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Trials volume 22Article : Cite this article. Metrics details. Liver transplantation is the only effective therapy for this disease. Patients with HPS have ificant exercise limitations, impacting their quality of life and associated with poor liver transplant outcomes.

Many patients with HPS exhibit orthodeoxia—an improvement in oxygenation in the supine compared to the upright position. We hypothesize that exercise capacity will be superior in the supine compared to the upright position in such patients. Participants will be randomized to cycle ergometry in either the supine or upright position.

The primary outcome will be the difference in the stopping time between exercise positions, compared with a repeated measures analysis of variance method with a mixed effects model approach. The model will be adjusted for period effects. HPS patients have hypoxemia leading to ificant exercise limitations.

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If our study is positive, a supine exercise regimen could become a routine prescription for patients with HPS and orthodeoxia, enabling them to exercise more effectively. Future studies could explore the corresponding effects of a supine exercise training regimen on physiologic variables such as long-term exercise capacity, quality of life, dyspnea, and liver transplantation outcomes.

Registered on 1 July Peer Review reports. It is defined by the combination of [ 1 ] liver dysfunction or portal hypertension, [ 2 ] intrapulmonary vascular dilatations, and [ 3 ] abnormal oxygenation [ 2 ]. Liver transplantation is the only known effective therapy for this disease [ 3 ]. Participants with liver disease have reduced exercise capacity compared to normal controls [measured by peak oxygen consumption VO 2peak ] [ 45 ] due to a combination of deconditioning, malnutrition-associated muscle weakness, and anemia [ 6 ]. Exercise tolerance is further impaired in patients with HPS [ 789 ], who have more dyspnea and a reduced New York Heart Association functional class, compared to patients with cirrhosis who do not have HPS [ 10 ].

Formal exercise testing data are available in four small reports and one large cross-sectional study and demonstrate reduced exercise capacity and profound exercise desaturation in HPS Table 1. These studies support the concept that an abnormal pulmonary circulation contributes to exercise limitation in HPS and that patients with HPS experience severely reduced aerobic capacity, beyond that found in those with cirrhosis without HPS [ 7891112 ].

This is a combination of an increased distance between the alveolar membrane and the red blood cells in the center of dilated capillaries, causing an effective diffusion abnormality, along with a reduced resistance to flow causing increased perfusion through the dilated capillaries—which reduces available time for equilibration between the alveolar gas and the blood [ 13 ].

These IPVDs are often most prominent at lung bases [ 14 ]. Accordingly, due to the gravitational redistribution of blood flow to the lung bases in the upright position, there is an increase in blood volume passing through IPVDs, resulting in a worsening diffusion-perfusion defect when moving from the supine to the upright position [ 15 ]. This is often associated with a perception of increased dyspnea when upright called platypnea [ 14 ]. Limited current physiologic data suggest an important role for hypoxemia in the exercise limitation caused by HPS, suggesting that HPS patients with orthodeoxia may have a greater exercise capacity when exercising in the supine position compared to the conventional upright position.

studies have compared upright to supine exercise in various populations. In healthy individuals, although cardiac output increases in the supine exercise due to an increased preload and stroke volume [ 161718 ], there is also reduced blood flow to the leg muscles [ 19 ], resulting in reduced muscle oxygen uptake, more profound muscle deoxygenation [ 20 ], and a lower anaerobic threshold [ 19 ] compared to the upright exercise.

In patients with comorbidities, supine exercise has generally been found to worsen physiologic parameters compared to upright exercise, including a drop in alveolar ventilation with an increase in partial pressure of end tidal CO 2 [ 21 ] in patients with chronic obstructive pulmonary disease COPDa failure to increase left ventricular ejection fraction in patients with hypertension [ 22 ], and ST segment depression possibly indicating a lower ischemic threshold in patients with coronary artery disease [ 23 ].

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However, positional effects on exercise in patients with HPS, and the unique impact of orthodeoxia have not been reported. The primary aim of our study is to evaluate the effect of the supine position on exercise in HPS participants with orthodeoxia, compared to exercise in the upright position. Our primary objective is to study the effect of supine position, compared to the upright position, on exercise parameters in participants with HPS and orthodeoxia. We hypothesize that these participants will have improved exercise time when supine, compared to upright.

