Abstract
Background It is hypothesized that increasing physical fitness and daily physical activity can lead to a reduction in fatigue. However, standard medical care following liver transplantation seldom includes rehabilitation that focuses on physical fitness and physical activity.
Objective The aim of this study was to explore whether a rehabilitation program can reduce fatigue in recipients of liver transplants. Furthermore, effects on physical fitness, physical activity, and cardiovascular risk were studied, and adherence, satisfaction, and adverse events were assessed.
Design This was an uncontrolled intervention study.
Setting The study took place in an outpatient rehabilitation clinic.
Patients Eighteen recipients of a liver transplant who were fatigued participated in a 12-week rehabilitation program including physical exercise training and counseling on physical activity. The primary outcome measure was fatigue. Other outcome measures were: aerobic capacity, muscle strength, body fat, daily physical activity, lipid profile, and glycemic control. All measurements were performed before and after the rehabilitation program. Adherence, satisfaction, and adverse events were registered.
Results After the program, participants were significantly less fatigued, and the percentage of individuals with severe fatigue was 22% to 53% lower than before the program. In addition, aerobic capacity and knee flexion strength were significantly higher, and body fat was significantly lower after the program. Participants were able to perform physical exercise at the target training intensity, no adverse events were registered, and attendance (93%) and mean patient satisfaction (8.5 out of 10, range=7–10) were high.
Limitations No control group was used in the study.
Conclusions A rehabilitation program consisting of exercise training and physical activity counseling is well tolerated and seems promising in reducing fatigue and improving fitness among recipients of liver transplants.
Fatigue is a major problem following liver transplantation.1–3 In a previous longitudinal study of recipients of liver transplants, 20% reported being fatigued, 40% reported being severely fatigued, and the remaining 40% reported no fatigue. This prevalence did not decrease during the 2-year follow-up, suggesting that fatigue is a chronic problem following liver transplantation.4 Furthermore, fatigue was found to be associated with low daily physical activity levels and poor physical fitness.5,6 These authors5,6 hypothesized that recipients of liver transplants experience a cycle of fatigue leading to inactivity, which leads to a reduction in physical fitness, which in turn leads to more fatigue.
In healthy people and those with other chronic illnesses, a rehabilitation program including physical exercise and counseling on physical activity has been reported to favorably affect fatigue.7–11 Standard medical care following liver transplantation seldom includes rehabilitation focusing on physical fitness and physical activity.12–14 Previously, we reported that a rehabilitation program including physical exercise and counseling on physical activity can favorably influence daily functioning, participation, and health-related quality of life among recipients of a liver transplant who were fatigued.15 However, to our knowledge, the effects of such a rehabilitation program on fatigue and on physical fitness, physical activity, and cardiovascular risk have not been studied previously. Therefore, we performed a secondary analysis on our previously published parent study with the aim to explore whether a rehabilitation program, consisting of supervised exercise training and counseling on physical activity, improves fatigue in recipients of liver transplants. Furthermore, the effects of the program on physical fitness, daily physical activity, and risk of cardiovascular disease were evaluated. Because the rehabilitation program was expected to be rather burdensome for fatigued and severely fatigued recipients of liver transplants, adherence, satisfaction, and possible adverse events of the participants of the program also were studied.
Method
Design Overview
The study design was uncontrolled; all participants took part in the rehabilitation program. This design was chosen because the effects of a rehabilitation program that could be rather burdensome for a group of individuals with fatigue who had received a liver transplant, including those with severe fatigue, were studied for the first time. All participants underwent transplantation at least 1 year prior to study initiation; therefore, no large change in fatigue, other than due to the intervention, was expected.
Setting and Participants
Participants were recruited from outpatient recipients of liver transplantation at Erasmus University Medical Center between September 2006 and April 2007. Inclusion criteria were: (1) fatigued (defined as a Fatigue Severity Scale [FSS] score ≥4),3 (2) aged between 18 and 65 years, and (3) liver transplantation at least 1 year prior to study initiation. People were excluded for: (1) multiorgan transplant, (2) severe comorbidity (eg, recurrent cholangitis or cancer), (3) insufficient knowledge of the Dutch language, or (4) contraindication for exercise or progressive maximal cycle ergometer test (eg, cardiovascular disease). Eligible people received information handouts. Written informed consent was obtained from all participants.
