Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD), with a 1- and 5-year survival of 93.8% and 81.3%, respectively, across UK liver transplant centers.1 Malnutrition is a frequent burden in ESLD, reported in >50% of patients with decompensated liver disease and long recognized as a prognostic and therapeutic determinant in ESLD.2 Physical deconditioning and sarcopenia result from the combined effects of impaired dietary intake, altered macronutrient and micronutrient metabolism, chronic inflammation, and low physical activity.3 Frailty is the end result of prolonged sarcopenia and physical deconditioning. The frailty syndrome is itself associated with a higher rate of complications in the perioperative period, including susceptibility to infection, hepatic encephalopathy and ascites, and is an independent predictor of lower survival in cirrhosis and patients undergoing LT.4,5 Measures should be taken to address poor physical fitness and frailty in this cohort. Attention is turning toward the development of effective exercise or lifestyle intervention programs known as “prehabilitation” for patients awaiting LT, where involvement of a liver multidisciplinary team is essential, particularly with respect to tailored physical and nutritional intervention.
Recent studies have shown a beneficial impact of preoperative exercise for patients with colon and rectal cancer6-8 in terms of cardiorespiratory fitness,7 respiratory muscle endurance,6 fatigue, and physical health perceptions.8 A reduction in postoperative hospital length of stay in the intervention group has been demonstrated when prehabilitation has been used in both cardiac and major vascular surgery.9
There is currently only limited data available to determine the effects of exercise in the complex cohort of patients with ESLD awaiting LT. A 2018 meta-analysis sought to assess the effects of exercise on patients with cirrhosis,10 revealing only 4 small studies with 81 patients included. A limited range of clinical conditions were studied and heterogenous outcome measures reported. Associations with improvement in peak oxygen consumption (VO2peak),11 exercise capacity11-13 quality of life,13 reduced fatigue,11 and hepatic venous pressure gradient14 were found.
Knowledge pertaining to the field of exercise training before LT is still at an early stage; indeed, there is no existing evidence that patients with decompensated liver disease awaiting transplantation would simply comply with a prehabilitation program. There is considerable scope for further evaluation to define the optimal prehabilitation program to keep patients well on the liver transplant waiting list. This single-center study was designed to address the issue of feasibility, and it forms the first stage in a larger program of work to investigate the impact of perioperative exercise training on patients awaiting LT.
We wanted to know whether it would be possible to engage patients in a program of intense, supervised aerobic exercise, in a hospital setting over a period of 6 weeks. We designed a simple feasibility study to determine this, understand fitness levels in patients awaiting LT, and see if there were any signals of fitness improvement when compared with a group of matched patients not involved in an exercise program.
MATERIALS AND METHODS
This single-center cohort study assessed the feasibility of a 6-week, structured, prehabilitation program in patients awaiting LT. It also compared levels of fitness before and after the program with a demographically matched control group awaiting LT who did not undergo exercise training. Ethical approval for this study was granted by London Bromley Research Ethics Committee (16/LO/0762). Local NHS permission was granted by the Royal Free London NHS Trust. Written consent was obtained for all patients. Trial registration was not considered necessary for this nonrandomized internal feasibility study.
Study Setting and Participants
Patients aged ≥18 years with a diagnosis of cirrhotic liver disease awaiting LT at the Royal Free Hospital (RFH) were invited to join a 6-week exercise training program. The study ran from June 2016 to December 2017. Patients were eligible for inclusion once they were formally listed for LT. Invitation to the exercise program was based on the distance potential participants lived from the hospital as the exercise intervention was delivered within the hospital in an outpatient clinic. It was assumed that those patients living a long distance from the hospital would be unable to make this journey 3 times a week for 6 weeks. The study was limited to cirrhotic patients given the high prevalence of physical inactivity, compounded by multiple other factors, including malnutrition, decreased hepatic protein synthesis, hypermetabolism, low testosterone, and an increase in inflammatory cytokines, alongside cardiac and skeletal muscle deconditioning and the potential for an exercise intervention to limit decline.
Specific exclusion criteria were noncirrhotic liver disease, an oncological diagnosis as the primary reason for transplantation, and a contraindication to exercise training or testing (according to the American Thoracic Society and American College of Chest Physicians guidelines).15 Given that the primary aim of this study was feasibility, formal randomization was not considered necessary and the study was not designed to detect differences in outcomes. The patients in the “standard care” cohort (no exercise program) were matched with those in the exercise group according to specific demographic criteria: age, sex, and disease severity (model for end-stage liver disease score). Once patients were matched, allocation to study arms was a function of geographical location and logistical ability to commit to attending hospital 3 times per week.
