Aerobic Exercises, Autonomic Dysfunction, Autonomic Nervous System, Cirrhosis, Endothelial Function, Flow Mediated Dilation, Heart Rate Variability, Lifestyle Modification, Physical Activity, Physical Functional Performance, Physical Inactivity, Sarcopenia
Conditions
Keywords
Cirrhosis, Autonomic nervous system, Endothelial function, Aerobic exercise
Brief summary
The goal of this randomized controlled trial is to investigate whether a 16-week structured aerobic exercise program combined with nutritional consultation can improve autonomic and endothelial function in patients with compensated cirrhosis. Study Design: This assessor-blinded, parallel-group randomized controlled trial will be conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Fifty adults with compensated (Child-Pugh class A) cirrhosis will be recruited during routine hepatology clinic visits. Eligible participants are aged 45-75 years, have a sedentary lifestyle (\<150 minutes of moderate or \<75 minutes of vigorous physical activity per week), and have abstained from alcohol for at least six months. Exclusion criteria include active or recently treated hepatocellular carcinoma (within three months), severe portal hypertension complications (untreated large varices, prior variceal bleeding, or severe gastropathy), transjugular intrahepatic portosystemic shunt (TIPS), unstable cardiac disease, orthopedic limitations, morbid obesity (BMI \>35 kg/m²), or current use of alpha- or beta-blockers that affect autonomic function. Intervention: Participants will be randomly assigned to either the intervention or control group. Both groups will receive nutritional consultation and individualized dietary guidance at baseline, week 8, and week 16. Nutritional goals are set at 35 kcal/kg/day and 1.2 g/kg/day of protein intake. If targets are unmet, the dietitian will provide individualized recommendations to support adequate intake. The intervention group will participate in a 16-week aerobic exercise program consisting of brisk walking at moderate intensity (50-70% of maximal heart rate), totaling 150 minutes per week. The program includes two phases: * Phase 1 (Weeks 1-4): Combined hospital-based (1 session per week) and home-based exercise under physical therapist supervision, with gradual intensity titration. * Phase 2 (Weeks 5-16): Fully home-based exercise following prescribed intensity and frequency, with weekly follow-up via telephone or messaging to monitor adherence, safety, and exercise log completion. The control group will maintain their usual physical activity levels while receiving the same schedule of nutritional consultations and weekly follow-up for monitoring compliance and adverse events. Outcomes: Primary outcomes include changes in autonomic and endothelial function after 16 weeks. * Autonomic function will be assessed using the Ewing autonomic battery test (HR response to standing, deep breathing, and Valsalva maneuver; BP response to posture and sustained handgrip) and heart rate variability (HRV) indices (SDNN, RMSSD, LF/HF ratio). * Endothelial function will be evaluated using flow-mediated dilation (FMD) of the brachial artery, analyzed via Cardiovascular Suite™ software to assess nitric oxide-dependent vasodilation. Secondary outcomes include: 1. Splanchnic hemodynamics: Changes in celiac and superior mesenteric artery (SMA) blood flow measured via mesenteric Doppler ultrasound (Vivid IQ, GE Healthcare). Time-averaged mean velocity (TAMV), vessel diameter, and blood flow will be recorded at baseline and post-intervention. 2. Sarcopenia-related measures: Muscle mass (DEXA, BIA), muscle strength (handgrip dynamometry), and physical performance (6-minute walk test). 3. Laboratory outcomes: Serum ammonia, liver function tests, fasting glucose, albumin, renal function, and coagulation profile. 4. Correlative analyses: Associations between (a) muscle mass and serum ammonia, and (b) muscle mass and autonomic parameters (e.g., HRV indices).
Detailed description
An additional non-invasive assessment, Mesenteric Duplex Doppler Ultrasound, will be performed to evaluate mesenteric and portal blood flow as an exploratory parameter.