Intervention
The rehabilitation program had a duration of 12 weeks and included: (1) 24 supervised 1-hour exercise training sessions, consisting of both aerobic and strength training, twice weekly, and (2) 4 physical activity counseling sessions, at weeks 1, 4, 8, and 12. Physical exercise training was conducted in groups of 2 to 4 participants. Counseling sessions were individual. All exercise training and counseling sessions were conducted by a physical therapist at the Department of Rehabilitation Medicine at Erasmus University Medical Center.
Aerobic training consisted of 30-minute ergometer cycling starting at an intensity of 40% to 50% of heart rate reserve (HRR) and increasing to 70% to 80% of HRR using the Karvonen method.16 We aimed for a mean target intensity of 60% of HRR over the 12-week program, in accordance with American College of Sports Medicine (ACSM) guidelines.17 Strength training sessions were for 30 minutes and aimed at training major muscle groups (ie, quadriceps femoris, biceps brachii, gluteus maximus, and abdominal muscles). Over the 12-week period, the intensity and number of repetitions were gradually increased from 1 set of 10 to 15 repetitions at 30% of the 1-repetition maximum (1RM) to 3 sets of 20 repetitions at 60% of 1RM (moderate intensity).17 After each training session, participants indicated the strenuousness of their training from 0 (“no effort at all”) to 10 (“maximal effort”) using the Borg Category Scale for Rating of Perceived Exertion.18
The purpose of the physical activity counseling sessions was to promote a physically active lifestyle. The counseling was based on the Active After Rehabilitation program, which was developed by the EMGO Institute, VU Medical Center (Amsterdam, the Netherlands), and HealthPartners Health Behavior Group (Minneapolis, Minnesota).19 The counseling sessions were based on the transtheoretical model.20 Sessions were supported by written materials specific to each participant's stage of change at that moment. Participants received information about activities, sports, and health and discussed facilitators, barriers, and physical activity possibilities.
Outcome Measures
All measurements were conducted 1 week before and 1 week after the 12-week rehabilitation program.
Fatigue.
We assessed fatigue using 3 questionnaires capturing 3 different aspects of fatigue. First, we used the FSS, which is a validated 9-item questionnaire assessing the impact of fatigue on an individual's daily functioning.21,22 Scores range from 1 to 7. A score between 4.0 and 5.1 was defined as “fatigue,” and a score greater than or equal to 5.1 or higher was defined as “severe fatigue.”3 Second, a horizontal visual analog scale (VAS)23,24 was used to assess fatigue in general during the previous month. The VAS consisted of a 100-mm line, with 0 indicating “no fatigue experienced” and 100 indicating “the most severe fatigue.” Scores higher than 50 indicate severe fatigue.25 Last, participants completed the fatigue severity subscale of the Checklist Individual Strength (CIS–fatigue). This scale assesses feelings of fatigue experienced in daily life during the previous 2 weeks. The CIS–fatigue subscale consists of 8 items, with scores ranging from 8 to 56 and with higher scores indicating greater fatigue.26 A score of 35 or higher indicates severe feelings of fatigue.26 The CIS–fatigue subscale has good reliability, validity, and sensitivity.27,28
Physical fitness: aerobic capacity.
Aerobic capacity was measured with a progressive maximal aerobic test on a cycle ergometer (ER800, Jaeger Toennies, Breda, the Netherlands). The test started at 20 W, and resistance was increased every minute by 15 or 20 W, depending on the ability of the participants. Individual protocols were constructed such that the total time ranged from 8 to 12 minutes. The pedal rate was 60 rpm. The test was terminated when the participant stopped due to exhaustion or was unable to maintain the pedal rate. We measured gas exchange and heart rate continuously using a breath-by-breath gas analysis system (K4b2, COSMED, Rome, Italy). Aerobic capacity was defined as the mean oxygen uptake during the final 30 seconds of the test (V̇o2peak, in mL·min−1 and in mL·kg−1·min−1). Furthermore, the Six-Minute Walk Test (6MWT) was performed.29 The distance walked during 6 minutes was recorded. On the day prior to the physical fitness tests, we checked hemoglobin concentrations because hemoglobin levels may vary due to renal insufficiency or immunosuppressants.30
Physical fitness: muscle strength.