Assessment of Fitness
Self-reported activity status was assessed at baseline using the Duke activity status index score.16 Serial CPET was used to objectively assess change in cardiopulmonary fitness at the following time points: baseline (wk 0), at the midpoint of the exercise training to guide the subsequent exercise prescription (wk 3; exercise group only), at the end of the 6-week exercise program, and a final CPET at week 12. All CPETs were performed using an electromagnetically braked cycle ergometer (Corival, Lode, Gronigen, the Netherlands) and breath-by-breath analysis system (Cortex, Leipzig, Germany). The CPET protocol involved patients resting for 3 minutes, undergoing 3 minutes unloaded exercise on a static bike, then between 6 and 10 minutes of appropriate incrementally ramped exercise (dependent on patient fitness), during which cycling intensity was gradually increased. Patients were fitted with a facemask to enable continuous measurement of respiratory variables. Finger prick hemoglobin concentration was routinely measured before each CPET (Hemocue, Ängelholm, Sweden). CPET data were analyzed by the same 2 trained practitioners (1 was blinded to patient identification). Anaerobic threshold (AT) and VO2peak were used to assess changes in fitness. Where disagreement in AT interpretation of >10% occurred, a third blinded expert was asked to interpret AT position.
Following the baseline CPET, patients were asked to attend 3 weekly exercise training sessions for 6 weeks. Outpatient sessions were held at the RFH, London, UK, and patients traveled from home for each appointment. Each training session consisted of 40 minutes (including 5-min warm-up and 5-min cool-down) of interval training on an electromagnetically braked cycle ergometer (Optibike Ergoselect 200; Ergoline, GmbH, Bitz, Germany). The exercise training intensities were formulated according to the CPET data of an individual at weeks 0 and 3, and altered according to measured work rates at VO2 for AT and VO2peak. The interval training protocol consisted of alternating moderate (80% of work rate at VO2 at AT: 4 × 3-min intervals) to severe (50% of the difference in work rates between VO2 at peak exercise and VO2 at AT: 4 × 2-min intervals) intensities (total 20 min) for the first 2 sessions. This was then increased to 40 minutes (6 × 3-min intervals at moderate intensity and 6 × 2-min intervals at severe intensity).
Power Intervals Were Calculated for Each Subject as Follows
Moderate-intensity exercise: (work load at VO2 and AT-2/3 of work ramp) × 80%
Severe-intensity exercise: ((Work load at VO2 Peak – work load at AT-2/3 of work ramp) × 50% )+ work load at AT
Comparison (Control) Group
A comparator “usual care” group was created by selecting patients matched to those in the exercise group according to age, sex, and model for end-stage liver disease score. These patients underwent CPET at 0, 6, and 12 weeks, but no exercise program was initiated. Once patients were demographically matched, allocation to study groups was based on geography and logistics; the patient living farthest from the hospital was allocated to the control group to avoid any logistical issues with 3 weekly hospital visits.
Both the groups received standardized nutritional assessment and advice, at baseline and 6 weeks. Difficulties in the accurate assessment of nutritional status in patients with cirrhosis are widely recognized, given that many of the markers associated with malnutrition are intrinsically affected in liver disease (eg, albumin and lymphopenia). Therefore, skeletal muscle evaluation provides an objective means to determine nutritional status.3,17
Assessment was made and nutritional advice given by the same specialist liver transplant dietitian at baseline (before first CPET) and again before the week 6 CPET for all patients in both the exercise and comparator groups. The RFH Global Assessment Data Collection Form was used which encompasses measures of body mass index (BMI), mid-arm muscle circumference (MAMC), triceps skinfold thickness (TSF), and handgrip strength combined with details of dietary intake18 (see supplementary material). The RFH Global Assessment Data Collection Form has been validated as a nutritional assessment method specifically for this patient population.18
Usual recent dietary intake was assessed using a self-reported diet history. Details of any dietary restrictions and nutritional support supplements were recorded. These data were used to provide an overall impression of the adequacy of the diet in relation to estimated daily requirements, for energy (35–40 kcal/kgBW/day) and protein (1.2–1.5 g/kgBW/day).19-22 Intakes were categorized as adequate if they met estimated requirements, inadequate if they did not meet estimated requirements but exceeded 500 kcal/day, or negligible if they provided <500 kcal/day.18
An estimated dry weight was determined using clinical assessment, previously documented weights, ascitic volumes removed at paracentesis, and published guidelines. BMI was calculated from the estimated dry weight and height.18 Mid-arm circumference and TSF were measured on the nondominant arm using Holtain/Tanner Whitehouse skinfold callipers (Holtain, Crymych, UK) and a tape measure. MAMC was then calculated using the following formula:
MAMC and TSF measurements were compared with published standards24 and MAMC expressed in relation to the fifth percentile, for the appropriate age and gender category.18
All participants were invited to a follow-up CPET at 12 weeks after baseline if they were still awaiting LT. The purpose of this was to determine any alteration in level of fitness from week 6 to 12.
