Abstract
Background Functional impairment is common in people with chronic liver disease (CLD), and improvement is expected following liver transplantation (LT). The Six-Minute Walk Test (6MWT) is an objective measure of functional performance.
Objective The aims of this study were: (1) to evaluate the feasibility of 6MWT performance after LT, (2) to compare post-LT 6MWT performance over time between patients with and without CLD, (3) to determine when post-LT 6MWT performance approaches expected values, and (4) to investigate predictors of poor 6MWT performance.
Methods The 6MWT was performed by 162 consecutive ambulatory participants (50 healthy controls, 62 with CLD, 50 with LT). Sex, age, and body mass index were used to predict expected 6MWT performance. Chi-square testing, analysis of variance, and Pearson coefficients compared percentage of predicted 6-minute walk distance (%6MWD) across groups. Multivariable mixed models assessed predictors of improvement.
Results The participants' mean age was 53.5 years (SD=13.0), 39.5% were female, and 39.1% were nonwhite. At 1-month post-LT, only 52% of all LT recipients met the inclusion criteria for 6MWT performance. Mean %6MWD values for female participants improved from 49.8 (SD=22.2) at 1 month post-LT to 90.6 (SD=12.8) at 1 year post-LT (P<.0001), which did not differ statistically from the CLD group (X̅=95.9, SD=15.6) or the control group (X̅=95.6, SD=18.0) (P=.58). However, at 1-year post-LT, mean %6MWD values for male participants (X̅=80.4, SD=19.5) remained worse than for both the CLD group (X̅=93.3, SD=13.7) and the control group (X̅=91.9, SD=14.3) (P=.03). Six-Minute Walk Test performance was directly correlated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical component score (r=.51, P<.01) and was inversely correlated with nonalcoholic steatohepatitis (r=−.52, P<.01) and diabetes (r=−.48, P<.05). In multivariate analysis adjusted for age and sex, hepatitis C independently predicted 6MWT improvement (estimated β=69.8, standard error=27.6, P=.01).
Limitations A significant proportion of patients evaluated for enrollment were excluded due to level of illness early after LT (n=99, 47.4%). Thus, sampling bias occurred in this study toward patients without significant postoperative complications.
Conclusions The 6MWT is a simple test of physical functioning but may be difficult to apply in LT recipients. The 6MWT performance improved following LT but was lower than expected, suggesting a low level of fitness up to 1 year following LT.
The liver plays a central role in metabolism, influencing the function of almost all organs and systems. For this reason, patients with severe liver disease display systemic manifestations of liver failure, such as malnutrition, loss of muscle mass and function, cardiovascular dysfunction, and respiratory distress. The combination of these factors leads to global motor impairment, decreased exercise tolerance, and physical inactivity.1 After liver transplantation (LT), quality of life has been reported to improve, but complaints of limitations in daily function continue.2 Better quality of life is reported among patients who are physically active after LT.3 However, little is known about whether or when recipients regain full functional capacity after LT. Knowledge of expected recovery trajectories may help better inform patients of expected recovery times and allow early rehabilitation interventions in patients with delayed recovery.
One of the tests used to assess functional capacity is the Six-Minute Walk Test (6MWT). The 6MWT is easy to apply, involves low operating costs, and evaluates tolerance of physical effort, effectiveness of therapies and rehabilitation programs, and the functional state of the cardiovascular and respiratory systems.4 Initially, the 6MWT was used for patients with respiratory diseases, but currently it is commonly used to evaluate functional performance in a variety of medical conditions. The 6MWT is approved to assess physical capacity and determine prognosis in patients with heart failure and chronic obstructive pulmonary disease.5,6 It also has been used to predict mortality among patients with pulmonary hypertension and in candidates for lung transplantation.7,8 Other indications for use of the 6MWT include peripheral vascular disease, cystic fibrosis, lung cancer, fibromyalgia, and old age.4,9–12 In patients with chronic liver disease (CLD), the 6MWT determines functional capacity and predicts mortality in those on the LT waiting list.13,14
Data are limited on the feasibility and utility of 6MWT performance after LT. In a published study of 13 inpatients who underwent the 6MWT within 2 weeks of LT, 6MWT performance was shown to improve over time in those patients who were enrolled in a formal rehabilitation program.15 In addition, other small-scale studies have shown that the performance on the 6MWT after LT correlates well with cardiorespiratory physical fitness and oxygen consumption as measured by venous pulse oximetry.14,16 These findings suggest that the 6MWT could be used to estimate aerobic capacity and assist in rehabilitation planning after LT.
