Supine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia: Study Protocol for a Randomized Controlled Crossover Trial

Supine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia: Study Protocol for a Randomized Controlled Crossover Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Supine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia: Study Protocol for a Randomized Controlled Crossover Trial Harsh Parikh, Eric Lui, Marie E Faughnan, Abdul Al-Hesayen, Stephanie Segovia, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-308658/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background : The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis and characterized by intrapulmonary vascular dilatations and abnormal oxygenation. Liver transplantation is the only effective therapy for this disease. Patients with HPS have significant exercise limitation, 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. Methods : We propose a randomized controlled cross-over trial in patients with HPS and orthodeoxia, comparing the effect of supine versus upright position on exercise. Participants will be randomized to cycle ergometry in either the supine or upright position, followed by a crossover to the alternate position after a minimum of 1 day to a maximum of 4 weeks. Exercise will be performed at a constant work rate of 70-85% of the predicted peak work rate until the “stopping time” is reached, defined by exhaustion, profound desaturation, or safety concerns (drop in systolic blood pressure or life-threatening arrhythmia). The primary outcome will be the difference in stopping time between exercise positions. Discussion : HPS patients have hypoxemia leading to significant exercise limitation. 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. Trial registration : The ClinicalTrials.gov Protocol Registration and Results System (PRS): NCT04004104. Registered on 1 st July 2019. https://clinicaltrials.gov/ct2/show/NCT04004104 Translational Medicine Internal Medicine Integrative & Complementary Medicine Hepatopulmonary syndrome Orthodeoxia Exercise limitation Randomized crossover control study Tolerable limit Liver transplantation. Figures Figure 1 Background The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis ( 1 ). 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 ). Exercise in the Hepatopulmonary Syndrome Participants with liver disease have reduced exercise capacity compared to normal controls [measured by peak oxygen consumption (VO 2peak )] ( 4 , 5 ) due to a combination of deconditioning, malnutrition-associated muscle weakness, and anemia ( 6 ). Exercise tolerance is further impaired in patients with HPS ( 7 – 9 ), 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 ). Authors have hypothesized that this exercise desaturation is the result of increased shunt physiology, worsening diffusion due to increased pulmonary blood flow with reduced capillary transit time (a physiologic phenomenon called the “diffusion-perfusion defect”), and a reduced mixed venous oxygen content, the impact of which on arterial oxygen saturation is magnified by the former two effects ( 9 ). 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. Table 1 Previous literature reporting exercise testing in patients with HPS Study Exercise findings Thorens, et al., 1992 (11) HPS case report (n = 1); constant work rate test* • Worsening physiologic shunt (from 12% at rest to 26% with exercise) Epstein, et al., 1998 (7) HPS (n = 5) vs cirrhosis † (n = 19); incremental cycle ergometry • Reduced VO 2peak (55% predicted in HPS vs 72% predicted in cirrhosis) • Progressive exercise hypoxemia • Earlier onset of the anaerobic threshold • Elevated dead space ventilation Whyte, et al., 1998 (9) HPS (n = 8); incremental cycle ergometry • Progressive exercise desaturation • Diminished achieved workload (mean 48% predicted) • Reduced mixed venous oxygen content Nusair, et al., 2005 (8) HPS case report (n = 1); incremental cycle ergometry • Reduced VO 2peak (41% predicted) • Progressive exercise hypoxemia • Marked dyspnea • Worsening physiologic shunt Faustini-Pereira, et al., 2015 (12) HPS (n = 92) vs cirrhosis‡ (n = 86); modified Bruce protocol* • Reduced VO 2peak (80.2% predicted in HPS vs 86.7% predicted in cirrhosis) • Reduced 6-minute walk distance (341m in HPS vs 416m in cirrhosis) * Exercise modality not specified † “Cirrhosis” defined as PaO 2 ≥ 90 mmHg and alveolar-arterial oxygen gradient < 20 mmHg (negative contrast echo not required) ‡ “Cirrhosis” defined as alveolar-arterial oxygen gradient < 20 mmHg (negative contrast echo not required) HPS denotes hepatopulmonary syndrome; VO 2peak denotes maximum rate of oxygen consumption measured during incremental exercise; m denotes meters Orthodeoxia in the Hepatopulmonary Syndrome Intrapulmonary vascular dilatations (IPVDs) are believed to cause the hypoxemia of HPS through a “diffusion-perfusion defect” ( 11 ). 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 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 ). A corresponding drop in partial pressure of arterial oxygen (PaO 2 ) of greater than 5% or 4 mmHg in the upright compared to the supine position is called orthodeoxia ( 1 ). This is often associated with a perception of increased dyspnea when upright called platypnea ( 14 ). Study rationale and purpose 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. Previous 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 ( 16 – 20 ), there is also reduced blood flow to the leg muscles ( 21 ), resulting in reduced muscle oxygen uptake, more profound muscle deoxygenation ( 22 ), and a lower anaerobic threshold ( 21 ) 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 forced vital capacity ( 23 ) and alveolar ventilation (with an increase in partial pressure of end tidal CO 2 ) ( 24 ) in patients with chronic obstructive pulmonary disease (COPD), a failure to increase left ventricular ejection fraction in patients with hypertension ( 25 ), and ST segment depression possibly indicating a lower ischemic threshold in patients with coronary artery disease ( 26 ). However, positional effects on exercise in patients with HPS, and the unique impact of orthodeoxia have not been reported. Herein, we seek to evaluate the effect of the supine position on exercise in HPS participants with orthodeoxia, compared to exercise in the upright position. Methods And Design Objective and hypothesis Our 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. Trial design This will be a randomized controlled cross-over trial, conducted in the Canadian HPS Program [an HPS clinical and research program founded in 2005 ( www.hpscare.com ), consisting of sites in Toronto, Ontario (Unity Health Toronto and University Health Network), and Montreal, Quebec (Centre hospitalier de l'Université de Montréal)]. Consenting participants (to be consented by independent research personnel; see Appendix 1 for Consent Form) will be randomized (through a random-number generator and with concealed allocation) to start with either a supine or upright exercise test on a bicycle ergometer. Subsequently, participants will complete the alternate test on a separate day, within 4 weeks of the first test (Fig. 1 ). Participants Participants will be sequentially recruited from the Canadian HPS Program Database between late 2019 to approximately mid 2023 (including a pause due to SARS-COV-2 for much of 2020). Eligibility criteria are outlined in Table 2 . Table 2 . Eligibility Criteria Inclusion criteria · Moderate HPS: o Liver disease (evidence of synthetic liver dysfunction and/or portal hypertension on biochemistry and/or imaging) o Moderate Hypoxemia § PaO 2 64 (1) o Intrapulmonary vascular dilatations (microbubbles seen in the left heart ≥ 3 cycles after the right heart on saline contrast echocardiography) · Presence of orthodeoxia (PaO 2 decrease by > 4 mmHg when patient moves from supine to upright position) Exclusion criteria · Pulmonary hypertension o Echocardiographic estimated right ventricular systolic pressure ≥ 50 mmHg and/or o Right heart catheterization mean pulmonary artery pressure > 25 mmHg with pulmonary capillary wedge pressure ≤ 15 mmHg · Significant obstructive ventilatory impairment (FEV1/FVC ratio < 0.65) (14) · Known significant coronary artery disease · Significant neurologic, orthopedic or rheumatological disorders preventing use of a cycle ergometer · Other absolute contraindications to submaximal exercise testing (27) o Uncontrolled cardiac arrhythmia with hemodynamic compromise o Symptomatic severe aortic stenosis o Decompensated heart failure o Acute cardiopulmonary illness (e.g. venous thromboembolism, myocarditis, pericarditis, endocarditis, acute aortic dissection) · Moderate or severe ascites PaO 2 denotes partial pressure of arterial oxygen; FEV1/FVC denotes forced expiratory volume in one second over forced vital capacity; AaDO 2 denotes alveolar-arterial oxygen gradient [PAO 2 – PaO 2 , where PAO 2 = [FiO 2 (P atm − P H2O ) − PaCO 2 / 0.8] (AO 2 denotes partial pressure of alveolar oxygen; FIO 2 denotes inspiratory oxygen fraction; P atm denotes atmosphere pressure; P H2O denotes water vapor partial pressure; PaCO 2 denotes arterial carbon dioxide pressure) Exercise protocol Each participant will perform a constant work rate exercise test (CWRET). The constant work rate will be individualized for each participant and set at 70–85% of their estimated peak work rate ( 28 ), targeting an estimated test duration of 180–480 seconds (to increase chances that exercise limitation is due to the physiologic effects of exercise rather than physical discomfort or boredom ( 29 )). Peak work rate will be estimated from a previous room air 6-minute walk test (6MWT) performed within the last 6 months (peak work rate = 0.168 x 6MWD (m) – 4.085) ( 30 ). The CWRET will include a warmup period consisting of 1 minute of rest followed by an immediate ramp-up to the predetermined target constant work rate ( 28 , 29 ). 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 peddling frequency through a biofeedback display, along with standardized verbal encouragement throughout. For each participant, exercise in each position will be standardized with respect to the proper seat adjustment relative to leg length and pedaling cadence. Upright cycle ergometry will be performed on the Corival Ergometer Bicycle (LODE B.V. Medical Technology Groningen, Netherlands) at an angle of 90 o . Supine cycle will be performed on the Stress EchoBed ® (Medical Positioning Inc., USA) at an angle of 0 o . For both tests, all measurements will take place through a pitot tube spirometer. Volume and flow calibrations (pitot tube spirometer) and gas calibration (Ergo Card Analyzer, Medisoft, USA) will be performed within 1 hour of the exercise test and Bio calibration will be performed on the pitot tube spirometer every 3 months. Inspiratory capacity will be measured before and after exercise. Before, after, and throughout exercise, we will measure: oxygen uptake (VO 2 ) and carbon dioxide production (VCO 2 ) (measured breath-by-breath, averaged over 30-second epochs); oxygen saturation and heart rate (continuously, by pulse oximetry and 12-lead electrocardiography, respectively); blood pressure (every 2 minutes, by manual sphygmomanometry); and subjective dyspnea and leg fatigue (every 1 minute, by modified Borg scale) ( 31 ). 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.e. participant does not wish to continue or is unable to maintain a minimum peddling frequency of 40 rpm for ≥ 10 seconds) [defined as the “tolerable limit” (tLIM)]; 2) desaturation below a set point for ≥ 30 seconds; 3) a drop in systolic blood pressure by ≥ 10 mmHg from baseline; or 4) the appearance of life-threatening arrhythmias (such as significant ventricular arrhythmias or high-grade heart block). The low saturation set point will be chosen individually for each participant, as the lower of 80% ( 29 ), or the nadir desaturation seen on baseline room air 6MWT. If participants experience arrhythmic or hemodynamic-related stopping criteria on the first of the protocolized exercise tests, they will be excluded from the study and the second exercise test will not be attempted. Stopping time will be defined as the duration of pedaling during the constant workload exercise test before a stopping criterion was met. Participants will be reminded to bring running shoes and comfortable exercise clothes, to ensure that they have eaten before the test, to take all usual medications, and to avoid major exercise for 24 hours before the test. A physician with expertise in cardiopulmonary exercise testing will be in attendance for monitoring throughout test procedures. Outcome measures Exercise tests will be analyzed by a pulmonologist with experience in cardiopulmonary exercise test interpretation. This assessor will be masked to exercise position. Primary outcome measure The primary outcome is 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 outcome measures Secondary outcomes will include differences in the following variables at isotime: oxygen uptake (VO 2 ); minute ventilation (VE); work rate; heart rate (HR); arterial oxygen saturation (SpO 2 ); dyspnea; 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 ). In patients who reach anaerobic threshold (AT) in both positions, we will compare time to reach AT, and VO 2 , VE/VCO 2 , and cardiac output at AT in each position. Relationships between key variables will be compared graphically, including VCO 2 over VO 2 ; HR over VO 2 ; VE over VCO 2 ; end tidal CO2 (PetCO 2 ) over time; saturation over time; VE over time; VO 2 /HR (“oxygen pulse”) over time and HR over time. We will also conduct exploratory subgroup analyses, investigating the effects of baseline values such as PaO 2 and degree of orthodeoxia on exercise variables. Recruitment and power 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 previously proven very challenging ( 32 , 33 ). Our recruitment will be further limited by the fact that only a subset of patients with HPS have 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. To estimate feasible recruitment, we searched the literature for studies describing the prevalence of orthodeoxia in cohorts of ≥ 10 HPS patients. However, we found only 4 small reports (14–20 patients each) reporting a highly variable prevalence of orthodeoxia, ranging from 14–88% of HPS participants (Table 3 ). Table 3 Characteristics of Orthodeoxia in Patients with Hepatopulmonary Syndrome Author Mean Upright † PaO 2 (mmHg) Prevalence of Orthodeoxia‡, N (%) Mean Room air PaO 2 in patients with Orthodeoxia (mmHg) (SD) Orthodeoxia (supine PaO 2 - upright PaO 2 ; mmHg) Krowka, et al., 1993 (34) 44.0 14/16 (87.5) Upright: 44.0 ± 9 Supine: 62.0 ± 14 18.0 Martinez, et al., 1999 (35) 65.2 2/5 (40.0) Upright: 51.0 ± 3 Supine: 61.5 ± 2 10.5 Martinez, et al., 2001 (36) 75.0 2/14 (14.3) Upright: 63.5 ± 21 Supine: 71.5 ± 21 8.0 