sex- and age-specific comparisons.109,110 Handgrip strength is also a component of the Fried Frailty Index (see section on frailty). In the pediatric SOT population, field tests such the number of push-ups and sit-ups are used to evaluate upper body and core muscle strength, respectively.74
When designing a resistance-training exercise program, the 1-repetition maximum is used to evaluate strength and determine the appropriate training loads for each muscle group being trained.8,55 One-repetition maximum is also re-evaluated at regular intervals to progress resistance exercises and evaluate the effectiveness of the training program.8
Anthropometric measures of body composition, including body weight, BMI, and waist circumference, as well as more advanced measures to obtain estimates of fat mass and fat-free mass using tools such as dual X-ray absorptiometry (D-XA) and bioelectrical impedance analysis, are commonly used in trials of exercise training in SOT recipients.30 In clinical practice, the use of anthropometric measures and bioelectrical impedance analysis are more feasible as they require less time, cost, and technical expertise to conduct. Although exercise training alone may only result in modest weight loss;60,71,111 body composition (low muscle mass and high fat mass), weight gain, and obesity are important concerns posttransplant especially due to the increased cardiovascular risk associated with immunosuppressant medications.112 Overweight and obesity may be linked to delayed graft function, as well as increased risk for cardiovascular disease and metabolic syndrome.113–115
Health-related Quality of Life
HRQL is evaluated using patient-reported outcome measures (PROMs). PROMs are of particular interest in exercise interventions, as they directly capture the patient’s perspective on their health.116 In a meta-analysis, HRQL was found to improve with exercise training across 10 studies including heart, liver, and lung transplant recipients.6 The most commonly used HRQL questionnaire used in exercise trials is the SF-36, which is a generic HRQL questionnaire. In the pediatric population, the PedsQL instrument is widely used in both chronic disease and posttransplant populations.117,118
There are several outcome domains that have been studied to a lesser extent in exercise trials but are associated with adverse outcomes pre- and posttransplant. These outcome domains may also be improved with exercise and physical activity but require further investigation in SOT populations.
Metabolic and Cardiovascular Risk Factors
There is a large burden of cardiovascular disease and posttransplant diabetes in SOT recipients,119,120 which is attributed in part to immunosuppressive agents.112 In the general population, exercise and regular physical activity can reduce the risk of cardiovascular events121 and prevent cardiovascular disease risk factors, such as hypertension, dyslipidemia, and impaired glucose regulation.122 There is preliminary evidence in lung and kidney transplant recipients that some of these risk factors may improve with exercise training.54,123 However, more trials are needed to determine the optimal dose and types of exercise training that impact cardiovascular and metabolic risk in SOT.
Frailty and Sarcopenia
There is an increasing focus on the evaluation of frailty and sarcopenia across SOT candidates and recipients, including pediatrics.124–126 Frailty and sarcopenia may be modifiable by exercise training, as shown in older adult populations127 and chronic disease,128 though these constructs have not yet been assessed as outcomes of exercise training trials in SOT. However, both frailty and sarcopenia have important associations with adverse events, such as waitlist mortality, hospital readmissions, and posttransplant mortality, across organ groups.124,129–132 In the SOT literature, frailty is commonly assessed using the Fried Frailty Index,133 which focuses on 5 key signs and symptoms and is commonly referred to as “phenotypic frailty.” Other comprehensive frailty indices134 incorporate chronic diseases, cognitive function, mental health, and socio-demographic factors; however, these have not been as well studied in SOT candidates or recipients. Emerging evidence suggests that frailty also exists in pediatric transplant candidates and there is initial work toward the development of a pediatric-specific frailty scale.126 Sarcopenia, which refers specifically to the loss of muscle mass and function associated with aging and chronic disease,135 has also been evaluated in SOT candidates and recipients. The focus of sarcopenia assessments has been on evaluating muscle mass from D-XA136,137 or single-slice CT scans to obtain abdominal,138 psoas,137,139 or thoracic muscle area.140 Sarcopenia has also been reported in pretransplant pediatric populations with kidney, liver, or intestinal failure using psoas muscle area from CT.141 A recent study in pediatric liver transplant recipients found that sarcopenia, defined by low skeletal muscle mass index from D-XA, was associated with poor growth and increased hospitalizations posttransplant.142 In adult lung transplant candidates, sarcopenia has been evaluated using the consensus definition, low muscle mass, plus one of low strength or function, in which muscle weakness was found to be more prevalent than muscle wasting.143
The evaluation of physical frailty and sarcopenia includes the assessment of mobility using functional tests such as timed sit-to-stand tests (30 or 60 s sit-to-stand; or 5 times sit-to-stand)144 or the SPPB (a composite test consisting of gait speed, tandem standing balance, and 5 times sit-to-stand).145 These functional tests are primarily dependent on the strength and function of the lower extremity muscles. They are feasible to conduct in the clinical setting as they require no specialized equipment and have little space and time requirements. In lung transplant candidates, the SPPB has been used a marker of physical frailty with a cutoff score of ≤7 out of 12 points (lower scores denoting increasing frailty).146
Bone mineral density (BMD) has been studied as a primary outcome in 4 randomized trials of exercise training in SOT recipients55,111,147,148 and in several additional studies as a secondary outcome.30 No studies to date have evaluated incidence of fractures or fracture risk. Bone health is improved through specific exercise training aimed at increased loading on the bone,55,147 which may not be the goal of all exercise programs. Also, measurement of BMD and bone strength requires imaging modalities, such as D-XA, quantitative computed tomography, which are not readily available in all clinical settings and require technical expertise.