The purposes of the current prospective study were: (1) to explore the utilization of the 6MWT as a tool to assess functional capacity among outpatient ambulatory LT recipients and (2) to estimate trajectories of expected improvement in functional capacity after LT. The objectives of this exploratory study were: (1) to evaluate the feasibility of the 6MWT after LT, (2) to compare 6MWT performance over time among LT recipients and among participants with and without CLD, (3) to determine whether or when 6MWT approaches expected values following LT, and (4) to investigate the factors that may predict poor 6MWT performance following LT. Based on our clinical experience, we hypothesized that the 6MWT would be an effective tool to assess functional capacity after LT and that 6MWT performance in LT recipients would approach that of participants without liver disease within 6 months of transplantation. We also hypothesized that obesity and age would predict poor 6MWT performance following LT.
Materials and Method
Sample
The study enrolled consecutive patients aged between 18 and 75 years who underwent LT at our institution over a 2-year period (April 20, 2012, through March 5, 2014) as part of an exploratory study to assess 6MWT feasibility and performance. Patients with well-compensated CLD were recruited from the general hepatology clinic at our institution and were matched by age and sex to the LT cohort. Age- and sex-matched healthy controls were recruited from the general medicine clinic or from staff at our institution. All participants gave informed consent prior to the study.
Study exclusion criteria were myocardial infarction or unstable angina within 1 month of enrollment, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure 100 mm Hg), and resting heart rate >120 or <50 beats per minute. Patients who were relisted for LT, needed assistance with ambulation, were receiving supplemental oxygen or hemodialysis, or had significant liver synthetic dysfunction or evidence of portal hypertension (total bilirubin >10 mg/dL, international normalized ratio >2, hepatic encephalopathy, or ascites requiring paracentesis) (n=99 LT recipients) also were excluded.
Study Visits
Participants were assessed in the LT population during routine office visits, which are scheduled per clinical protocol at our institution to occur at 1, 3, 6, 9, and 12 months after LT. Participants in the CLD and control groups were assessed at a single visit. As a major goal of the study was to assess the feasibility of 6MWT performance in an LT population, study visits were conducted as part of routine clinical care. Thus, not all visits occurred for every patient at every time point due either to missed patient appointments or inability of the investigators to perform the study at the time of the routine office visit (Fig. 1). Data, including demographics, etiology of liver disease, comorbidities, laboratory parameters, medications, transplant and actual model for end-stage liver disease (MELD) score, and smoking history, were collected by chart review. At the time of 6MWT performance, body composition, including body mass index (BMI), lean body mass, and fat mass, was determined by anthropometric measurements, including height, weight, mid-arm circumference, and waist circumference. Presence of peripheral edema on examination was noted.
Patient performance and characteristics of Six-Minute Walk Test (6MWT) completion. The number of individuals assessed at each time point after liver transplantation (LT) was: 1 month (n=50), 3 months (n=34), 6 months (26), 9 months (n=25), and 12 months (n=25). n=number of LT recipients, v=number of scheduled office visits.
In order to measure health-related quality of life (HRQoL), participants were asked to complete the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) just prior to participating in each 6MWT. The SF-36 is a validated instrument that comprises 8 multi-item scales (physical functioning, physical role limitations, emotional role limitations, bodily pain, general health, emotional well-being, energy, and social functioning). The scores on these scales are aggregated into 2 summary scores: the physical component score and the mental component score.17 Both are norm-based scores, with a higher number indicating better HRQoL. Participant responses were entered into a computerized scoring program that provided the standard scoring algorithms and the physical and mental component scores. These scores were used as measures of HRQoL.