Gomez, et al., 2004 (37) 69.0 5/20 (25.0) Upright: 59.0 ± 6 Supine: 67.0 ± 5 8.0 Current Study * 51.8 37/56 (66.1) Upright: 48.1 ± 14 Supine: 61.9 ± 12 13.8 * Analysis performed in patients at the Toronto site of the Canadian HPS Database with a PaO 2 < 80 mmHg, absence of significant concurrent lung disease contributing to hypoxemia, and absence of concurrent portopulmonary hypertension. †All studies defined “upright” as the sitting position, except Krowka 1993 ( 34 ) and the current study, which defined it as the standing position. ‡ All studies defined orthodeoxia as a drop in partial pressure of arterial oxygen (PaO 2 ) of greater than 5% or 4 mmHg in the upright compared to the supine position, except Martinez 1999 ( 35 ), which defined it as a drop in PaO 2 greater than 10 mmHg in the upright compared to the supine position. We hypothesized that these variations in prevalence may have been due to 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 significant 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. Factors including baseline PaO 2 , etiology of liver disease, age, VO 2 , minute ventilation, and diffusion lung capacity of carbon monoxide (DLCO) were not significant predictors ( 37 ). 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. A priori, we identified the following candidate baseline predictors: age, sex, PaO 2 , MELD score, DLCO, macroaggregated albumin (MAA) shunt fraction, 6MWD, and presence of clubbing. We found that 37 out of 56 patients (66%) had orthodeoxia. In univariate analyses, lower baseline upright PaO 2 and DLCO were significant predictors of orthodeoxia in HPS (Table 4 ). Table 4 Differences in Baseline Clinical Characteristics Between Hepatopulmonary Syndrome Patients With and Without Orthodeoxia (Current Cohort) Characteristic No Orthodeoxia Orthodeoxia P value † Age (years) N Mean ± SD 19 63.8 ± 11.9 37 60.4 ± 10.7 0.302 Sex – male N (%) 8 (44.4) 22 (59.5) 0.294 MELD score * N Mean ± SD 17 14.0 ± 3.8 36 12.4 ± 3.4 0.144 DLCO (% predicted) N Mean ± SD 18 64.0 ± 14.7 35 50.2 ± 14.7 0.005 MAA Shunt Fraction (%) (38) N Mean ± SD 10 17.2 ± 23.2 30 22.0 ± 13.8 0.551 Shunt Fraction on 100% FiO 2 (%) (39) N Mean ± SD 19 13.4 ± 6.0 34 14.6 ± 8.3 0.571 6MWD (meters) N Mean ± SD 7 418.6 ± 109.2 10 441.8 ± 147.8 0.715 Clubbing N (%) 12 (63.2) 22 (61.1) 0.882 PaO 2 (upright) (mmHg) N Mean ± SD 19 59.0 ± 13.0 37 48.1 ± 14.3 0.006 * MELD score denotes model for end-stage liver disease score; DLCO denotes diffusion lung capacity for carbon monoxide; MAA denotes macroaggregated albumin; FiO 2 denotes fraction of inspired oxygen; 6MWD denotes 6-minute walk distance; PaO 2 denotes partial pressure of arterial oxygen. N denotes total number of participants; SD denotes standard deviation. † Univariate analyses are presented for each variable; continuous variables assessed with a 2-sample t- test and categorical variables with a chi-squared test; Variables were assessed on the same day as orthodeoxia, or within an interval of ≤ 1 year. To our knowledge, this is by far the largest analysis of both the prevalence and risk factors for orthodeoxia in HPS. Given that patients with orthodeoxia had more severe hypoxemia, it was not surprising that our more “severe” HPS cohort (compared to other reports) had a high observed orthodeoxia prevalence of 66.1% (Table 3). We complimented this with an analysis of our current active HPS database, revealing that six patients currently meet inclusion criteria. Additionally, a review of referrals in the last 3 years reveals that an average of 4 eligible patients are referred to our program each year. Based on a pessimistic recruitment target of 50%, this analysis of the Canadian HPS Program Database suggests that we will be able to recruit 10 eligible participants to this study in the 4-year recruitment window allowed by study funding. A crossover design has previously been successfully employed in patients with HPS ( 32 ). The advantage of the crossover design 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 ( 40 ). The crossover design is well-suited to an exercise intervention because there is no anticipated therapeutic carryover effect, obviating the need for a washout (we allowed for a 1 day minimum “washout” period for recovery from the prior exercise test). We established a 4-week maximum period between tests to minimize any possible period effect (i.e. to prevent significant disease progression by the time of the second test). 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 design, 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 design to evaluate the effect of hyperoxia (which has a similar physiologic impact to supine position in our cohort) on CWRET stopping time ( 41 ), 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 significantly with hyperoxia compared to room air (21.9 ± 12.9 versus 11.6 ± 10.0 minutes, p < 0.001) ( 41 ), with a pooled standard deviation for change in exercise duration of 11.5 minutes. Applying this standard deviation, our crossover trial with a target sample size of 10 participants will be able to detect a difference of ≥ 2.85 minutes between the two interventions with power of 80% and a two-sided alpha of 0.05. An increase in exercise time of 2.85 minutes is clinically meaningful in other hypoxemic diseases. In COPD, the minimal clinically important difference (MCID) for tLIM on CWRET is an increase of 33% or 105 seconds from baseline ( 29 ). Bronchodilator trials suggest that clinical outcome improvements correspond to tLIM improvements of > 60 seconds ( 29 ). Accordingly, an improvement of 2.85 minutes (171 seconds) would likely be clinically significant in our participants, who have more severe baseline exercise limitation than typical patients with COPD. With an estimated upright test duration of 3–8 minutes in our design ( 29 ), a change of 2.85 minutes would represent an improvement of between 36%-95%, which again suggests a clinically meaningful improvement. Statistical analysis Continuous variables will be reported as mean (median) +/- standard deviation; and categorical variables will be reported as proportions or percentages. 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 account for the carry-over effect. Relationships between variables and between baseline characteristics and exercise test results will be explored with parametric or non-parametric tests of correlation, as appropriate. We will also test for period and carryover effects. The significance level (α) will be set at < 0.05. Discussion 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 use of a CWRET protocol in a cohort with this disease. Given the novelty of our research question and approach, development of this study posed a number of unique challenges and opportunities which merit discussion. Study Population and Design We chose to include patients with at least moderate HPS (PaO 2 < 80 mmHg), in order to ensure that the degree of observed orthodeoxia is both clinically and physiologically significant. Tissue oxygen delivery (DO 2 ), which 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. Given the flat shape of this curve at higher PaO 2 levels, changes in PaO 2 of just over 4 mmHg (the definition of orthodeoxia) would not result in any significant changes in oxygen saturation in patients with a baseline PaO2 ≥ 80 mmHg. 