Interventions
BEHAVIORALAerobic exercise + Nutrition consultant
Participants in the intervention group will engage in 150 minutes of moderate aerobic exercise weekly for 16 weeks, primarily brisk walking or jogging. For the initial four weeks, they will visit the hospital weekly for guidance and participate in home-based exercise following a protocol totaling 150 minutes of moderate aerobic exercise in the form of brisk walking or jogging. Healthcare professionals will help adjust exercise intensity based on heart rate (60-80% of maximum) and perceived exertion (RPE 12-15), while monitoring vital signs and adverse events. After, they will transition to a home exercise program for twelve weeks, recording exercise details in a logbook. Weekly follow-up calls will ensure adherence and monitor adverse events. They will be provided with nutritional recommendations by a dietitian, the same as the control group.
BEHAVIORALNutrition consultant
Participants will maintain their physical activity at the same level as before enrolling in the study. However, they will be provided with nutritional recommendations by a dietitian, which include 1.2 grams of protein per kilogram of ideal body weight daily and a calorie intake of 35 kilocalories per kilogram of ideal body weight per day. To assess adherence and make necessary adjustments, participants will complete a 3-day food record at the beginning of the study, at week 8, and at the end of the study at week 16. If participants encounter difficulties adhering to the recommended nutritional intake, the dietitian will provide additional guidance to help them meet the requirements.
Sponsors
King Chulalongkorn Memorial Hospital
Chulalongkorn University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* The diagnosis of cirrhosis is confirmed either through liver biopsy ,and/or compatible features on ultrasonography/ computer tomography or magnetic resonance imaging. * The age range is between 45 and 75 years. * Participants are classified as Child Pugh score class A. * Participants report a physical inactivity, defined as engaging in physical activity for less than 150 minutes of moderate-intensity physical activity per week, or less than 75 minutes of vigorous-intensity physical activity per week, or an equivalent combination of both.
Exclusion criteria
* Active hepatocellular carcinoma (HCC) or remission of HCC within the past 3 months. * Untreated large esophageal varices (EV) greater than F2 or history of upper gastrointestinal bleeding from portal hypertension or gastric varices. * Active or history of hepatic encephalopathy (HE). * Inpatient hospitalization for any reason or discharge from the hospital within the past 3 months. * Complete portal vein thrombosis. * Transjugular intrahepatic portosystemic shunt. * Contraindications to exercise, such as recent myocardial infarction, unstable angina, electrocardiography changes within the past 24 hours, complete heart block, acute congestive heart failure, uncontrolled hypertension, hemoglobin level less than 11 g/dL, platelet count less than 50,000 cells/mm 3 . * End-stage renal disease without dialysis. * Severe orthopedic problems that limit the ability to exercise. * Inability to communicate with the research team via telemedicine system. * Body mass index (BMI) exceeding 35 kg/m 2 . * On alpha or beta-blocker
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-domain Heart Rate Variability (HRV) Parameters: SDNN and RMSSD and SDANN | Change from Baseline (week 0) at Week 16 | Heart rate variability (HRV) was assessed using a 15-minute resting ECG recording. This table reports three time-domain measures: 1) SDNN (Standard deviation of all NN intervals), 2) RMSSD (Root mean square of successive differences), and 3) SDANN (Standard deviation of the average NN intervals). These parameters reflect autonomic nervous system activity and cardiac vagal tone. All data are reported in milliseconds. Higher values indicate better autonomic regulation. Only these three time-domain parameters are presented in this table. |