Physical activity level has been used as an outcome in a few studies of exercise training in SOT recipients.54,67 There is some evidence that structured exercise training with behavioral interventions improves physical activity levels in some chronic disease populations.149,150 Evaluation of daily physical activity can be done using self-reported questionnaires or objective measures using pedometers and accelerometers. One study also examined sedentary time,54 which is gaining more attention based on its association with cardiovascular risk in the general population. Furthermore, low levels of physical activity has been associated with increased body weight in lung transplant recipients,151 depressive symptoms,152 increased mortality in kidney27 and reduced HRQL in kidney and liver transplant recipients.153
In the pediatric population, developmental motor skills are important building blocks for participation in physical activity and exercise. Motor proficiency is associated with physical activity levels in children.154,155 Children with chronic disease may demonstrate lower motor proficiency and may perceive themselves as less competent to participate in physical activity than their healthy peers, thus developing a preference for more sedentary activities.26,155 Several outcome measures have been used to assess motor development in children pre- and posttransplant, including the Mullen Scales of Early Learning, Movement ABC, Bruininks-Oseretsky Test of Motor Proficiency, and the Bayley Scales of Infant Development.
Recommendations for Outcomes in Exercise and Physical Activity in SOT
- Exercise (aerobic) capacity should be routinely assessed in SOT candidates and recipients using CPET (if feasible) or functional walk test, such as the 6MWT. In pediatrics, the PACER may also be used as a field test for exercise capacity in higher functioning children.
- Muscle strength should be routinely evaluated to determine the presence of muscle weakness in pre- and posttransplant periods. Quadriceps and handgrip strength may be used as general indicators of overall lower and upper body muscle strength, respectively. In pediatrics, field tests measuring strength (curl-ups, push-ups) and the Bruininks-Oseretsky Test of Motor Proficiency can be used to compare age and gender norms.
- Body composition using BMI and waist circumference should be included in the routine assessment of SOT candidates and recipients.
- HRQL should be routinely evaluated using standard, PROMs such as the SF-36 (adults) or PedsQL (pediatrics).
- Emerging outcomes, such as cardiovascular and metabolic risk factors, frailty, sarcopenia, indices of BMD, bone strength and fractures, level of physical activity, and motor development (in pediatrics), can be considered as part of the evaluation but their inclusion depends on the goals of the exercise program and the expertise of the team (Table 5).
CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH
In summary, based on the available evidence and the opinion of our expert panel, we recommend that exercise training should be offered in the pre- and posttransplant phases for both adults and children.
There are few studies (although most are not RCTs) in the pretransplant phase in adults and the available evidence is insufficient to provide specific guidelines on the dose of exercise and program duration to obtain optimal benefits. However, there is some evidence on the effectiveness and safety of exercise pretransplant that was used, along with the opinion of our expert panel, to make recommendations about exercise training for this phase of the transplantation journey. Nevertheless, larger and well-conducted trials of exercise that specifically include transplant candidates are still needed. Future studies in this topic should focus on the effects of exercise during the waiting period on waitlist outcomes, such as healthcare utilization, mortality, frailty, and early posttransplant clinical outcomes, such as hospital length of stay.
Most of the evidence for exercise training in the transplantation journey falls in the posttransplant phase. There is high quality evidence in adult to support posttransplant exercise training programs that consist of aerobic training of moderate-to-vigorous intensity, 3 to 5 times a week for a minimum of 8 weeks or combined aerobic plus resistance training. Further studies on the effects of exercise delivered long-term posttransplant (>12 mo) are needed particularly in liver and lung transplant recipients. These studies should focus on innovative strategies to enhance long-term adherence to physical activity posttransplant and on important health outcomes, such as physical activity level, cardiovascular risk factors, diabetes, graft and immune function, as well as survival.
In the pediatric population, there is no RCTs pre- or posttransplant, and there is considerable variability in the type of exercise interventions that have been studied, limiting the ability to provide specific exercise guidelines. However, based on the existing evidence in the pediatric transplant population and conditions that lead to transplantation as well as on the opinions of experts, we recommend exercise training pre- and posttransplant in the pediatric population. There is an urgent need for further studies such as multicenter RCTs (to obtain adequate sample sizes) to establish the effectiveness of exercise and the appropriate dose (type, frequency, intensity) for optimizing benefits in pediatric transplant candidates and recipients, and the impact on long-term outcomes.
Compared with other chronic diseases, such as diabetes, heart disease, and chronic obstructive pulmonary disease, the field of physical rehabilitation in SOT (specifically in kidney and liver transplantation) is understudied and, in addition, there are various barriers to implementing exercise programs in transplant centers.1,24 The importance of this position statement is that it is a key step toward raising awareness of the importance of exercise interventions in this population among transplant professionals. With increased knowledge on the benefits of exercise in the adult and pediatric transplant population, professionals will be in a better position to ensure that physical rehabilitation be an integral component of pre- and posttransplant care. Creation and implementation of these programs might be challenging specifically in a healthcare scenario, where cost is always a concern; however, creative solutions such as home-based or tele-rehabilitation programs as well as program delivery using e-health applications might address these challenges. Further research will be needed to determine the feasibility, acceptability, and effectiveness of these innovative ways of delivering exercise programs for transplant patients. Finally, another approach to address barriers related to the implementation of exercise programs and physicians’ lack of time and confidence in counseling about exercise and physical activity156 is to establish clear referral pathways for transplant patients to access qualified exercise professionals through rehabilitation centers or community-based programs.
The authors thank the Leading Clinical Practice Committee of the CST for their support in the development of this position statement. The research conducted in preparation for this position statement took place within and was supported by Canadian Network for Rehabilitation and Exercise for Solid Organ Transplant Optimal Recovery (CAN-RESTORE), which is part of the Canadian Donation and Transplantation Research Program (CDTRP). The authors thank the members of CAN-RESTORE and CST who provided valued feedback on this position statement.
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