Data were examined for normality using the Shapiro-Wilk test. Continuous data were presented as median with interquartile range or mean with SD for normally distributed data and categorical data as number (percentage). Paired data were compared using Mann–Whitney analyses (continuous, non-normal distribution) or t test analyses (continuous, normal distribution). All tests were 2 tailed, and significance was taken as P < 0.05. Statistics were calculated using IBM SPSS Statistics, Version 24.0. IBM Corp, Armonk, NY.
A total of 16 patients were recruited to the exercise group and 17 to the standard care group (a total of 33 patients); there were no differences in demographic data between groups (Table 1). There were no differences in self-reported activity status between groups at baseline as reflected in the Duke activity status index score. Baseline mean hemoglobin concentration was lower in the exercise group at 108.6 (20.8) g/L versus 117.6 (19.8) g/L in controls (P = 0.21). Nine of the 16 patients in the exercise group completed the 6-week exercise program (56%). In the control group, 11 out of 17 patients (65%) completed CPETs at week 6. Transplantation and clinical deterioration were the predominant reasons for patient drop-out (see Figure 1 for study flow diagram); none of the patients dropped out of the intervention group due to an inability to complete the exercise prescribed to them. Deterioration was largely the result of obstructive cholangiopathy and need for hospitalization.
Of the 20 patients (61%) completing the 6-week study period (9 in the exercise arm and 11 in the control group), a further 5 (25%) did not complete the 12-week follow-up CPET (4 were in the control group); transplantation being the primary reason for this with 3 patients receiving a liver. One patient withdrew from the control arm as they did not want to do a third CPET test and another control arm patient deteriorated due to profound decompensation of cirrhotic liver disease necessitating hospitalization.
There were no incidents of worsening cirrhotic decompensation as a result of the exercise, and no adverse incidents related to exercise training were reported. Compliance with the prescribed exercise training was high with 127 out of the overall total of 135 exercise sessions (94%) completed by the 9 patients finishing the exercise intervention.
CPET measures at baseline and at weeks 6 and 12 are displayed in Table 2. There was an increase in VO2peak in the exercise group from a mean (SD) of 16.2 (±3.4) mL/kg/min at baseline rising to 18.5 (±4.6) mL/kg/min at week 6 (P = 0.02). By week 12 (6 wk after exercise cessation), the mean VO2peak reduced to 17.4 (±3.0) mL/kg/min. In the control group, VO2peak decreased from a mean of 19.0 (± 6.1) to 17.1 (±6.0) mL/kg/min at week 6 (P = 0.03). Figure 2 illustrates VO2 at AT and peak across both exercise and comparator groups at baseline, week 6, and week 12. There was a significant increase in mean VE/VCO2 (ratio of ventilation to carbon dioxide output) at AT in the control group, rising from a baseline value of 30.9 (4.0) to 33.6 (4.5) at week 6.
The anthropometric measures (as per the RFH global assessment tool), at baseline and week 6 assessments, are displayed in Table 3. There was no overall change in BMI (dry weight) in either group across the study period; patients in the exercise group had a higher BMI than controls at baseline. An increase in mean handgrip strength from 26.4 (±7.5) kg at baseline to 29.4 (±6.4) kg at week 6 was observed in the exercise group (P = 0.05), while handgrip in the control group was 29.1 (±10.7) kg at baseline and 30.5 (±13) kg at week 6 (P = 0.80). There was no change in mid-arm circumference over the 6-week study period in either group. The mean MAMC in the exercise group was 28.6 (±4.6) cm at baseline and 29.9 (±5.7) cm after 6 weeks of training (P = 0.22), indicating an increase in muscle mass, whereas, the mean MAMC in the control group was 24.2 (±3.3) cm at baseline and 23.5 (±3.7) cm at week 6 (P = 0.16).
Of the 20 patients who completed the 6-week study period, 16 had received their liver transplants with 1 patient still on the waiting list 1 year after the end of the study. Two patients (1 in the exercise and 1 in the control group) were delisted as they clinically improved, hence no longer meeting transplantation criteria, and 1 control patient went on to be delisted due to profound decompensation and deterioration. The mean time to transplant with respect to completion of the 6-week exercise training period was 165 (118) days in the exercise group and 192 (211) days in the control.