We assessed isokinetic knee extensor (quadriceps) and knee flexor (hamstrings) strength with a Biodex dynamometer (Biodex Medical Systems, Shirley, New York), recording strength as torque (in newton-meters). After 5 familiarization repetitions, isokinetic strength was measured at 60°/s with 5 maximal contractions. Peak torque was defined as the maximum torque generated during one series of repetitions.
Physical fitness: body composition.
Body mass was measured using a Cormier Paribel weighing chair (FH Balances Cormier, Romainville, France). Body mass index (BMI, kg/m2) was calculated from height and body mass. Four skinfold thickness measurements (biceps, triceps, subscapular region, and suprailiac region) were performed twice on the right side of the body with a Harpenden Skinfold Caliper (Burgess Hill, United Kingdom). The mean of 2 measurements was used as representative for each site. Percentage of body fat was predicted from skinfold thickness according to the method of Durnin and Womersley.31
Daily physical activity.
Daily physical activity was objectively measured for 48 hours during 2 consecutive weekdays using an accelerometry-based activity monitor (Temec Instruments, Kerkrade, the Netherlands).32 One accelerometer was attached to each thigh, and 2 accelerometers were attached to the sternum. All accelerometers were connected to a data recorder, which the participants wore in a padded bag around the waist. Participants were instructed to continue their ordinary routines but were not able to swim or take a bath or shower during the 2 test days. To avoid measurement bias, we explained the principles of the activity monitor to the participants after finishing the last measurement. Data were analyzed per day and, because there were no intra-day differences, averaged over the 2 days. Outcome measures were: duration of dynamic activities (%), mean motility (g), and motility during walking (g). Duration of dynamic activities was assessed as a percentage of 24 hours and included walking, stair climbing, running, cycling, and general noncyclic movement. Body motility was determined from the variability of the signal. Mean motility represents intensity and duration of daily physical activity, and motility during walking represents walking speed.
We also assessed perceived daily physical activity using the 7-day recall Physical Activity Scale for Individuals With Physical Disabilities (PASIPD), which identifies leisure time, household activities, and work-related physical activities.33,34
Cardiovascular risk.
Lipid profile and glycemic control were measured to obtain an indication of risk of cardiovascular disease. Nonfasting venous blood samples were obtained. Lipid profile parameters were: the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C ratio) and the ratio of low-density lipoprotein cholesterol to HDL-C (LDL-C/HDL-C ratio). To assess glycemic control, we measured glycosylated hemoglobin (HbA1c).
Adherence, satisfaction, and adverse events.
We assessed the proportion of training sessions attended and the reasons for missed sessions, the achieved training intensity, participants' satisfaction with the program as rated on a 10-point scale (a higher score indicates higher satisfaction), and adverse events. We defined adverse events as any injuries or events that occurred during testing or training (musculoskeletal or cardiorespiratory).
Data Analysis
For statistical analysis, we used SPSS version 16.0 for Windows (SPSS Inc, Chicago, Illinois). We compared fatigue severity and aerobic fitness, muscle strength, body composition, daily physical activity, lipid profile, and glycemic control before and after the rehabilitation program using the nonparametric Wilcoxon matched pairs signed ranks test. Significance was set at P≤.05. Adherence, satisfaction, and adverse events were described and reported as means with standard deviations.
Role of the Funding Source
The study was supported by grants from NUTS OHRA (project no. SNO-T-0601-41).
Results
The Figure shows the flow of participants through the study. A total of 18 participants completed the study. Characteristics of the participants are presented in Table 1. The pharmacologic regimens of the participants remained stable during the program, except for one participant whose antihypertensive medication was reduced 2 weeks after study initiation.
Flowchart of participants throughout the study. a Excluded because of various comorbidities or contraindications for exercise or maximal exercise test. b Not interested because of distance (n=17), lack of time (n=11), fatigue (n=10), or no reason (n=29). c Losses due to relapse of psychological problems (n=1) and relapse of intestinal disorder (n=1).