6MWT
Functional capacity was determined by using the 6MWT. The 6MWT was conducted according to American Thoracic Society guidelines and supervised by qualified trained technicians.4 In brief, the participant was instructed to walk at his or her own pace along a straight, flat 30-m-long hallway marked at 1-m intervals. Heart rate, blood pressure, and oxygen saturation were measured and Borg Rating of Perceived Exertion score18 (based on an exertion scale where 0=no exertion and 10=very severe exertion) was obtained at the start (0 minutes) and end (6 minutes) of the walk test. Participants were asked to cover as much ground as possible in 6 minutes but were allowed to stop if there were symptoms of dyspnea or leg pain. The distance (in meters) was recorded at the end of the 6 minutes (ie, 6-minute walk distance [6MWD]). The absolute 6MWD uses only the number of meters walked, but the walking distance is dependent on various factors, such as age, sex, and BMI. There are a sufficient number of studies dealing with standardization of the 6MWT for healthy individuals. However, to our knowledge, these norms have not been validated in a postsurgical LT population. As normative 6MWD data are not available in this population, we chose to use percentage of predicted 6MWD (%6MWD) based on age and sex to assist with standardization of the reported values. Ideal 6MWD values were calculated using reference equations provided by Enright and Sherrill.19 The test results were recorded as absolute 6MWD or %6MWD, which were calculated as follows19,20:
Male ideal 6MWD=1,140 − (5.61 × BMI) − (6.94 × age)
Female ideal 6MWD=1,017 − (6.24 × BMI) − (5.83 × age)
%6MWD=(absolute 6MWD/ideal 6MWD) × 100
Data Analysis
The demographic features, laboratory data, and 6MWD scores for the 3 cohorts are summarized using frequency counts and percentages for categorical variables and means and standard deviations for continuous variables. Comparisons among cohorts were made using the chi-square test for categorical variables and analysis of variance for continuous variables. Correlations among the 6MWD, SF-36 scores, and patient characteristics were determined using Pearson or Spearman correlation coefficients and were calculated according to absolute 6MWD and %6MWD measured at the 1-month (initial) visit. Comparisons of participant characteristics and performance on the 6MWT over time following LT were conducted using longitudinal mixed-effects models adjusted for sex and age. Mixed-effects models were constructed with absolute 6MWD as the dependent variable; with sex, age, participant characteristics, and time as main fixed effects; and with baseline intercept and slope as random effects. Generalized linear models were utilized to compare absolute 6MWD in the CLD and control groups with the final walk for the LT cohort. These linear models were adjusted for sex, age, and participant characteristics of interest. Logistic regression models were constructed to determine univariate predictors (P<.10) of poor performance at 1 month following LT. Poor performance on the 6MWT was defined as performance below the mean absolute 6MWD for the LT cohort (<250 m for women and <430 m for men). No sample size estimation was performed, as this study was designed as a feasibility study to determine whether a larger trial should be undertaken among LT recipients to assist with rehabilitation planning. All statistical analyses were conducted using SAS version 9.3 (SAS Inc, Cary, North Carolina).
Role of the Funding Source
Dr VanWagner is supported by the American Association for the Study of Liver Diseases (AASLD) Foundation and the National Institutes of Health's National Center for Advancing Translational Sciences, grant number KL2TR001424. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Ms Uttal is supported by the Northwestern University Honors Program in Medical Education (HPME) Undergraduate Summer Research Program. The sponsors played no role in the development of the manuscript.