Once patients have provided assent to the clinician, they will be contacted by independent research personnel, either by phone or in-person during clinic visits, to seek informed consent see Additional file 1 for the consent form. Consenting patients will be randomized to start with either a supine or upright exercise test on a bicycle ergometer. The allocation sequence will be generated by a research coordinator in advance, through a computerized random generator.

This research coordinator will as the testing order for each newly recruited participant, and only this person will have access to the allocation sequence, which will remain concealed from study investigators at all times. The eligibility criteria are outlined in Table 2. This will be followed by an immediate ramp-up to the predetermined target constant work rate [ 2526 ]. Patients will be instructed to pedal at a rate between 50 and 60 revolutions per minute rpm and will be provided with constant feedback on pedaling frequency through a biofeedback display. We will also provide standardized verbal encouragement throughout [ 28 ], relating when they are above or below the target pedaling frequency, congratulating them when they are within the target frequency, and encouraging them to continue pedaling for as long as they feel able to.

For each participant, exercise in each position will be standardized with respect to the proper seat adjustment relative to leg length and pedaling cadence. For both tests, all measurements will take place through a pitot tube spirometer. Inspiratory capacity will be measured before and after exercise. Participants will continue exercising until they reach one of the following stopping criteria: 1 the point at which, after standardized encouragement, the participant is unable to continue because of symptoms i.

Stopping time will be defined as the duration of pedaling during the constant workload exercise test before a stopping criterion was met.

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During the test, the stopping time and criterion will be determined by agreement between the PI and the experienced technician conducting the test. Upon agreement, the time and criterion will be deated within the CPET software and independently recorded on a data collection sheet by a research assistant the assistant will also use a stopwatch during the test to independently record timing, ensuring that stopping time is measured in duplicate to for any system failures or errors.

A physician with expertise in cardiopulmonary exercise testing will be in attendance for monitoring throughout test procedures. Given the small sample size and the high relative safety of the exercise intervention, we will not be performing official interim analyses or creating a data and safety monitoring board. However, if any safety event occurs during study conduct, the investigators will immediately re-evaluate the safety of the protocol and overall study.

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Upon completion, patients will not only be notified of the overall study and publication, but also of their individual performance and whether supine exercise was found to be beneficial in their case. Exercise tests will be analyzed by a pulmonologist with experience in cardiopulmonary exercise test interpretation. This assessor will be masked to exercise position. The primary outcome will be the difference in stopping time between the upright and supine exercise positions.

We will exclude participants who stopped the exercise test due to either life-threatening arrhythmia or a drop in systolic blood pressure from the primary outcome analysis. Secondary outcomes will include differences in the following variables at isotime: oxygen uptake VO 2minute ventilation VEwork rate, heart rate HRarterial oxygen saturation SpO 2dyspnea, leg fatigue, change in inspiratory capacity, and carbon dioxide production VCO 2. We will also compare the reason for stopping exercise leg fatigue, dyspnea, other and maximum minute ventilation VE max. We will also conduct exploratory subgroup analyses, investigating the effects of baseline values such as PaO 2 and degree of orthodeoxia on exercise variables.

Given that HPS is a rare disease, and a majority of patients progress to either liver transplant or death relatively soon after diagnosis [ 10 ], recruitment to prospective trials in HPS has ly proven very challenging [ 3031 ]. Our recruitment will be further limited by the fact that only a subset of patients with HPS has orthodeoxia. Accordingly, we first estimated a recruitment target based on feasibility then set out to determine whether the demonstrable effect size with this sample would be both plausible and clinically meaningful.

We hypothesized that these variations in prevalence may have been due to the differences in covariates which predict orthodeoxia between study populations; however, the only study to attempt to explore predictors of orthodeoxia was that by Gomez and colleagues, in which the only ificant predictors of orthodeoxia in a cohort of 20 patients with HPS were a lower baseline cardiac index and higher mean distribution of upright alveolar ventilation.