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 ( 7 – 9 , 12 ). Given the severe baseline disease in our expected patient population (Table 3 ), with a predicted mean PaO 2 drop of 20 mmHg at peak exercise ( 7 ), we believe that an incremental exercise protocol would result in profound desaturation requiring cessation for safety reasons, with a high resulting likelihood of a submaximal test. Accordingly, the main variable of interest in an incremental exercise protocol - VO 2peak , would not likely be achieved in most participants. To address this, we chose a high-intensity CWRET, which has been widely used to assess changes in exercise tolerance following interventions in other chronic hypoxemic lung diseases ( 29 ). The constant work rate in a CWRET is typically set at 70–85% of peak work rate measured on incremental exercise testing (IET) ( 29 ). 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-minute walk distance (6MWD) in patients with COPD ( 30 ) ( 42 ). Given that peak work rate is affected by ventilatory impairment and dynamic hyperinflation in COPD, neither of which appear to play a role in HPS, this represents a vulnerability in our testing protocol. Safety The primary outcome in our study is stopping time, as determined by either reaching tLim or experiencing desaturation to our pre-set safety stopping criterion, which is the lower of 80% or the nadir desaturation seen on room air 6MWT. There have been no reports of adverse events while performing CWRET ( 29 ). While there is no definitive threshold at which arterial desaturation becomes hazardous ( 29 ), cardiopulmonary exercise testing (CPET) guidelines from the American Thoracic Society and American College of Chest Physicians suggest a saturation of ≤ 80% (with accompanying signs and symptoms of severe hypoxemia) as one of the indications for exercise termination ( 43 , 44 ). However, patients with HPS are well adapted to hypoxemia ( 1 ). These patients often present after a prolonged period of undiagnosed hypoxemia and are encouraged to exercise to preserve muscle mass despite significant exercise desaturation (which occurs even with oxygen supplementation) ( 45 , 46 ). Furthermore, many patients who require oxygen do not use it at all times ( 47 ). Accordingly, and because many patients in our severe population would desaturate to 80% at rest or with minimal exertion while upright, we added an individualized stopping criterion set at the nadir desaturation experienced on room air 6MWT. This novel approach will enable patients with severe disease to perform a sufficient amount of exercise for positional differences to be detectable and given that it likely reflects a level of desaturation that patients typically experience in their daily lives, will maintain a reasonable margin of safety. Clinical relevance of the potential results Exercise has been shown to have numerous health benefits, ranging from reducing the risk of heart disease, stroke, osteoporosis, diabetes, and cancer, to improving mental health ( 48 ). Unfortunately, patients with HPS are unable to realize the short- or long-term (training) benefits of exercise due to severe exercise limitation caused by hypoxemia. If our hypothesis proves correct, a supine exercise protocol would empower these patients to exercise for longer periods of time. Furthermore, supine exercise could enable a more effective long-term exercise training program. Exercise training results in improvements in exercise capacity, including maximum oxygen uptake (VO 2max ), VO 2peak , and muscle mass in patients with cirrhosis ( 4 , 49 , 50 ). This could be particularly impactful for patients with HPS awaiting liver transplant, given that this is the only treatment for HPS, and that pre-transplant exercise capacity predicts post-transplant survival ( 51 , 52 ). Every 100- meter increase in baseline 6MWD is associated with a 52% reduction in 1-year post-transplant mortality ( 53 ), and preoperative exercise capacity independently predicts respiratory complications post-liver transplant ( 54 ). Furthermore, the median liver transplant wait time in severe HPS is 200 days ( 55 ), and these patients experience progressive hypoxemia ( 3 , 45 ), resulting in worsening exercise limitation while awaiting transplant. It is also of note that the HPS patients being targeted by this intervention – those with orthodeoxia – tend to have a lower baseline PaO 2 and are thus more likely to require a liver transplant for HPS. If positive, this study will establish the efficacy of supine exercise in this population, enabling this to become a routine part of HPS management, including in non-transplant and pre-transplant settings. This evidence would be required to justify the cost and complexity of a supine exercise prescription. Our results would warrant future studies investigating the long-term physiologic and clinical benefits of a supine exercise training program in HPS, including effects on patient-relevant outcomes such as quality of life, dyspnea, and liver transplant outcomes. Our data suggest that two thirds of patients with at least moderate HPS have orthodeoxia, representing a significant population of patients (particularly, those with the most severe disease) that could stand to benefit. We also believe that findings from our unique exercise protocol will advance understanding of the physiology of this disease and lay the foundations for larger future studies. Limitations It is important to note that our findings will only be applicable to patients with HPS who have orthodeoxia. As noted, 66% of patients with at least moderate HPS had orthodeoxia in our cohort, but smaller studies have reported an orthodeoxia prevalence as low as 14% ( 36 ) in all-comers with HPS, and this requires further study. We also note that while orthodeoxia is measured in the supine versus the standing position, the upright bicycle exercise protocol more closely simulates sitting than standing, and prior reports have suggested that orthodeoxia is less pronounced in the sitting compared to the standing position ( 56 ). A smaller positional change in PaO 2 could reduce the predicted effect of position on exercise capacity. Trial Status Protocol version #3, version date 27 August 2019. Enrollment into the trial has started and is expected to be finalized by approximately December 1, 2022. List Of Abbreviations HPS Hepatopulmonary syndrome; VO2 peak :Peak oxygen consumption; IPVDs:Intrapulmonary vascular dilatations; PaO 2 :Partial pressure of arterial oxygen; COPD:Chronic obstructive pulmonary disease; FEV1/FVC:Forced expiratory volume in one second over forced vital capacity; AaDO2:Alveolar-arterial oxygen gradient; AO 2 :Partial pressure of alveolar oxygen; P atm :Atmosphere pressure; P H2O :Water vapor partial pressure; PaCO 2 :Arterial carbon dioxide pressure; CWRET:Constant work rate exercise test; 6MWT:Six minute walk test; RPM:Revolutions per minute; tLIM:Tolerable limit; VO 2 :Oxygen uptake; VE:Minute ventilation; HR:Heart rate; SpO 2 :Arterial oxygen saturation; VCO 2 :Carbon dioxide production; VE max :Maximum minute ventilation; AT:Anaerobic threshold; DLCO:Diffusion lung capacity of carbon monoxide; MELD:model for end-stage liver disease score; MAA:macroaggregated albumin; FiO 2 :fraction of inspired oxygen; 6MWD:Six minute walk distance; SD:Standard deviation; MCID:Minimal clinically important difference; DO 2 :Tissue oxygen delivery; IET:Incremental exercise testing; CPET:Cardiopulmonary exercise testing; VO 2max :maximum oxygen uptake. Declarations Ethics approval and consent to participate The study was reviewed and approved by the Research Ethics Board at Unity Health Toronto (REB #19-127). Consent for publication All data will be presented as a mean or median. No individual data will be included in the manuscript. Availability of data and materials The datasets generated and/or analysed during the current study will be made available by the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study will be funded by the Michael Locke Term Chair in Knowledge Translation and Rare Lung Disease Research. The funder had no role in the conception or design of this protocol and will have no role in data analysis or study publication. Authors’ contributions HP, EL, SG, MEF, AAH: Study conception and design. HP, EL, SS, SG: Acquisition of data. HP, EL, SG, MEF: Analysis and interpretation of data. HP, EL, SG: Drafting of the manuscript. HP, EL, SS, MEF, AAH, SG: Critical revision of the manuscript for important intellectual content. HP, EL, SG: Statistical analysis. SG: Obtained funding. SS, SG: Administrative, technical, or material support. SG: Study supervision. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank Jenna Sykes for statistical advice, and Eva Leek and Dejan Lukic for operational advice. Authors’ Information 1 Li Ka Shing Knowledge Institute, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. 2 Department of Medicine, University of Toronto, Canada. 3 Division of Respirology, St. Michael's Hospital, Toronto, Canada. 4 Division of Cardiology, St Michael's Hospital, Toronto, Canada. * These authors contributed equally to this work. References Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, et al. 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Effect of tripod position on objective parameters of respiratory function in stable chronic obstructive pulmonary disease. Indian J Chest Dis Allied Sci. 2009;51(2):83-5. Ross BA, Brotto AR, Fuhr DP, Phillips DB, van Diepen S, Bryan TL, et al. The supine position improves but does not normalize the blunted pulmonary capillary blood volume response to exercise in mild COPD. J Appl Physiol (1985). 2020;128(4):925-33. Schulman DS, Tugoen JF, Flores AR, Dianzumba S, Reichek N. Left ventricular ejection fraction during supine and upright exercise in patients with systemic hypertension and its relation to peak filling rate. Am J Cardiol. 1995;76(1):61-5. Wetherbee JN, Bamrah VS, Ptacin MJ, Kalbfleisch JH. Comparison of ST segment depression in upright treadmill and supine bicycle exercise testing. J Am Coll Cardiol. 1988;11(2):330-7. Fletcher GF AP, Kligfield P, et al. Exercise standards for testing and training: A scientific statement from the American Heart Association. Circulation. 2013;128(8):873-934. Puente-Maestu L, Villar F, de Miguel J, Stringer WW, Sanz P, Sanz ML, et al. Clinical relevance of constant power exercise duration changes in COPD. Eur Respir J. 2009;34(2):340-5. Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, et al. Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur Respir J. 2016;47(2):429-60. Kozu R, Jenkins S, Senjyu H, Mukae H, Sakamoto N, Kohno S. Peak power estimated from 6-minute walk distance in Asian patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Respirology. 2010;15(4):706-13. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377-81. Gupta S, Faughnan ME, Lilly L, Hutchison S, Fowler R, Bayoumi AM. Norfloxacin therapy for hepatopulmonary syndrome: a pilot randomized controlled trial. Clin Gastroenterol Hepatol. 2010;8(12):1095-8. Kawut SM, Ellenberg SS, Krowka MJ, Goldberg D, Vargas H, Koch D, et al. Sorafenib in Hepatopulmonary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Liver Transpl. 2019;25(8):1155-64. Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue. Chest. 1993;104(2):515-21. Martinez G, Barbera JA, Navasa M, Roca J, Visa J, Rodriguez-Roisin R. Hepatopulmonary syndrome associated with cardiorespiratory disease. J Hepatol. 1999;30(5):882-9. Martinez GP, Barbera JA, Visa J, Rimola A, Pare JC, Roca J, et al. Hepatopulmonary syndrome in candidates for liver transplantation. J Hepatol. 2001;34(5):651-7. Gomez FP, Martinez-Palli G, Barbera JA, Roca J, Navasa M, Rodriguez-Roisin R. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology. 2004;40(3):660-6. Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology. 1998;114(2):305-10. Sarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017;34(1):47-60. Gupta S, Faughnan ME, Tomlinson GA, Bayoumi AM. A framework for applying unfamiliar trial designs in studies of rare diseases. J Clin Epidemiol. 2011;64(10):1085-94. Schaeffer MR, Ryerson CJ, Ramsook AH, Molgat-Seon Y, Wilkie SS, Dhillon SS, et al. Effects of hyperoxia on dyspnoea and exercise endurance in fibrotic interstitial lung disease. Eur Respir J. 2017;49(5). Kirkham AA, Pauhl KE, Elliott RM, Scott JA, Doria SC, Davidson HK, et al. Utility of Equations to Estimate Peak Oxygen Uptake and Work Rate From a 6-Minute Walk Test in Patients With COPD in a Clinical Setting. J Cardiopulm Rehabil Prev. 2015;35(6):431-8. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8):1531-40. American Thoracic S, American College of Chest P. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003;167(2):211-77. Gupta S, Castel H, Rao RV, Picard M, Lilly L, Faughnan ME, et al. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am J Transplant. 2010;10(2):354-63. Khan AN, Al-Jahdali H, Abdullah K, Irion KL, Sabih Q, Gouda A. Pulmonary vascular complications of chronic liver disease: Pathophysiology, imaging, and treatment. Ann Thorac Med. 2011;6(2):57-65. Bender BG. Nonadherence in chronic obstructive pulmonary disease patients: what do we know and what should we do next? Curr Opin Pulm Med. 2014;20(2):132-7. Fentem PH. ABC of sports medicine. Benefits of exercise in health and disease. BMJ. 1994;308(6939):1291-5. Campillo B FP, Bonnet JC, Atlan G. Submaximal oxygen consumption in liver cirrhosis. Evidence of severe functional aerobic impairment. J Hepatol 1990:163-7. Ritland S PC, Knudsen T, Skrede S. Improvement of physical capacity after long-term training in patients with chronic active hepatitis. Scand J Gastroenterol. 1983;18:1083-7. Dharancy S, Lemyze M, Boleslawski E, Neviere R, Declerck N, Canva V, et al. Impact of impaired aerobic capacity on liver transplant candidates. Transplantation. 2008;86(8):1077-83. Epstein SK, Freeman RB, Khayat A, Unterborn JN, Pratt DS, Kaplan MM. Aerobic capacity is associated with 100-day outcome after hepatic transplantation. Liver Transpl. 2004;10(3):418-24. Carey EJ, Steidley DE, Aqel BA, Byrne TJ, Mekeel KL, Rakela J, et al. Six-minute walk distance predicts mortality in liver transplant candidates. Liver Transpl. 2010;16(12):1373-8. Magalhaes CBA, Nogueira IC, Marinho LS, Daher EF, Garcia JHP, Viana CFG, et al. Exercise Capacity Impairment Can Predict Postoperative Pulmonary Complications after Liver Transplantation. Respiration. 2017;94(3):272-8. Sulieman BM, Hunsicker LG, Katz DA, Voigt MD. OPTN policy regarding prioritization of patients with hepatopulmonary syndrome: does it provide equitable organ allocation? Am J Transplant. 2008;8(5):954-64. Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis. 1989;140(6):1631-5. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-308658","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":25702265,"identity":"845b396d-9db3-4344-a483-06b53193dd40","order_by":0,"name":"Harsh Parikh","email":"","orcid":"","institution":"St Michael's Hospital Li Ka Shing Knowledge Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Harsh","middleName":"","lastName":"Parikh","suffix":""},{"id":25702266,"identity":"7082615b-5b22-42e8-8f75-52d8f0a7e4af","order_by":1,"name":"Eric Lui","email":"","orcid":"","institution":"St Michael's Hospital Li Ka Shing Knowledge Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Lui","suffix":""},{"id":25702267,"identity":"e09e006b-e05e-43cb-83b1-5e12e73c7ab1","order_by":2,"name":"Marie E Faughnan","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marie","middleName":"E","lastName":"Faughnan","suffix":""},{"id":25702268,"identity":"4965e65a-1841-4474-9824-8a22424dea7a","order_by":3,"name":"Abdul Al-Hesayen","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Abdul","middleName":"","lastName":"Al-Hesayen","suffix":""},{"id":25702269,"identity":"2de07144-b8ab-4329-b14c-ab064f2e938c","order_by":4,"name":"Stephanie Segovia","email":"","orcid":"","institution":"St Michael's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Segovia","suffix":""},{"id":25702270,"identity":"1e2f0de5-3840-4ea8-99e8-93e3b00755eb","order_by":5,"name":"Samir Gupta","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIiWNgGAWjYBAC+QYGhgNQNuMDBgYJMGJ4ABfEBAYHYFrYGJgNgOolwFoSEg4w8ODSAmexMbCBFBOhhf104uEKhtrE7fLNz6p5d1jUGdxuPvgh8ccdBnv2Bux+6cndcPAMw/HEnW1sZrd5z0hIGNw5liyRkPCMgYcHh38OALU0MBxL3HCMAailDajlRo4BUMthBh6JBOxazr+FaWH/VgzRkv/5B14tN8C21AC18JgxQ21hw2uLwQ2QLQYHjHe25RRLzm2TkJx5I83MIiHtMA/PGex+ke/P3fyxoaJOdjvz8Y0f3rbV8fPdSH5844PNYTn2duwhBrXrMCKCFKBm44oWGKhDaJHHZ/YoGAWjYBSMSAAAzXBox+F7ChAAAAAASUVORK5CYII=","orcid":"","institution":"University of Toronto","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Samir","middleName":"","lastName":"Gupta","suffix":""}],"badges":[],"createdAt":"2021-03-08 05:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-308658/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-308658/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":8999419,"identity":"28f11130-dda8-485d-8e1f-d9feb15fb6e8","added_by":"auto","created_at":"2021-05-10 13:59:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8305,"visible":true,"origin":"","legend":"Study Design","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-308658/v1/510d30a2769d585a1bb0bdd5.png"},{"id":13692011,"identity":"109f10f9-500a-4c5f-8d5f-4570a569e10d","added_by":"auto","created_at":"2021-09-17 12:41:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":495814,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-308658/v1/7a7aa305-ac02-4aac-b98f-0330ec2f6a3c.pdf"},{"id":8999067,"identity":"a089cf8d-6e5b-43dc-934c-0f4391a8b7ed","added_by":"auto","created_at":"2021-05-10 13:56:12","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":266752,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITChecklistBMCTrials.doc","url":"https://assets-eu.researchsquare.com/files/rs-308658/v1/748baf899e0150f65af1e6d3.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSupine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia: Study Protocol for a Randomized Controlled Crossover Trial\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eThe hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It is defined by the combination of: 1) liver dysfunction or portal hypertension; 2) intrapulmonary vascular dilatations; and 3) abnormal oxygenation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Liver transplantation is the only known effective therapy for this disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eExercise in the Hepatopulmonary Syndrome\u003c/h2\u003e \u003cp\u003eParticipants with liver disease have reduced exercise capacity compared to normal controls [measured by peak oxygen consumption (VO\u003csub\u003e2peak\u003c/sub\u003e)] (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) due to a combination of deconditioning, malnutrition-associated muscle weakness, and anemia (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Exercise tolerance is further impaired in patients with HPS (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), who have more dyspnea and a reduced New York Heart Association functional class, compared to patients with cirrhosis who do not have HPS (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). 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\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Authors have hypothesized that this exercise desaturation is the result of increased shunt physiology, worsening diffusion due to increased pulmonary blood flow with reduced capillary transit time (a physiologic phenomenon called the \u0026ldquo;diffusion-perfusion defect\u0026rdquo;), and a reduced mixed venous oxygen content, the impact of which on arterial oxygen saturation is magnified by the former two effects (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). 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.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrevious literature reporting exercise testing in patients with HPS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExercise findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThorens, et al., 1992 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPS case report\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1); constant work rate test*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Worsening physiologic shunt (from 12% at rest to 26% with exercise)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpstein, et al., 1998 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPS (n\u0026thinsp;=\u0026thinsp;5) vs cirrhosis\u003csup\u003e\u0026dagger;\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;19); incremental cycle ergometry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u0026bull; Reduced VO\u003csub\u003e2peak\u003c/sub\u003e (55% predicted in HPS vs 72% predicted in cirrhosis)\u003c/p\u003e \u003cp\u003e\u0026bull; Progressive exercise hypoxemia\u003c/p\u003e \u003cp\u003e\u0026bull; Earlier onset of the anaerobic threshold\u003c/p\u003e \u003cp\u003e\u0026bull; Elevated dead space ventilation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhyte, et al., 1998 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPS (n\u0026thinsp;=\u0026thinsp;8); incremental cycle ergometry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Progressive exercise desaturation\u003c/p\u003e \u003cp\u003e\u0026bull; Diminished achieved workload (mean 48% predicted)\u003c/p\u003e \u003cp\u003e\u0026bull; Reduced mixed venous oxygen content\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNusair, et al., 2005 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPS case report (n\u0026thinsp;=\u0026thinsp;1); incremental cycle ergometry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Reduced VO\u003csub\u003e2peak\u003c/sub\u003e (41% predicted)\u003c/p\u003e \u003cp\u003e\u0026bull; Progressive exercise hypoxemia\u003c/p\u003e \u003cp\u003e\u0026bull; Marked dyspnea\u003c/p\u003e \u003cp\u003e\u0026bull; Worsening physiologic shunt\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFaustini-Pereira, et al., 2015 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPS (n\u0026thinsp;=\u0026thinsp;92) vs cirrhosis\u0026Dagger; (n\u0026thinsp;=\u0026thinsp;86);\u003c/p\u003e \u003cp\u003emodified Bruce protocol*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Reduced VO\u003csub\u003e2peak\u003c/sub\u003e (80.2% predicted in HPS vs 86.7% predicted in cirrhosis)\u003c/p\u003e \u003cp\u003e\u0026bull; Reduced 6-minute walk distance (341m