There were no deaths in the postoperative period until hospital discharge in either group. Post-transplant outcome data are presented in Table 4. The median with interquartile range hospital length of stay for the index transplant admission in the exercise group was 13 (6) and 30 (13) days in the control group, a difference of 13 days (P = 0.02).
This study demonstrated that it was safe and feasible to engage patients with cirrhotic liver disease awaiting LT surgery in an intense, supervised exercise program comprised of 3 sessions a week in a hospital outpatient clinic for a total of 6-weeks. While the study was not designed or powered to detect differences in secondary outcomes, we observed an increase in VO2peak in patients who underwent the exercise program, which declined 6 weeks after cessation of the program. This suggests that exercise has the potential to improve aerobic fitness but that this gain is lost and deconditioning occurs once exercise stops. In contrast, a decline in VO2peak was observed in a matched control group, suggesting that this patient group becomes progressively more unfit over time, probably as a result of their underlying disease and lack of exercise. In addition, handgrip strength improved in the exercise group, suggesting that lower limb exercise may have a more systemic impact.
This study demonstrated that it was feasible to motivate patients to attend hospital 3 times a week and participate in an aerobic exercise training program while awaiting LT. We observed a high rate of compliance with exercise sessions in our center in those selected based on the distance they lived from the hospital. It is perfectly reasonable to assume that compliance would be far less were patients to have lived further away, as was the case in the comparator group of this study. Given that many patients awaiting LT nationally live a substantial distance from their transplant center, an intense method of exercise intervention may not be appropriate for all of them due to the logistics of travel. A modified approach to training patients in their local hospital, a local gymnasium, or within their own home could be viable alternatives. Future research should seek to address this area and involve patients with the design of studies to optimize what will work best for them in this regard.
This study has a number of limitations. Due to the feasibility design, participants were not randomized, there was no observer blinding, and the sample size was not powered to detect differences in physiological or postoperative outcomes. All these factors increase the chance of confounding and a type 2 error in the presented data. The purpose of collecting these data, however, was to determine the level of fitness in patients awaiting LT in our center, the heterogeneity in that measure, and whether there was a signal of improvement in fitness in the exercised group versus the nonexercised group. All of this information will be essential for the design of a more comprehensive study aimed at evaluating the efficacy of an exercise intervention. A further limitation of this study was the notable drop-out rate of participants, with 13 patients (39.4%) in total (7 in exercise and 6 in control) failing to complete the 6-week study period. This information is also crucial for the design of future studies. Five of these patients were transplanted shortly after recruitment, which is an inherent, unpredictable risk specific to the study population. Likewise, attrition due to patient medical deterioration is also not an unexpected finding given the comorbid nature of the cohort. What is important to note, however, is that no patients in the exercise cohort dropped out because they were physically or logistically unable to complete the program. This demonstrates that the amount of exercise prescribed was tolerable by all patients. Postoperative outcomes following LT are highly multifactorial, and attributing the significant reduction in hospital length of stay to preoperative exercise in the context of an inadequately powered trial would be but inappropriate, particularly given the lag time from completion of exercise to transplantation. However, it is an association that merits further research.
Existing LT literature demonstrates consistently that malnutrition adversely impacts upon post-transplant morbidity and mortality20,25-27; likewise, an association between low cardiopulmonary reserve and 90-day post-transplant mortality has been shown.28 We have demonstrated that a preoperative exercise training program alongside structured nutritional advice may aid in maintaining muscle mass and strength. It follows that close attention to nutrition and physical optimization on the liver transplant waiting is essential and indeed an emerging research target.
Having demonstrated that intense aerobic exercise training is feasible in patients with cirrhosis awaiting LT and that there may be measurable improvements in fitness, urgent follow-up research is required in this area. Modification of our design with the input of patients could result in a deliverable intervention that will have a tangible effect on the long-term outcomes of this patient population. A greater understanding of the dose-response relationship of exercise and outcomes is required, along with a more detailed understanding of factors that determine ongoing patient engagement with complex interventions such as this. Our collaborative interdisciplinary approach sets a precedent for future studies to build upon, and a multicenter study to assess efficacy is now required. Exercise has been shown to be effective in improving the health and well-being of almost every patient group it has been applied to,29 and it is highly likely this could be the case for patients with ESLD who are awaiting transplantation surgery.
We thank all the patients who contributed to this study while awaiting their LTs.