Participant Characteristics (N=18)a
Fatigue
Median scores on the 3 fatigue questionnaires (FSS, VAS, and CIS–fatigue) before and after the rehabilitation program are shown in Table 2. After the program, all 3 questionnaires showed a significantly lower score in mean fatigue (P<.05). Table 3 shows the percentage of participants with severe fatigue before and after the rehabilitation program.
Fatigue, Physical Fitness, and Daily Physical Activity Before and After the 12-Week Rehabilitation Program (N=18)a
Percentage of Participants With Severe Fatiguea (N=18)
Aerobic Capacity, Muscle Strength, Body Composition, and Daily Activity
Results are shown in Table 2. All measures of aerobic capacity were significantly higher after the program (P<.05). There were no differences in hemoglobin before and after the rehabilitation program. With regard to muscle strength, only the absolute peak torque of knee flexion was significantly higher after the program (P=.041). Before the program, 10 of 18 participants were obese (BMI >30 kg/m2). After the program, BMI was unaltered; however, body fat was significantly lower (P=.049). Daily physical activity levels before and after the program did not differ significantly. Also, for lipid profile and glycemic control, no significant differences were found (Tab. 4).
Biochemical Markers Before and After the 12-Week Rehabilitation Program (N=18)a
Adherence, Satisfaction, and Adverse Events
On average, participants attended 93% (range=75%–100%) of the training sessions. The primary reason for missed sessions was fatigue. The mean training intensity over the 12 weeks was 60.0% of HRR (SD=7.7), with an average perceived exertion of 4.1 (“somewhat strenuous”). Four participants achieved the target intensity of 70% to 80% HRR during the last 4 training sessions. During the 10th week, we reduced the training intensity for one participant who reported having musculoskeletal pain. The mean intensity of the strength training was 51% of 1RM. No training-related injuries or adverse events occurred. The mean satisfaction score was 8.5 out of 10 (range=7–10).
Discussion
To our knowledge, this is the first study to evaluate a rehabilitation program that may be rather burdensome for recipients of liver transplants who are fatigued or severely fatigued and its effects on fatigue and on physical fitness, daily physical activity, and cardiovascular risk. Unfortunately, this study did not include a control group; therefore, the results have to be interpreted with caution. It appears that a 12-week rehabilitation program including supervised physical exercise and physical activity counseling is well tolerated and is promising in reducing fatigue. Furthermore, after the rehabilitation program, aerobic capacity and knee flexion strength were higher and body fat was lower than at baseline. Adherence was acceptable, participant satisfaction was high, and no adverse advents were reported.
Significant improvements in fatigue score after the rehabilitation program are consistent with the results of studies of people with chronic fatigue syndrome and people with fatigue and multiple sclerosis that also used the FSS, VAS, and CIS–fatigue questionnaires.35,36 This level of improvement is considered clinically relevant.37–39 Also, the percentage of people with severe fatigue in our study was much lower (22%–53% lower) after the program. However, the long-term effects of such a program are unknown and should be addressed in future studies.
The increase in V̇o2peak was low compared with aerobic improvements of 5% to 25% following systematic endurance training programs in the general population.40 However, 12-week training studies in patients with heart failure and survivors of cancer also showed relatively small V̇o2peak improvements of 7% to 10%.41–44 Improvements in the submaximal 6MWT, which is physiologically similar to daily activity, also were somewhat lower than those in a study of people with heart failure.45 We expected larger improvements in physical fitness, especially given the relatively low physical fitness of participants before the program commenced (30% lower aerobic capacity compared with age- and sex-matched healthy individuals as measured in our research laboratory). The relatively small improvements in V̇o2peak may be explained by the relatively low number of weekly training sessions. Because of fatigue, work conflicts, and long distances to the training site, training sessions were 2 times per week instead of the recommended 3 times per week.17 To attain larger training effects in future programs, additional home-based exercises should be considered. Although we found a small but significant reduction in body fat, we did not observe decreases in BMI. This finding also has been demonstrated in previous studies and may be explained by increases in lean body mass.46,47
At the end of the 12-week rehabilitation program, there was no significant increase in physical activity. However, even before the program began, activity levels were already relatively high: median dynamic activity durations (9.8%) were comparable to mean dynamic activity durations of people who were able-bodied (11.2%).48 It is remarkable that physical activity levels were found to be normal, despite the fatigue. We could speculate that the recipients of liver transplants in the current study were fatigued because they were too active with regard to their physical fitness levels and overburdened themselves. However, the results of our previous study5 showed that lower physical activity levels were associated with more fatigue.