Results
Participant Characteristics
One hundred sixty-two ambulatory participants (50 in LT group, 62 in CLD group, and 50 in control group) consented and participated in the study protocol. The demographic features, laboratory data, and MELD scores calculated at the time of the 6MWT for the 3 cohorts are summarized in Table 1. The mean age of the participants was 53.5 years (SD=13.0), 39.5% of the participants were female, and 39.1% if the participants were nonwhite. Alcohol (28%) was the primary cause of liver disease among the LT cohort compared with hepatitis C (30%) in the CLD cohort. Cirrhosis was present in only 35% of the CLD cohort. Of note, the average MELD score among the CLD cohort was 6.0 (SD=4.8), confirming well-compensated CLD. Weight and BMI were significantly different across cohorts, with the CLD group having the highest BMI values across the cohorts for both men (X̅=29.5, SD=6.2) and women (X̅=31.2, SD=5.7) (P<.001). The CLD group also had the largest waist circumference, and, of note, none of the participants in this group had significant ascites on enrollment (P=.03). Diabetes was significantly more prevalent in the LT cohort, with 38% of men and 42% of women having a diagnosis of diabetes at their final walk following LT (P<.001). Hyperlipidemia and hypertension also were more prevalent in both the CLD and LT cohorts compared with the control group (P<.05 for all comparisons). Serum albumin was highest among the controls (men: X̅=4.4 g/dL, SD=0.5; women: X̅=4.5 g/dL, SD=0.4; P<.001), and hemoglobin was the lowest among LT recipients (men: X̅=11.2 g/dL, SD=2.1; women: X̅=11.1 g/dL, SD=2.2; P<.001). Aspirin usage, prescribed via a standard protocol to prevent hepatic artery thrombosis after LT, was more than 90% in the LT group, with significantly lower usage in other cohorts (P<.001).
Comparison of Consecutive Study Participants With No Liver Disease, Those With Chronic Liver Disease, and Those Who Underwent LT (2012–2014)a
6MWT Feasibility After LT
Two hundred nine participants underwent LT at our institution during the study period (April 2012–March 2014). Of these participants, 110 (52.6%) met inclusion criteria for enrollment at 1 month following LT, and 59 (28.2%) consented to enrollment, with 273 visits completed (Fig. 1). Of the 59 post-LT recipients who initially met the inclusion criteria, 50 (84.7%) completed at least one walk. The LT recipients successfully completed the 6MWT during 128/273 (46.9%) of all previously scheduled clinic visits (Fig. 1). The majority of the LT recipients (n=45) missed a subsequent walk at one or more time points, but only 16/45 (35.5%) were due to not meeting inclusion criteria (Fig. 1). Most failures in completion of the test were due to missed appointments, primarily due to rehospitalization (n=12, 20 visits missed). The number of individuals assessed at each time point after LT was: 1 month (n=50), 3 months (n=34), 6 months (n=26), 9 months (n=25), and 12 months (n=25). The mean follow-up time for the LT cohort was 6.1 months (SD=5.2) after LT. Notably, there were no adverse events during performance of the 6MWT and no study-related deaths or withdrawals.
LT Recipient 6MWT Performance Over Time Versus That of the CLD and Control Groups
A significant proportion of LT recipients (53.1%) missed one or more scheduled follow-up appointments at the prespecified time points, so data on all participants at every time point (ie, 1 month, 3 months, and so on) are not available. Therefore, we chose to assess, on average, at what time point LT recipients completed their first and last 6MWTs and the associated distances walked. Thus, the LT recipients' mean absolute 6MWD and %6MWD were 379.7 m (SD=122.4) and 65.3 (SD=22.8), respectively, at a mean of 71.8 days (SD=65.1), improving to 431.5 m (SD=90.7) and 79.1 (SD=19.9), respectively, by a mean of 287.3 days (SD=138.2) following LT (P<.01, Fig. 2). Women had lower initial absolute 6MWD and %6MWD values (295 m and 56.4% versus 409 m and 68.4%, respectively), but they improved more than men (381 m and 76.4% versus 455 m and 80.4%, respectively) over time (P=.02 for trend) (Fig. 2). At 1, 3, 6, and 9 months, both male and female LT recipients performed below the absolute 6MWD and %6MWD of both CLD and control cohorts (Fig. 2, P<.0001). By 1 year post-LT, both male and female LT recipients' absolute 6MWD remained significantly worse than that of the CLD and control cohorts (Fig. 2A, P=.02). In contrast, %6MWD values for male LT recipients' (X̅=80.4, SD=19.5) remained significantly worse than those for the CLD cohort (X̅=93.3, SD=13.7) and the control cohort (X̅=91.9, SD=14.3) (P=.03 and .10, respectively, Fig. 2B). Notably, at the first post-LT walk, only 5/50 (10.0%) of LT recipients were enrolled in a formal rehabilitation program, and none were participating at 1 year. After controlling for age, sex, and other participant characteristics, the CLD and control groups had significantly higher 6MWD values compared with the LT group (P<.01).
