Exercício na reabilitação física de cirróticos: um estudo piloto randomizado

Arq Gastroenterol ag Arquivos de Gastroenterologia Arq. Gastroenterol. 0004-2803 1678-4219 Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia e Outras Especialidades - IBEPEGE. RESUMO Contexto: O exercício físico retarda o processo sarcopênico e pode reverter a perda de força muscular, melhorar a qualidade de vida e prognóstico em cirróticos. Objetivo: O objetivo foi verificar os efeitos do exercício aeróbico presencial versus domiciliar sobre variáveis fadiga, força muscular respiratória e periférica, capacidade funcional e qualidade de vida em pacientes com cirrose compensada. Métodos: Os pacientes foram selecionados por conveniência, estratificados e randomizados em exercício presencial supervisionado (n=13) e exercício domiciliar sem supervisão diária (n=12). Os pacientes foram submetidos a um programa de exercícios físicos aeróbicos, com duração progressiva de 30 minutos a 1 hora, duas vezes por semana durante 12 semanas. Antes de iniciar o programa e a cada 4 semanas, todos os pacientes de ambos os grupos foram avaliados quanto à fadiga (escala de gravidade da fadiga), força muscular respiratória (Pimáx e Pemáx) e periférica (pico de torque do quadríceps concêntrico), capacidade funcional (distância caminhada de 6 minutos) e qualidade de vida (questionário Short Form-36 Health Survey). Resultados: O grupo presencial apresentou redução da fadiga (P<0,001), aumento da força muscular inspiratória (P<0,001), expiratória (P<0,001), e periférica (P<0,001), da DTC6 (P<0,001) e melhora da qualidade de vida. O grupo domiciliar não apresentou melhora significativa nessas variáveis. Conclusão: Um programa presencial de exercícios aeróbicos moderados em pacientes com cirrose compensada reduz a fadiga, melhora a capacidade funcional e qualidade de vida, aumenta força muscular respiratória e periférica. Os exercícios físicos domiciliares não provocam os mesmos efeitos adaptativos nesta população. INTRODUCTION Cirrhosis is the final stage of progressive liver fibrosis and represents the 14th leading cause of death worldwide1,2. The disease modifies liver function and affects, among others, muscle tissue, causing significant muscle mass loss, which reaches pathological levels characterizing sarcopenia3. Sarcopenia is a progressive and generalized syndrome of loss of skeletal muscle and muscle strength, and results from the imbalance between protein synthesis and degradation due to nutritional, metabolic and biochemical abnormalities, and increases patient morbidity and mortality4,5. In addition, it causes damage to body composition, aerobic capacity, muscle strength and power production, resulting in impairments in functionality and quality of life. It is an independent mortality factor, which implies a worse clinical outcome6. Cirrhotic patients have a high prevalence of sarcopenia and physical inactivity, which, added to aging, malnutrition, decreased hepatic protein synthesis, hypermetabolism, increased inflammatory cytokines, hyperammonemia and low testosterone levels, allow muscle deconditioning, resulting in reduced cardiovascular reserve, increased physical fragility and decreased strength and quality of life7,8. There is no effective treatment to reverse cirrhosis and management focuses on treating the primary disease, managing complications and liver transplantation. However, a poor physical condition, even after the transplant, has a negative impact on the success of the procedure, resulting in lower survival9-11. Research on the benefits of physical activity in cirrhotic patients is at an early stage, but suggests that physical exercise is essential as it delays the sarcopenic process12, increases muscle mass and strength13-15, improves functionality16,17, reduces the risk of falls18 and fatigue19, promotes glycemic control20, increases protein synthesis21 and provides better quality of life19,22 enabling a better prognosis. This