| Time Domain Outcome: pNN50 | Change from Baseline (week 0) at week 16 | A time-domain measure of heart rate variability (HRV) reflecting parasympathetic activity. It is calculated as the percentage of successive normal-to-normal (NN) intervals that differ by more than 50 milliseconds. Data were collected using 3-lead ECG during a 15-minute resting period." |
| HRV Frequency Domain Measures: TP, HF, LF, VLF | Change from Baseline (week 0) at Week 16 | Assessment of frequency-domain components of heart rate variability, including Total Power (TF), High Frequency (HF), Low Frequency (LF), and Very Low Frequency (VLF). Analysis was performed using Adinstrument (tm) on a 15-minute ECG recording at rest. These parameters reflect the power distribution across different frequency bands and represent autonomic nervous system activity. Data presented in the table represent the change from baseline to Week 16. |
| Changes in Ewing Autonomic Battery Test Scores (Improved, No Change, Worsened) | Change from Baseline (week 0) and Week 16 | Categorical assessment of changes in autonomic function using the Ewing Autonomic Battery test. Participants are classified into three categories: 'Improved', 'No change', or 'Worsened' based on their composite score changes from baseline to Week 16. Results are reported as the number of participants in each category. |
| Endothelial Function Test: Change in Flow-mediated Dilation (FMD) | Change from Baseline (week 0) at Week 16 | Assessment of the change in brachial artery flow-mediated dilation (FMD) from baseline to Week 16. FMD was determined by ultrasound as the percentage increase in arterial diameter during reactive hyperemia compared to baseline diameter. Results are reported as the percentage change (%). Positive values indicate an improvement in endothelial-dependent vasodilation. |
| HRV Frequency Domain Measures: Low Frequency/High Frequency (LF/HF) Ratio | Change from baseline (week 0) to week 16 | The LF/HF ratio is calculated as the ratio between the absolute power of the Low Frequency (LF) and High Frequency (HF) bands. It is used as an index of sympathovagal balance. Results are reported as a ratio (unitless). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscle Mass Change | Change from Baseline (week 0) at week 16 | Lean appendicular mass (kg) from Dual energy X-ray absorptiometry (DXA) |
| Physical Function | Change from Baseline (week 0) at week 16 | 6-minute walk test (minute) |
| Muscle Strength Change | Change from Baseline (week 0) at week 16 | Handgrip strength (kg) from dynamometer |
| Splanchnic Volume Flow | Baseline and after 16-week intervention | Blood-flow parameters derived from mesenteric Doppler ultrasound (celiac and superior mesenteric arteries, portal vein) were obtained as exploratory markers of splanchnic circulation. |
| The Association Between Changes in Muscle Mass and Changes in Serum Ammonia Levels | Baseline and Week 16 | Assessment of the correlation between the change in appendicular muscle mass index (measured by appendicular mass divided by height squared via Dual-Energy X-ray Absorptiometry; DXA) and the change in serum ammonia levels from baseline to week 16. Statistical significance is evaluated using Spearman's rank correlation coefficient for non-normally distributed data. |
Countries
Thailand
Contacts
PRINCIPAL_INVESTIGATORSirinda Kittiprachakul
King Chulalongkorn Memorial
Participant flow
Recruitment details
Participants were recruited from patients attending the Liver Unit of the Division of Gastroenterology, Department of Medicine, at King Chulalongkorn Memorial Hospital. The recruitment period spanned from March 12, 2024, to June 30, 2025.
Pre-assignment details
A total of 525 patients who visited the Liver Unit, Division of Gastroenterology, at King Chulalongkorn Memorial Hospital were screened for eligibility. Potential participants were evaluated based on the inclusion and exclusion criteria. Of those screened, 475 patients were excluded prior to randomization: 303 did not meet the specific study criteria, and 172 declined to participate in the study for personal reasons or lack of interest in the intervention