Percentage of predicted 6-minute walk distance (6MWD) and absolute 6MWD over time stratified by group and sex. At 1, 3, 6, and 9 months, both male and female recipients of liver transplantation (LT) performed below the absolute 6MWD and %6MWD of both chronic liver disease (CLD) and healthy control (HC) cohorts (P<.0001). (A) By 1 year post-LT, LT recipient absolute 6MWD remained significantly worse than that of the CLD and HC cohorts (P=.02). (B) In contrast, male participants' (but not female participants') %6MWD remained significantly worse (X̅=80.4, SD=19.5) than that of the CLD cohort (X̅=93.3, SD=13.7, P=.03) and the HC cohort (X̅=91.9, SD=14.3, P=.10).
Predictors of 6MWT Performance
Table 2 summarizes the predictors of 6MWT over time adjusted for age and sex in LT recipients. Only postoperative fatigue score and etiology of liver disease were predictive of 6MWD over time. The postoperative fatigue score was an independent predictor of worse 6MWD over time (estimated β=−18.9, standard error [SE]=5.3, P<.01). Hepatitis C status predicted improved 6MWD over time (estimated β=69.8, SE=27.6, P=.013), and nonalcoholic steatohepatitis (NASH) predicted worse 6MWD over time (X̅=115.3, SE=47.6, P=.018).
6MWT Characteristics Among Liver Transplant Candidates Over Timea
The LT recipients' absolute 6MWD showed a moderate direct correlation with serum albumin (r=.50, P<.01), hemoglobin (r=.53, P<.01), the physical and mental component scores of the SF-36 (r=.51, and .29, respectively, P<.01), and hepatitis C status (r=.59, P<.01) (Tab. 3). On the other hand, LT recipients' absolute 6MWD demonstrated an inverse correlation with age (r=−.43, P<.01), diabetes status (r=−.48, P<.05), serum alanine aminotransferase (ALT) (r=−.22, P<.05), aspartase aminotransferase (AST) (r=−.29, P<.05), and NASH (r=−.52, P<.01) (Tab. 3). In univariate analysis, MELD score, prewalk heart rate, and prewalk systolic blood pressure predicted poor performance on the 6MWT at 1 month following LT, defined as performance below the mean 6MWD for the LT cohort (<250 m for women and <430 m for men; Tab. 4). Similar findings were seen for prediction of poor 6MWT performance over time following LT (data not shown).
Pearson and Spearman Correlation Coefficients for Absolute 6MWD and %6MWD Among the Liver Transplant Recipients (n=50)a
Univariate Predictors of Poor Performancea on the Six-Minute Walk Test at 1 Month After Liver Transplantationb
In terms of clinical outcomes, LT recipients with no rehospitalizations had a longer 6MWD at one month following LT compared with recipients with at least one rehospitalization after LT (X̅=452.4 m [SD=95.2] versus X̅=402.8 m [SD=77.9]; P=.096) (data not shown). Rehospitalization status was not a predictor of changes in 6MWD over time. There was one recorded death in a single patient who was rehospitalized with sepsis 2 weeks after performance of the 6MWT, which was not thought to be study-related. There was no correlation between 6MWT performance and pre-LT MELD score, acute cellular rejection, or graft survival.
Discussion
The present exploratory preliminary study demonstrates that the 6MWT applies to a small proportion of the overall LT population. Even in those able to complete the 6MWT, the distance walked by LT recipients was found to be lower than that walked by healthy participants or those with CLD up to 1 year following LT, highlighting the need to improve physical functioning in this population. Furthermore, the study showed that a significant minority of LT recipients are enrolled in a formal rehabilitation program after LT, thus highlighting an opportunity for intervention. The following discussion will focus on answering the questions posed by our initial preliminary study objectives.