study aimed to verify the effects of moderate aerobic exercise in person versus at home on fatigue, respiratory and peripheral muscle strength, functional capacity and quality of life in patients with compensated cirrhosis. METHODS This study is a randomized controlled, parallel, open-label, 2-arm clinical trial approved by the Research Ethics Committee (CEP) of the Federal University of Health Sciences of Porto Alegre (UFCSPA) and the Santa Casa de Misericordia Hospital Complex (n° 3805918 and 3938979, respectively) and was registered in the ReBec Clinical Trials registry database (n. RBR-3gtcvjU111112367585). All patients gave their informed consent before being included in the study. Cirrhotic patients from 18 to 75 years old, of both genders, with cirrhosis of any etiology, in outpatient follow-up, were included. Due to the risk of increased portal pressure and bleeding from esophageal varices, patients with decompensated liver disease, characterized by Class C of the Child-Turcotte-Pugh score, with manifestations of portal hypertension (splenomegaly, grade III esophageal varices, increased portal vein or collateral circulation) were excluded. Patients with dietary supplementation with amino acids, recent hospitalization, neuromuscular diseases or orthopedic alterations that compromised the performance of tests or physical exercises, or with contraindications for the same were also excluded. Patients were selected by convenience, stratified according to age and gender and randomized by the researchers, using the Microsoft Excel® program, into two groups: Face -to-face group (FG) and home group (HG). A trained researcher (P1) performed all assessments of patients in both groups and a second trained researcher (P2) supervised physical activity in the FG and guided exercises to the HG. The face-to-face assessments and interventions were performed simultaneously by the researchers in the same laboratory. Thus, blinding was only possible for the professional who performed the analysis statistic. In-person exercise protocol Patients filled out an evaluation form, prepared by the researchers, with demographic and clinical characteristics. Subsequently, they were evaluated by P1, regarding respiratory and peripheral muscle strength, functional capacity, quality of life and fatigue. In the following session, supervised by P2, they performed aerobic exercises twice a week, for 12 weeks. The first session consisted of 5 minutes of warm-up, followed by 30 minutes of treadmill walk, at the maximum speed tolerated by the patient, according to the Borg scale23. Two minutes of walking were added to each session, up to a limit of 50 minutes of walking, time maintained until the end of the protocol. All patients were reassessed at the 4th, 8th and 12th weeks of exercise. Home exercise protocol Patients were evaluated in the same way as the face-to-face group by P1 and then instructed by P2 to perform a 5-minute warm-up period followed by walking on level ground, twice a week, for 12 weeks. As in the face-to-face group, each day, they added 2 minutes of walking, until reaching 50 minutes, at the maximum tolerated speed. Patients were instructed to discontinue exercise in the event of malaise, arrhythmias, dizziness, shortness of breath and to seek medical attention as soon as possible. All patients were reassessed in person at the 4th, 8th and 12th weeks of exercise. Variables analyzed Fatigue was assessed using the Fatigue Severity Scale (FSS), where a score equal to or greater than four indicates severe fatigue24 Respiratory muscle strength was measured through maximal inspiratory (Pimáx) and expiratory (Pemáx) pressure, using the Globalmed® MVD 500 digital manovacuometer. To assess peripheral muscle strength, concentric isokinetic peak torque (PT) values were used, in Newton/Meters (Nm), generated by the knee extensor muscles of the dominant limb in the Biodex System 3 Isokinetic Dynamometer with the Biodex Advantage software