Use of Six-Minute Walk Test to Measure Functional Capacity After Liver Transplantation

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.