Is the 6MWT Feasible After LT?
One of the main objectives of the current study was to determine the feasibility of 6MWT performance in an outpatient ambulatory post-LT population as the standard of care. Only 52.6% of LT recipients at our institution met the inclusion criteria for participation, highlighting the high prevalence of frailty and disability in this population. However, when 6WMT feasibility was assessed in terms of a percentage of ambulatory outpatients, participation was high over the study period, with nearly 85% of eligible participants completing at least one post-LT 6MWT. There were significant issues with participant attrition throughout the study. Although 50 individuals performed the 6MWT at 1 month, only 26 completed the 6MWT at 6 months, and 25 completed it at 12 months. We believe that this attrition was a result of a combination of both patient and systems factors. For the former, follow-up in the LT clinics was not optimal as planned, and given this was a preliminary study without significant funding resources, we had to enroll patients when they came for their clinic visits. For the systems issue, we had a study team of students and medical residents who were trained to administer the 6MWT, but they were not always available, and we did not have a research coordinator or physical therapist to administer the 6MWT. As we continue to address functional capacity in our LT recipients, we are working closely with our rehabilitation and physical therapy team to initiate a standardized approach to measurement of 6MWD, in addition to other tests of physical function in order to assist with rehabilitation planning. This preliminary study allowed us, as an institution, to identify systems- and patient-related factors that impede our recipients' ability to be assessed for functional debilitation and to receive rehabilitation care.
How Does 6MWT Performance After LT Compare With That Of Individuals With and Without CLD?
We demonstrated that adult LT recipients walked a shorter distance on the 6MWT compared with the normal values of both healthy adults and those with CLD of the same age and sex, suggesting a lower level of fitness in a post-LT population. This finding is consistent with prior research demonstrating that although physical fitness and muscle strength increase dramatically during the first postoperative year, they remain 10% to 20% less than in age- and sex-matched sedentary individuals.14 Limitations in exercise capacity could partly be caused by the influence of immunosuppressive medication (eg, glucocorticoids, calcineurin inhibitors). In addition to preventing rejection, these medications might influence both skeletal muscles and the cardiovascular system.21 One of the side effects of prednisone is muscle weakness, and calcineurin inhibitors may affect the sympathetic system, resulting in a reduction of heart rate and decreased mitochondrial skeletal muscle respiration.22 Obesity and metabolic syndrome also are common after LT and may affect functional capacity.23 Reduced skeletal muscle mass, termed “sarcopenia,” also is more prevalent in patients with metabolic syndrome.24 Hence, changes in skeletal muscle mass following LT may contribute to a reduced quality of life and to the development of post-LT metabolic syndrome. Of note, we observed that there was a trend toward poorer performance on the 6MWT among those individuals who received LT for NASH, which is highly associated with metabolic syndrome. Further study is needed to elucidate the clinical implications of this finding and whether targeted interventions in this population especially are needed.
When Does LT Recipient 6MWT Performance Approach Expected Performance of Those Without Liver Disease?
Based on our clinical experience, we hypothesized that 6MWT performance would improve within 6 months of LT and thus chose to enroll participants beginning at 1 month post-LT in order to capture the “natural history” of functional recovery post-LT. Therefore, several findings in the current study are surprising. First, there was an overall low percentage of eligible LT recipients who met our initial criteria for enrollment, again highlighting the illness burden and frailty in this population. Second, 50% of the participants were unable to complete the study, and up to 25% of these losses to follow-up were due to a clinical decline. Finally, at 6 months post-LT, both male and female participants' 6MWD scores remained below those with and without CLD, and at 1 year post-LT, male LT recipients' 6MWD scores still had not normalized. These findings highlight the need for rehabilitation planning among LT recipients.