version 3.0 (Biodex Medical Systems, Inc., Shirley, New York, USA). We evaluated the functional condition through the distance covered in the 6-minute walk test (6MWD), according to the American Thoracic Society guidelines25 and the quality of life through the Medical Outcomes Study, Short Form-36 Health Survey questionnaire (SF-36)26. Data analysis Quantitative variables were described by average and standard deviation and categorical, by absolute and relative frequencies. The comparison of averages was performed by the t-student test. Comparison of proportions was performed using Pearson’s chi-square or Fisher’s exact tests. Simultaneous intra- and inter-group comparisons were performed using the generalized estimating equations (GEE) model, complemented by the Least Significant Difference Test. The significance level adopted was 5% (P<0.05) and the analyzes were performed using the Statistical Program Package for the Social Sciences (SPSS) version 21.0. RESULTS This study was carried out between 2020 and 2021. Figure 1 shows the flow of patients in the study, according to the standards of CONSORT. FIGURE 1 Flow diagram of study participants according to CONSORT. Descriptive analysis of demographic characteristics of the patients analyzed in the study is shown in Table 1. TABLE 1 Sample characterization. Variables FG (n=13) HG (n=12) P Age (years) - mean ± SD 56.5±8.8 58.7±7.7 0.512 Gender - n (%) masculine 8 (61.5) 6 (50.0) 0.859 BMI (kg/m2) - mean ± SD 28.4±4.9 27.8±3.9 0.730 Years of study - mean ± SD 7.8±3.3 6.9±2.5 0.481 Etiology - n (%) 0.301 HCV 5 (38.5) 7 (58.3) Alcohol 2 (15.4) 0 (0.0) HCC 1 (7.7) 0 (0.0) NASH 2 (15.4) 1 (8.3) Alpha1 deficiency 1 (7.7) 0 (0.0) PBC 1 (7.7) 0 (0.0) HCV + CHC 0 (0.0) 1 (8.3) HCV + alcohol 0 (0.0) 1 (8.3) VHC+ CHC+ alcohol 0 (0.0) 2 (16.7) HBV + alcohol 1 (7.7) 0 (0.0) MELD - mean ± SD 11.0±4.2 12.3±4.4 0.446 CHILD - n (%) 0.593 A 12 (92.3) 10 (83.3) B 1 (7.7) 2 (16.7) No physical activity - n (%) 10 (76.9) 9 (75.0) 1,000 FG: face-to-face group; HG: home group; SD: standard deviation; BMI: body mass index; HCV: hepatitis C virus; HCC: hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; PBC: primary biliary cirrhosis; HBV: hepatitis B virus; MELD: Model For End-Stage liver Disease. The behavior of the variables Fatigue, Pi and Pemáx, Extension PT and 6MWD between the groups throughout the exercise program is shown in Table 2. Regarding fatigue, in the intragroup comparison, the FG showed a significant reduction at each evaluated moment, with significantly lower values from the 8th week and reduced by 1.86 points, on average, during the total follow-up period, while the HG increased by 0.10 points on average, this difference being statistically significant. TABLE 2 Comparison of Fatigue, MIP, Pemax, 6MWT and Peak Torque intra and intergroups. Variables FG (n=13) HG (n=12) P Mean±EP Mean±EP Fatigue Pre exercise 3.43±0.29d 3.76±0.44a 0.529 4th week 2.69±0.27c 3.73±0.49a 0.063 8th week 1.97±0.24b 3.80±0.48a 0.001 12th week 1.56±0.19a 3.86±0.44a <0.001 Pre-12th week difference -1.86 (-2.42 to -1.31) 0.10 (-0.36 to 0.56) <0.001 Pimáx (cmH2O) Pre exercise -72.9±6.0a -53.7±6.2 a 0.026 4th week -76.0±7.4a -58.5±6.2 a 0.072 8th week -88.6±6.3b -55.5±6.3 a <0.001 12th week -95.9±5.2c -56.2±5.3 a <0.001 Pre-12th week difference -23.0 (16.8 to 29.1) -2.5 (-3.5 to 8.5) <0.001 Pemáx (cmH2O) Pre exercise 108.8±6.7a 88.8±7.8a 0.052 4th week 118.6±8.9b 88.4±7.2a 0.008 8th week 125.9±8.2c 87.1±6.5a <0.001 12th week 137.3±8.1d 88.2±5.7a <0.001 Pre-12th week difference 28.5 (20.8 to 36.2) -0.65 (-10.3 to 9.0) <0.001 6MWT (m) Pre exercise 457.2±18.9a 389.2±13.9a 0.004 4th week 503.0±17.7b 411.8±15.1b <0.001 8th week 539.2±15.2c 407.7±15.4b <0.001 12th week 555.0±15.3d 400.9±14.7ab <0.001 Pre-12th week difference 97.8 (63.8 to 131.9) 11.7 (-1.3 to 24.7) <0.001 Extension PT (N) Pre exercise 126.3±11.9a 106.7±12.0a 0.246 4th week 154.9±14.4b 106.7±10.7a 0.007 8th week 159.5±15.6b 107.7±12.9a 