Baseline characteristics
| Characteristic | — |
|---|---|
| 6-Minute Walk test (6MWT) | 391.39 meters STANDARD_DEVIATION 91.64 |
| Age, Continuous | 63.16 years STANDARD_DEVIATION 6.37 |
| Appendicular mass/height^2 from DXA | 6.51 kg/m^2 STANDARD_DEVIATION 0.94 |
| Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ALT | 36.08 U/L STANDARD_DEVIATION 18.25 |
| Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) AST | 37.50 U/L STANDARD_DEVIATION 13.97 |
| Autonomic function test : Ewing autonomic battery test Mild dysfunction | 9 Participants |
| Autonomic function test : Ewing autonomic battery test Moderate dysfunction | 4 Participants |
| Autonomic function test : Ewing autonomic battery test No dysfunction | 6 Participants |
| Autonomic function test : Ewing autonomic battery test Severe dysfunction | 3 Participants |
| Body composion Fat Mass from BIA | 22.82 Kilograms STANDARD_DEVIATION 8.72 |
| Body composion Skeletal muscle mass from BIA | 24.07 Kilograms STANDARD_DEVIATION 5.08 |
| Body composion Total Fat Mass from DXA | 41.16 Kilograms STANDARD_DEVIATION 7.56 |
| Child-Pugh score score 5 | 47 Participants |
| Child-Pugh score score 6 | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Etiologies of cirrhosis Alcoholic cirrhosis | 1 Participants |
| Etiologies of cirrhosis Autoimmune hepatitis | 1 Participants |
| Etiologies of cirrhosis Hepatitis B | 17 Participants |
| Etiologies of cirrhosis Hepatitis C | 7 Participants |
| Etiologies of cirrhosis Non-alcoholic steatohepatitis (NASH) | 15 Participants |
| Etiologies of cirrhosis others | 1 Participants |
| Flow-mediated Dilation (FMD) | 6.21 Percent STANDARD_DEVIATION 3.77 |
| Handgrip strength | 28.86 kilograms STANDARD_DEVIATION 8.28 |
| Heart Rate Variability (HRV): Frequency Domain Measures High Frequency (HF) Power | 1445.00 ms^2 |
| Heart Rate Variability (HRV): Frequency Domain Measures Low Frequency (LF) Power | 1074.85 ms^2 |
| Heart Rate Variability (HRV): Frequency Domain Measures Total power (TP) | 4449.37 ms^2 |
| Heart Rate Variability (HRV): Frequency Domain Measures Very Low Frequency (VLF) Power | 1333.62 ms^2 |
| Heart Rate Variability (HRV): Time-Domain Measures including SDNN, SDANN, RMSSD RMSSD | 62.70 milliseconds |
| Heart Rate Variability (HRV): Time-Domain Measures including SDNN, SDANN, RMSSD SDANN | 62.73 milliseconds |
| Heart Rate Variability (HRV): Time-Domain Measures including SDNN, SDANN, RMSSD SDNN | 75.87 milliseconds |
| LF/HF Ratio (Low Frequency/High Frequency Ratio) | 0.93 Ratio |
| pNN50 | 9.42 % |
| Serum Albumin | 4.38 g/dL STANDARD_DEVIATION 0.29 |
| Serum ammonia | 50.18 µmol/L STANDARD_DEVIATION 26.83 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 6 Participants |
| Splanchnic Blood Flow Volume Celiac Artery Volume Flow | 859.18 ml/min STANDARD_DEVIATION 478.67 |
| Splanchnic Blood Flow Volume Portal Vein Volume Flow | 1737.13 ml/min STANDARD_DEVIATION 891.75 |
| Splanchnic Blood Flow Volume Superior Mesenteric Artery Volume Flow | 681.99 ml/min STANDARD_DEVIATION 337.28 |
| Splanchnic Vascular Velocity Celiac Artery: EDV | 42.25 centimeters per second (cm/s) STANDARD_DEVIATION 15.96 |
| Splanchnic Vascular Velocity Celiac Artery: PSV | 178.24 centimeters per second (cm/s) STANDARD_DEVIATION 57.19 |
| Splanchnic Vascular Velocity Celiac Artery: TAMAX | 86.81 centimeters per second (cm/s) STANDARD_DEVIATION 27.84 |
| Splanchnic Vascular Velocity Superior Mesenteric Artery: EDV | 21.98 centimeters per second (cm/s) STANDARD_DEVIATION 11.63 |
| Splanchnic Vascular Velocity Superior Mesenteric Artery: PSV | 174.05 centimeters per second (cm/s) STANDARD_DEVIATION 40.24 |
| Splanchnic Vascular Velocity Superior Mesenteric Artery: TAMAX | 59.97 centimeters per second (cm/s) STANDARD_DEVIATION 18.34 |
| Total Fat Mass from DXA | 36.69 kilograms STANDARD_DEVIATION 8.89 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 6 / 25 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
None listed