in HPS vs 416m in cirrhosis)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* Exercise modality not specified\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e \u0026ldquo;Cirrhosis\u0026rdquo; defined as PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;90 mmHg and alveolar-arterial oxygen gradient\u0026thinsp;\u0026lt;\u0026thinsp;20 mmHg (negative contrast echo not required)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026Dagger; \u0026ldquo;Cirrhosis\u0026rdquo; defined as alveolar-arterial oxygen gradient\u0026thinsp;\u0026lt;\u0026thinsp;20 mmHg (negative contrast echo not required)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHPS denotes hepatopulmonary syndrome; VO\u003csub\u003e2peak\u003c/sub\u003e denotes maximum rate of oxygen consumption measured during incremental exercise; m denotes meters\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eOrthodeoxia in the Hepatopulmonary Syndrome\u003c/h2\u003e \u003cp\u003eIntrapulmonary vascular dilatations (IPVDs) are believed to cause the hypoxemia of HPS through a \u0026ldquo;diffusion-perfusion defect\u0026rdquo; (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). 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 \u0026ndash; which reduces available time for equilibration between the alveolar gas and the blood (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These IPVDs are often most prominent at lung bases (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Accordingly, due to the gravitational redistribution of blood flow to 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 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). A corresponding drop in partial pressure of arterial oxygen (PaO\u003csub\u003e2\u003c/sub\u003e) of greater than 5% or 4 mmHg in the upright compared to the supine position is called orthodeoxia (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This is often associated with a perception of increased dyspnea when upright called platypnea (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy rationale and purpose\u003c/h2\u003e \u003cp\u003eLimited 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. Previous 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 (\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), there is also reduced blood flow to the leg muscles (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), resulting in reduced muscle oxygen uptake, more profound muscle deoxygenation (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), and a lower anaerobic threshold (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) 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 forced vital capacity (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and alveolar ventilation (with an increase in partial pressure of end tidal CO\u003csub\u003e2\u003c/sub\u003e) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) in patients with chronic obstructive pulmonary disease (COPD), a failure to increase left ventricular ejection fraction in patients with hypertension (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), and ST segment depression possibly indicating a lower ischemic threshold in patients with coronary artery disease (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, positional effects on exercise in patients with HPS, and the unique impact of orthodeoxia have not been reported.\u003c/p\u003e \u003cp\u003eHerein, we seek to evaluate the effect of the supine position on exercise in HPS participants with orthodeoxia, compared to exercise in the upright position.\u003c/p\u003e \u003c/div\u003e "},{"header":"Methods And Design","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eObjective and hypothesis\u003c/h2\u003e\n\u003cp\u003eOur 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eTrial design\u003c/h2\u003e\n\u003cp\u003eThis will be a randomized controlled cross-over trial, conducted in the Canadian HPS Program [an HPS clinical and research program founded in 2005 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04004104\" target=\"_blank\"\u003ewww.hpscare.com\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e), consisting of sites in Toronto, Ontario (Unity Health Toronto and University Health Network), and Montreal, Quebec (Centre hospitalier de l'Universit\u0026eacute; de Montr\u0026eacute;al)]. Consenting participants (to be consented by independent research personnel; see Appendix 1 for Consent Form) will be randomized (through a random-number generator and with concealed allocation) to start with either a supine or upright exercise test on a bicycle ergometer. Subsequently, participants will complete the alternate test on a separate day, within 4 weeks of the first test (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants\u003c/h2\u003e\n\u003cp\u003eParticipants will be sequentially recruited from the Canadian HPS Program Database between late 2019 to approximately mid 2023 (including a pause due to SARS-COV-2 for much of 2020). Eligibility criteria are outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Eligibility Criteria\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"647\"\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Moderate HPS:\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Liver disease (evidence of synthetic liver dysfunction and/or portal hypertension on biochemistry and/or imaging)\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Moderate Hypoxemia\u003c/p\u003e\n\u003cul style=\"list-style-type: square;\"\u003e\n\u003cli\u003e\u0026sect;\u0026nbsp; PaO\u003csub\u003e2\u003c/sub\u003e \u0026lt; 80 mmHg and\u003c/li\u003e\n\u003cli\u003e\u0026sect;\u0026nbsp; AaDO\u003csub\u003e2\u003c/sub\u003e \u0026ge; 15 mmHg or \u0026ge; 20 mmHg if age \u0026gt; 64 (1)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Intrapulmonary vascular dilatations (microbubbles seen in the left heart \u0026ge; 3 cycles after the right heart on saline contrast echocardiography)\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Presence of orthodeoxia (PaO\u003csub\u003e2\u003c/sub\u003e decrease by \u0026gt; 4 mmHg when patient moves from supine to upright position)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Pulmonary hypertension\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Echocardiographic estimated right ventricular systolic pressure \u0026ge; 50 mmHg and/or\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Right heart catheterization mean pulmonary artery pressure \u0026gt; 25 mmHg with pulmonary capillary wedge pressure \u0026le; 15 mmHg\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Significant obstructive ventilatory impairment (FEV1/FVC ratio \u0026lt; 0.65) (14)\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Known significant coronary artery disease\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Significant neurologic, orthopedic or rheumatological disorders preventing use of a cycle ergometer\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Other absolute contraindications to submaximal exercise testing (27)\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Uncontrolled cardiac arrhythmia with hemodynamic compromise\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Symptomatic severe aortic stenosis\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Decompensated heart failure\u003c/p\u003e\n\u003cp\u003eo\u0026nbsp;\u0026nbsp; Acute cardiopulmonary illness (e.g. venous