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Factors including baseline PaO 2etiology of liver disease, age, VO 2minute ventilation, and diffusion lung capacity of carbon monoxide DLCO were not ificant predictors [ 35 ]. Given these limited sample sizes upon which to base our estimates, we performed an analysis of the prevalence and predictors of orthodeoxia in patients in the Canadian HPS Program Database. To our knowledge, this is by far the largest analysis of both the prevalence and risk factors for orthodeoxia in HPS. We complimented this with an analysis of our current active HPS database, revealing that six patients currently meet the inclusion criteria.

A crossover de has ly been successfully employed in patients with HPS [ 30 ]. The advantage of the crossover de in rare diseases such as HPS is that each participant will undergo both interventions, and within-person comparisons will limit confounding and reduce inter-subject variability, thereby reducing the sample size required to demonstrate an effect [ 38 ].

We established a 4-week maximum period between tests to minimize any possible period effect i. The possibility of a period effect due to familiarity with the cycling exercise will be evaluated statistically. Calculating the demonstrable effect size in this sample 10 participants requires an estimate of the standard deviation of the expected change in stopping time between supine and upright positions. However, due to the novelty of this study de, there is no existing literature investigating supine exercise in patients with HPS.

We also did not find any studies comparing supine and upright exercise in patients with cirrhosis without HPS. However, we did identify a study that employed a crossover de to evaluate the effect of hyperoxia which has a similar physiologic impact to supine position in our cohort on CWRET stopping time [ 39 ], in patients with interstitial lung disease—a condition in which the primary abnormality is a reduced diffusion capacity, which may have a comparable physiologic impact on exercise as the diffusion-perfusion defect of HPS.

This study showed that exercise time increases ificantly with hyperoxia compared to room air An increase in exercise time of 2. Accordingly, an improvement of 2. Each step of the study process, including test conduct, data recording, and data analysis, will be conducted through the guidance of standard operating procedures SOPs. A research coordinator and the PI will be present at each exercise study to audit and ensure compliance of the test conduct and data recording with SOPs. A linking log will be used to track the recruitment of participants into the study.

Participant personal health information PHI such as full name, date of birth, MRN,and phone will be collected and stored within the master linking log. Only deated research personnel will have access to the data. Although no funds have been set aside to compensate the participant in the event of injury or illness related to the study procedures, the participant does not give up any legal rights for compensation by consenting to and participating in this study. We will employ a repeated measures analysis of variance method with a mixed effects model approach to compare the primary and secondary outcomes between interventions.

The model will be adjusted for the period in which the treatment was received to assess for the period effect. An interaction between treatment and period will be included to for the carryover effect. Relationships between variables and between baseline characteristics and exercise test will be explored with parametric or non-parametric tests of correlation, as appropriate. The normality of continuous variables will be evaluated using QQ plots and histograms.

Model residuals will be assessed graphically to ensure that the model satisfies the normality and constant variance assumptions. The outcome will be log-transformed to stabilize the variable, and possible correlation structures will be employed if the assumptions are found to be violated. We will also test for period and carryover effects. All analyses will be conducted in the R software, version 4. Our study aims to investigate the effect of position change on exercise capacity in HPS patients with orthodeoxia.

This will be the first study to describe exercise capacity in the supine position in HPS, the first to compare with upright exercise, and the first to describe the use of a CWRET protocol in a cohort with this disease. Given the novelty of our research question and approach, the development of this study posed a of unique challenges and opportunities which merit discussion. Tissue oxygen delivery DO 2which is the physiologic substrate for the hypothesized position-related changes in exercise capacity that we seek to demonstrate, is dependent on oxygen saturation, which is in turn correlated with PaO 2 through the sigmoidal oxyhemoglobin dissociation curve.

Our use of a CWRET protocol is novel in this population, as prior studies of exercise testing in HPS Table 1 have almost exclusively employed incremental exercise protocols [ 78912 ]. Accordingly, the main variable of interest in an incremental exercise protocol, VO 2peakwould not likely be achieved in most participants. To address this, we chose a high-intensity CWRET, which has been widely used to assess the changes in exercise tolerance following interventions in other chronic hypoxemic lung diseases [ 26 ].

Given that an IET was not feasible in our population, we instead adopted a validated prediction equation for estimating peak work rate based on 6-min walk distance 6MWD in patients with COPD [ 2741 ].

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