We did not observe any changes in cholesterol ratios or glycemic control after the program. In contrast, some studies in patients with type 2 diabetes have shown that exercise training reduces glycosylated hemoglobin (HbA1c).49–51 Because HbA1c in our patients was somewhat high, we would have expected the HbA1c to decrease. Possibly, the period (ie, 1 week) between biochemical profile measurements and program conclusion was too short to detect any effects of the program on these measurements.
The rehabilitation program was well tolerated. Adherence to the rehabilitation program was acceptable, and participants were very satisfied. In general, participants were able to perform the program at the intended intensities and attended most sessions. Participants mentioned long travel distance to the training location as the most important barrier to participation. Future training sites should be more conveniently located near participants' homes.
Limitations
We chose an uncontrolled design, which was a limitation of this study. However, this was the first time that such a rather burdensome rehabilitation program was studied in a fatigued group of recipients of liver transplants, including those with severe fatigue. Because the time since transplantation was, on average, 7.5 years (range=1.3–17), no change in fatigue and fitness was expected other than due to the rehabilitation program. Now that we have demonstrated that the rehabilitation program is well tolerated in this group, the next step should be a randomized controlled trial to be able to draw stronger conclusions on the program's effectiveness and working mechanisms. Also, an important element for further studies will be to assess the long-term effects of this rehabilitation program. Another limitation was that we were not able to take fasting blood samples. However, guidelines allow the use of nonfasting blood samples for measuring the parameters described here for estimation of risk of cardiovascular disease.52 Lastly, there was a possible selection bias in participant recruitment. Our participants were likely highly motivated, as illustrated by their willingness to attend 2 exercise sessions per week for 12 weeks at our rehabilitation department.
In conclusion, we have shown that a 12-week rehabilitation program, consisting of supervised physical exercise training and counseling on physical activity, is well tolerated and seems promising in reducing fatigue and improving physical fitness in recipients of liver transplants. Previously, it was reported that this rehabilitation program also can positively influence daily functioning, participation, and health-related quality of life among people with fatigue following a liver transplant.15 Taken together, the results of the current and previous studies suggest that such a rehabilitation program might be beneficial in recipients of liver transplants. Future studies with a control group, larger samples, and assessment of long-term effects are needed to to be able to draw stronger conclusions regarding the program's effectiveness and working mechanisms.
Footnotes
Dr van den Berg-Emons, Dr van Ginneken, Ms Nooijen, Professor Tilanus, Professor Kazemier, and Professor Stam provided concept/idea/research design. Dr van den Berg-Emons, Dr van Ginneken, Ms Nooijen, Professor Metselaar, Professor Kazemier, and Professor Stam provided writing. Dr van den Berg-Emons, Dr van Ginneken, Professor Metselaar, and Professor Tilanus provided data collection. Dr van den Berg-Emons, Dr van Ginneken, Ms Nooijen, and Professor Stam provided data analysis. Dr van den Berg-Emons, Dr van Ginneken, Professor Metselaar, Professor Tilanus, and Professor Stam provided project management. Dr van den Berg-Emons, Dr van Ginneken, and Professor Tilanus provided fund procurement. Dr van Ginneken, Professor Tilanus, Professor Kazemier, and Professor Stam provided study participants. Professor Tilanus and Professor Stam provided facilities/equipment. Ms Nooijen, Professor Tilanus, Professor Kazemier, and Professor Stam provided consultation (including review of manuscript before submission).
The authors thank the following people from Erasmus University Medical Center for their contributions to this study: the rehabilitation physicians, and physical therapist Marjorie Westerhof (Department of Rehabilitation Medicine), and Elly Nijsen, Lara Elshove, and Anneloes Wilschut (Department of Gastroenterology and Hepatology).
This study was supported by grants from NUTS OHRA (project no. SNO-T-0601-41).
The Medical Ethics Committee of Erasmus University Medical Center, Rotterdam, the Netherlands, approved the study.
- Received August 27, 2013.
- Accepted February 14, 2014.
- © 2014 American Physical Therapy Association
References
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