Fewer than 10% of the LT recipients were enrolled in a formal rehabilitation program despite their poor performance on the 6MWT. Garcia et al25 recently demonstrated in a study of 15 patients within 1 year of LT that randomization to an exercise intervention comprising 24 sessions of continuous 30-minute treadmill exercise improved distance walked on the 6MWT by 19.4%, in addition to increasing resting energy expenditure. There were no differences in the distance walked or resting energy expenditure in the control group. In addition, van den Berg-Emons et al26 recently demonstrated the beneficial effects of a 12-week rehabilitation program on 18 LT recipients. Severe fatigue was reduced up to 50%, and aerobic capacity significantly increased, as did the 6MWD. These preliminary data suggest that rehabilitation using supervised exercise training can positively affect daily functioning and fatigue among LT recipients and may help to improve HRQoL in this population.
What Are the Factors That Predict Poor 6MWT Performance After LT, and Does Poor Performance Predict Clinical Outcomes?
Aside from the participants' sex, only transplantation for NASH and posttest fatigue score predicted worse 6MWD values over time. Given the small sample, further study is needed to confirm these findings. Nonalcoholic steatohepatitis, which is associated with obesity and metabolic syndrome, is currently the third leading indication for LT, the second leading indication for transplant listing, and, in an era of effective therapy for hepatitis C, is anticipated to become the leading indication for LT in the next decade.27,28 Liver transplantation for NASH is associated with high levels of frailty before LT29 and high cardiovascular morbidity and mortality after LT.30–32 Importantly, physical activity has been shown to be an effective treatment for reduction of cardiovascular morbidity and for treatment of NASH.33 Identification and awareness of the unique issues facing the growing population of NASH LT candidates and recipients is of utmost importance for rehabilitation planning in this population. We confirm previous findings among patients with CLD that performance on the 6MWT positively correlates with serum albumin and hemoglobin levels and negatively correlates with age.34 A positive correlation between 6MWD and hemoglobin has been observed among patients with severe heart failure, where anemia is associated with poor physical function and increasing hemoglobin levels are correlated with improved exercise capacity as measured in cardiopulmonary exercise tests.35 We also have demonstrated that 6MWD negatively correlates with serum ALT and AST levels after LT, although performance on the 6MWT did not predict other liver graft–related outcomes such as acute cellular rejection or graft failure. However, in studies of patients with cirrhosis, walking less than 250 m on the 6MWT is associated with decreased survival.34 Only one death occurred in our patient cohort; thus, we are unable to examine the predictive ability of the 6MWT for survival after LT.
We did demonstrate that poor performance on the 6MWT correlates with an increased risk of rehospitalization after LT. Rehospitalization after LT is common: up to 40% of LT recipients are hospitalized within 30 days of LT.36–38 However, the factors that influence this high readmission rate are unknown. Among people with chronic obstructive pulmonary disease, a 6MWD of <200 m is predictive of both hospitalization and mortality.39,40 Future studies in larger longitudinal patient populations are needed to determine the predictive ability of the 6MWT to forecast morbidity and mortality after LT.
Limitations
Our study had several limitations. First, the 6MWD was not assessed prior to LT; therefore, assessment of individual trajectories in improvement of functional status cannot be assessed. However, we did not assess 6MWD until at least 1 month post-LT to allow for postsurgical recovery and to minimize differences in pre-LT level of sickness that might affect post-LT results. In addition, we looked at illness indicators prior to LT, including pre-LT MELD score and history of cardiopulmonary disease, which did not predict post-LT 6MWD performance.
Second, a significant proportion of patients evaluated for enrollment during the study period were excluded from the study due to level of illness early after LT (n=99, 47.4%). Thus, sampling bias occurred in this study toward patients without significant postoperative complications. We note that this finding limits the generalizability of the current study findings to those LT recipients without a complicated postoperative course. Although the 6MWT could not be safely performed in this subgroup, alternative assessments of functionality, such as frailty measures,29,41 could be considered in order to improve rehabilitation planning.
Third, both the control group and the CLD group completed only one walk compared with participants in the LT cohort, who completed several walks, which may predispose the study to measurement bias. However, other investigators have shown that in patients with stable chronic illness, the 6MWT is highly reproducible.42 In addition, the CLD group had an unexpected higher mean 6MWD than the control group. Notably, we excluded patients with CLD who were undergoing hemodialysis or who had significant synthetic dysfunction or evidence of portal hypertension. Thus, the CLD group in the current study represents well-compensated CLD rather than being reflective of a typical pre-LT population (eg, MELD scores >15).