0.010 12th week 167.3±16.6c 105.7±12.8a 0.003 Pre-12th week difference 41.0 (21.8 to 60.2) -1.03 (-8.78 to 6.72) <0.001 FG: face-to-face group; HG: home group; EP: standard error; a,b ,c,d equal letters do not differ by the least test significant difference (LSD) at 5% significance; Pimáx: maximum inspiratory pressure; Pemáx: maximum expiratory pressure; 6MWT: 6-Minute Walk Test; m: meters; PT: peak torque; N: Newton. The behavior of quality of life is shown in Table 3. The FG showed a statistically significant increase in the scores of almost all the SF-36 domains in relation to the HG. This increase was not significant in the mental health, social aspects and pain domains. TABLE 3 Comparison of intra and inter group quality of Life (SF-36). Variables FG (n=13) HG (n=12) P Mean ± EP Mean ± EP Functional capacity Pre exercise 73.8±4.7a 62.1±6.7a 0.149 12th week 93.5±4.7c 60.9±5.8a <0.001 Pre-12th week difference 19.7 (9.0 to 30.3) -1.17 (-9.32 to 6.97) 0.002 Physical aspects Pre exercise 51.9±11.4a 22.9±9.5 a 0.051 12th week 86.5±9.4c 30.0±9.0a <0.001 Pre-12th week difference 34.6 (15.0 to 54.2) 7.08 (-2.06 to 16.2) 0.013 Emotional aspects Pre exercise 48.7±10.0a 19.5±8.3ab 0.024 12th week 64.2±12.9ab 16.3±7.0a 0.001 Pre-12th week difference 15.4 (-4.64 to 35.5) -3.11 (-23.6 to 17.3) 0.017 Vitality Pre exercise 63.8±4.4a 57.1±6.0a 0.363 12th week 84.0±3.6c 55.5±6.1a <0.001 Pre-12th week difference 20.2 (12.6 to 27.7) -1.63 (-8.49 to 5.23) <0.001 Mental health Pre exercise 72.9±4.6a 64.0±6.4b 0.258 12th week 80.7±4.3a 59.6±5.5ab 0.003 Pre-12th week difference 7.73 (-5.94 to 21.4) -4.36 (-9.20 to 0.48) 0.102 Social aspects Pre exercise 69.3±6.0a 55.3±8.4a 0.174 12th week 81.3±6.6a 57.5±7.3a 0.016 Pre-12th week difference 12.0 (-2.76 to 26.7) 2.25 (-6.27 to 10.8) 0.263 Pain Pre exercise 61.2±5.7a 64.8±8.6a 0.727 12th week 75.3±8.5a 65.0±6.5a 0.339 Pre-12th week difference 14.1 (-8.07 to 36.2) 0.21 (-9.98 to 10.4) 0.265 General health Pre exercise 61.9±4.8a 52.1±5.7a 0.186 12th week 84.0±4.1c 56.4±5.0ab <0.001 Pre-12th week difference 22.1 (11.7 to 32.5) 4.28 (-1.76 to 10.3) 0.004 FG: face-to-face group; HG: home group; EP: standard error; a,b ,c,d Equal letters do not differ by the least test significant difference (LSD) at 5% significance. DISCUSSION There are still few studies that analyze the benefits and effects of physical exercise in cirrhotic patients, evaluating different patient profiles and physical activity modalities. The physical exercise protocols proposed for this population are still quite heterogeneous with very restrictive inclusion criteria. In the studies carried out to date, these exercises had different modalities, ranging from 6 weeks to 12 months, with sessions from 1 to 3 times a week, lasting up to 1 hour. Most studies have found positive and significant results with exercise in this population, although little is known about its clinical repercussions on the disease. In this study, we observed that patients in the FG did not show a significant improvement in the variables studied, when compared to patients in the HG. Professional supervision could contribute to better results27,28. Although fatigue is frequently reported by patients with cirrhosis, few studies have evaluated the symptom as an outcome with physical activity as an intervention. In our study, fatigue decreased in the FG and increased in the HG. A randomized clinical trial by Zenith et al showed that patients who performed supervised home exercise 3 times a week for 8 weeks also had symptom reduction19. In the FG, Pi and Pemáx reached an increase of 23 cmH2O and 28.5 cmH2O, respectively. We did not find studies that evaluated respiratory muscle strength as an outcome after exercise or physical activity in this population. We observed an increase in the 6MWD by 97 meters in the FG patients, a result corroborated by other studies14-17. The literature shows increments of 34 to 80 meters in patients who performed supervised