2. Plauth M, Merli M, Kondrup J, et al. ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr. 1997; 16:43–55
3. Duarte-Rojo A, Ruiz-Margáin A, Montaño-Loza AJ, et al. Exercise and physical activity for patients with end-stage liver disease: improving functional status and sarcopenia while on the transplant waiting list. Liver Transpl. 2018; 24:122–139
4. Laube R, Wang H, Park L, et al. Frailty in advanced liver disease. Liver Int. 2018; 38:2117–2128
5. Cederholm T, Barazzoni R, Austin P, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin Nutr. 2017; 36:49–64
6. Dronkers JJ, Lamberts H, Reutelingsperger IM, et al. Preoperative therapeutic programme for elderly patients scheduled for elective abdominal oncological surgery: a randomized controlled pilot study. Clin Rehabil. 2010; 24:614–622
7. Timmerman H, de Groot JF, Hulzebos HJ, et al. Feasibility and preliminary effectiveness of preoperative therapeutic exercise in patients with cancer: a pragmatic study. Physiother Theory Pract. 2011; 27:117–124
8. Brunet J, Burke S, Grocott MP, et al. The effects of exercise on pain, fatigue, insomnia, and health perceptions in patients with operable advanced stage rectal cancer prior to surgery: a pilot trial. BMC Cancer. 2017; 17:153
9. Barakat HM, Shahin Y, Khan JA, et al. Preoperative supervised exercise improves outcomes after elective abdominal aortic aneurysm repair: a randomized controlled trial. Ann Surg. 2016; 264:47–53
10. Brustia R, Savier E, Scatton O. Physical exercise in cirrhotic patients: towards prehabilitation on waiting list for liver transplantation. A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2018; 42:205–215
11. Zenith L, Meena N, Ramadi A, et al. Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014; 12:1920–6.e2
12. Román E, García-Galcerán C, Torrades T, et al. Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial. PLOS One. 2016; 11:e0151652
13. Román E, Torrades MT, Nadal MJ, et al. Randomized pilot study: effects of an exercise programme and leucine supplementation in patients with cirrhosis. Dig Dis Sci. 2014; 59:1966–1975
14. Macías-Rodríguez RU, Ilarraza-Lomelí H, Ruiz-Margáin A, et al. Changes in hepatic venous pressure gradient induced by physical exercise in cirrhosis: results of a pilot randomized open clinical trial. Clin Transl Gastroenterol. 2016; 7:e180
15. American Thoracic Society; American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003; 167:211–277
16. Hlatky MA, Boineau RE, Higginbotham MB, et al. A brief self-administered questionnaire to determine functional capacity (The Duke Activity Status Index). Am J Cardio. 1989; 64:651–654
17. McCullough AJ. Malnutrition in liver disease. Liver Transpl. 2000; 6:S85–S96
18. Morgan MY, Madden AM, Soulsby CT, et al. Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis. Hepatology. 2006; 44:823–835
19. Kondrup J, Müller MJ. Energy and protein requirements of patients with chronic liver disease. J Hepatol. 1997; 27:239–247
20. Hasse JM. Nutrition assessment and support of organ transplant recipients. JPEN J Parenter Enteral Nutr. 2001; 25:120–131
21. Schneeweiss B, Graninger W, Ferenci P, et al. Energy metabolism in patients with acute and chronic liver disease. Hepatology. 1990; 11:387–393
22. Madden AM, Morgan MY. Resting energy expenditure should be measured in patients with cirrhosis, not predicted. Hepatology. 1999; 30:655–664
23. Frisancho AR. Triceps skin fold and upper arm muscle size norms for assessment of nutrition status. Am J Clin Nutr. 1974; 27:1052–1058
24. Bishop CW, Bowen PE, Ritchey SJ. Norms for nutritional assessment of American adults by upper arm anthropometry. Am J Clin Nutr. 1981; 34:2530–2539
25. Pikul J, Sharpe MD, Lowndes R, et al. Degree of preoperative malnutrition is predictive of postoperative morbidity and mortality in liver transplant recipients. Transplantation. 1994; 57:469–472
26. Harrison J, McKiernan J, Neuberger JM. A prospective study on the effect of recipient nutritional status on outcome in liver transplantation. Transpl Int. 1997; 10:369–374
27. Selberg O, Böttcher J, Tusch G, et al. Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology. 1997; 25:652–657
28. Prentis JM, Manas DM, Trenell MI, et al. Submaximal cardiopulmonary exercise testing predicts 90-day survival after liver transplantation. Liver Transpl. 2012; 18:152–159
29. Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012; 2:1143–1211