We also note that the regression equation used in this study to predict expected 6MWD values accounts for about 40% of the individual variability in 6MWD.19 However, we present both %6MWD and absolute 6MWD values to assist in clinical interpretation of meaningful differences. Also of note, the increases in heart rate and perceived exertion (as measured with the Borg scale) were variable among participants, ranging from 2% to 16%, which suggests that effort was variable. Nevertheless, we emphasize that the 6MWT is a submaximal exercise test.43
Formal cardiopulmonary exercise testing provides a global assessment of the exercise response, an objective determination of functional capacity and impairment, determination of the appropriate intensity needed to perform prolonged exercise, quantification of factors limiting exercise, and a definition of the underlying pathophysiologic mechanisms such as the contribution of different organ systems involved in exercise. The 6MWT does not determine peak oxygen uptake, diagnose the cause of dyspnea on exertion, or evaluate the causes or mechanisms of exercise limitation. In addition, although the 6MWD is a sensitive marker of change in functional walking ability for patients with moderate-to-severe cardiopulmonary disease, its use in those with better-preserved exercise tolerance (which may include patients post-LT) is unclear. For example, a ceiling effect has been documented in patients with pulmonary arterial hypertension whose 6MWD was greater than 450 m, which also may occur in patients with other conditions, including after LT.44 Further research in this population is needed to determine whether a ceiling effect does exist after LT. Thus, consideration may need to be given to use of a more challenging test of exercise capacity in LT recipients who perform “well” on an initial 6MWT, such as a cardiopulmonary exercise test or an incremental shuttle-walking test.
In summary, our results indicate that the 6MWT is limited in its use as a clinical tool to assess functional capacity after LT. In participants who were able to complete a 6MWT, we demonstrated that performance improves over time post-LT but is significantly lower in comparison with values for healthy adults and even those with CLD of the same age, suggesting a lower level of fitness in this population. This finding highlights the frailty and poor functional capacity of LT recipients and identifies an opportunity for intervention, as <10% of study participants were enrolled in a formal rehabilitation program post-LT. Future studies will address the utility of the 6MWT in clinical management (eg, randomizing patients to undergo rehabilitation based on performance on the 6MWT versus standard of care), as well as the types of exercise interventions needed to improve functional capacity and quality of life after LT.
Footnotes
Dr Van Wagner, Ms Uttal, Dr Lee, Dr Wong, and Dr Levitsky provided concept/idea/research design. Dr VanWagner, Ms Uttal, and Dr Levitsky provided writing. All authors provided data collection. Dr VanWagner, Ms Uttal, Ms Lapin, Ms Subramanian, Mr Bustamante, and Dr Levitsky provided data analysis. Dr VanWagner, Dr Lee, Mr Bustamante, and Dr Levitsky provided project management. Dr VanWagner, Ms Uttal, and Dr Levitsky provided fund procurement. Dr VanWagner and Dr Levitsky provided participants. Dr Levitsky provided facilities/equipment and institutional liaisons. Dr Lee, Mr Bustamante, and Dr Levitsky provided administrative support. Ms Uttal, Dr Lee, Mr Bustamante, and Dr Levitsky provided consultation (including review of manuscript before submission).
The authors thank the participants of the study for their contribution to the study findings. They also thank the staff of the Comprehensive Transplant Center at Northwestern University for their assistance in completing the study protocol.
The Institutional Review Board of Northwestern University approved the study.
Dr VanWagner is supported by the American Association for the Study of Liver Diseases (AASLD) Foundation and the National Institutes of Health's National Center for Advancing Translational Sciences, grant number KL2TR001424. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Ms Uttal is supported by the Northwestern University Honors Program in Medical Education (HPME) Undergraduate Summer Research Program. The sponsors played no role in the development of the manuscript.
- Received July 11, 2015.
- Accepted March 10, 2016.
- © 2016 American Physical Therapy Association