face-to-face exercise similar to that performed in this study. A 30.5 m increase in 6MWD has been suggested as the minimum improvement needed to confer any clinical benefit, but this has not yet been validated in patients with cirrhosis28 The greatest increase in 6MWD was reported by Chen et al.17, of 151 meters, after intervention guided by a pedometer (P=0.03). FG patients showed a significant increase in PT. Aamann et al. obtained similar results when cirrhotic patients performed strength physical exercise three times a week15. Hiraoka et al. demonstrated a 5.6% increase in muscle strength after 12 weeks of aerobic exercise with daily step count goals (P<0.01). An 11% increase in lower limb strength was also reported over the same time period (P<0.01). However, patients received amino acid supplementation concurrently with exercise29. Despite being recommended, the application of physical exercise in cirrhotic patients is far behind other chronic diseases, possibly due to the chance of increased portal pressure. Garcia-Pagan et al. demonstrated that moderate exercise increases portal pressure in patients with portal hypertension and therefore, theoretically increases the risk of variceal bleeding30. Other barriers are the lack of specific supervised exercise programs available for this group of patients and the lack of evidence for safely and effectively prescribing and evaluating exercise31. Therefore, the results of current studies may not be easily generalizable to patients with more advanced liver disease, Child-Turcotte-Pugh C or very high MELD. However, recent controlled studies have shown safety, improvements in physical fitness, muscle mass and QOL32-34. A recent review showed that several studies investigated the effect of exercise on quality of life using different instruments with positive results35. We observed that the HG achieved lower scores in relation to the FG in all domains. Studies report that the lack of direct supervision can result in a loss of exercise effectiveness. This could be an explanation for our result36,37. The limitations of this study are mainly related to the lack of nutritional control of patients in both groups. In addition, restrictions imposed by the pandemic, such as the reduction in the number of professionals and patients with access to the institutions involved in this study and transport difficulties, lack of supplies for the acquisition of technologies, led to the impossibility of four patients from the FG to continue participating in the study. This scenario only made it possible to supervise the HG in the 4th, 8th and 12th weeks and not on a daily basis like the HG. Many of our patients did not have access to technology that supported applications that would allow us to do this follow-up, even virtually. However, this study produced statistically significant results, which makes us suppose that moderate aerobic physical exercise cannot be underestimated. In addition, it reinforces the importance of a trained professional supervision for this population. The challenge will be the development of studies with a representative sample, which may involve patients with decompensated disease, to assess the benefits of aerobic physical exercise, minimizing the risks imposed by physical activity with load. In the end, these activities could clarify the effects of exercise on the clinical evolution of these patients. CONCLUSION This study showed that 12 weeks of face-to-face sessions of moderate-intensity aerobic exercise, were able to reduce fatigue, strengthen respiratory and peripheral muscles, improve functional capacity and quality of life in cirrhotic patients with compensated disease. Physical activity at home did not have the same effects in these patients. REFERENCES 1 1. Moon AM, Singal AG, Tapper EB. contemporary epidemiology of chronic liver disease and cirrhosis. Clinic Gastroenterol Hepatol. 2020;18:2650-66. 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