thromboembolism, myocarditis, pericarditis, endocarditis, acute aortic dissection)\u003c/p\u003e\n\u003cp\u003e\u0026middot;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Moderate or severe ascites\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e denotes partial pressure of arterial oxygen; FEV1/FVC denotes forced expiratory volume in one second over forced vital capacity; AaDO\u003csub\u003e2\u003c/sub\u003e denotes alveolar-arterial oxygen gradient [PAO\u003csub\u003e2\u003c/sub\u003e \u0026ndash; PaO\u003csub\u003e2\u003c/sub\u003e, where PAO\u003csub\u003e2\u003c/sub\u003e = [FiO\u003csub\u003e2\u003c/sub\u003e (P\u003csub\u003eatm\u003c/sub\u003e \u0026minus; P\u003csub\u003eH2O\u003c/sub\u003e) \u0026minus; PaCO\u003csub\u003e2\u003c/sub\u003e / 0.8] (AO\u003csub\u003e2\u003c/sub\u003e denotes partial pressure of alveolar oxygen; FIO\u003csub\u003e2\u003c/sub\u003e denotes inspiratory oxygen fraction; P\u003csub\u003eatm\u003c/sub\u003e denotes atmosphere pressure; P\u003csub\u003eH2O\u003c/sub\u003e denotes water vapor partial pressure; PaCO\u003csub\u003e2\u003c/sub\u003e denotes arterial carbon dioxide pressure)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eExercise protocol\u003c/h2\u003e\n\u003cp\u003eEach participant will perform a constant work rate exercise test (CWRET). The constant work rate will be individualized for each participant and set at 70\u0026ndash;85% of their estimated peak work rate (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), targeting an estimated test duration of 180\u0026ndash;480 seconds (to increase chances that exercise limitation is due to the physiologic effects of exercise rather than physical discomfort or boredom (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e)). Peak work rate will be estimated from a previous room air 6-minute walk test (6MWT) performed within the last 6 months (peak work rate\u0026thinsp;=\u0026thinsp;0.168 x 6MWD (m) \u0026ndash; 4.085) (\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe CWRET will include a warmup period consisting of 1 minute of rest followed by an immediate ramp-up to the predetermined target constant work rate (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e). 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 peddling frequency through a biofeedback display, along with standardized verbal encouragement throughout. For each participant, exercise in each position will be standardized with respect to the proper seat adjustment relative to leg length and pedaling cadence. Upright cycle ergometry will be performed on the Corival Ergometer Bicycle (LODE B.V. Medical Technology Groningen, Netherlands) at an angle of 90\u003csup\u003eo\u003c/sup\u003e. Supine cycle will be performed on the Stress EchoBed \u0026reg; (Medical Positioning Inc., USA) at an angle of 0\u003csup\u003eo\u003c/sup\u003e. For both tests, all measurements will take place through a pitot tube spirometer. Volume and flow calibrations (pitot tube spirometer) and gas calibration (Ergo Card Analyzer, Medisoft, USA) will be performed within 1 hour of the exercise test and Bio calibration will be performed on the pitot tube spirometer every 3 months.\u003c/p\u003e\n\u003cp\u003eInspiratory capacity will be measured before and after exercise. Before, after, and throughout exercise, we will measure: oxygen uptake (VO\u003csub\u003e2\u003c/sub\u003e) and carbon dioxide production (VCO\u003csub\u003e2\u003c/sub\u003e) (measured breath-by-breath, averaged over 30-second epochs); oxygen saturation and heart rate (continuously, by pulse oximetry and 12-lead electrocardiography, respectively); blood pressure (every 2 minutes, by manual sphygmomanometry); and subjective dyspnea and leg fatigue (every 1 minute, by modified Borg scale) (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e). 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.e. participant does not wish to continue or is unable to maintain a minimum peddling frequency of 40 rpm for \u0026ge;\u0026thinsp;10 seconds) [defined as the \u0026ldquo;tolerable limit\u0026rdquo; (tLIM)]; 2) desaturation below a set point for \u0026ge;\u0026thinsp;30 seconds; 3) a drop in systolic blood pressure by \u0026ge;\u0026thinsp;10 mmHg from baseline; or 4) the appearance of life-threatening arrhythmias (such as significant ventricular arrhythmias or high-grade heart block). The low saturation set point will be chosen individually for each participant, as the lower of 80% (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e), or the nadir desaturation seen on baseline room air 6MWT. If participants experience arrhythmic or hemodynamic-related stopping criteria on the first of the protocolized exercise tests, they will be excluded from the study and the second exercise test will not be attempted. Stopping time will be defined as the duration of pedaling during the constant workload exercise test before a stopping criterion was met.\u003c/p\u003e\n\u003cp\u003eParticipants will be reminded to bring running shoes and comfortable exercise clothes, to ensure that they have eaten before the test, to take all usual medications, and to avoid major exercise for 24 hours before the test. A physician with expertise in cardiopulmonary exercise testing will be in attendance for monitoring throughout test procedures.\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n\u003ch2\u003eOutcome measures\u003c/h2\u003e\n\u003cp\u003eExercise tests will be analyzed by a pulmonologist with experience in cardiopulmonary exercise test interpretation. This assessor will be masked to exercise position.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003ePrimary outcome measure\u003c/h2\u003e\n\u003cp\u003eThe primary outcome is 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.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eSecondary outcome measures\u003c/h2\u003e\n\u003cp\u003eSecondary outcomes will include differences in the following variables at isotime: oxygen uptake (VO\u003csub\u003e2\u003c/sub\u003e); minute ventilation (VE); work rate; heart rate (HR); arterial oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e); dyspnea; leg fatigue; change in inspiratory capacity; and carbon dioxide production (VCO\u003csub\u003e2\u003c/sub\u003e). We will also compare the reason for stopping exercise (leg fatigue, dyspnea, other) and maximum minute ventilation (VE\u003csub\u003emax\u003c/sub\u003e). In patients who reach anaerobic threshold (AT) in both positions, we will compare time to reach AT, and VO\u003csub\u003e2\u003c/sub\u003e, VE/VCO\u003csub\u003e2\u003c/sub\u003e, and cardiac output at AT in each position. Relationships between key variables will be compared graphically, including VCO\u003csub\u003e2\u003c/sub\u003e over VO\u003csub\u003e2\u003c/sub\u003e; HR over VO\u003csub\u003e2\u003c/sub\u003e; VE over VCO\u003csub\u003e2\u003c/sub\u003e; end tidal CO2 (PetCO\u003csub\u003e2\u003c/sub\u003e) over time; saturation over time; VE over time; VO\u003csub\u003e2\u003c/sub\u003e/HR (\u0026ldquo;oxygen pulse\u0026rdquo;) over time and HR over time. We will also conduct exploratory subgroup analyses, investigating the effects of baseline values such as PaO\u003csub\u003e2\u003c/sub\u003e and degree of orthodeoxia on exercise variables.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eRecruitment and power\u003c/h2\u003e\n\u003cp\u003eGiven that HPS is a rare disease and a majority of patients progress to either liver transplant or death relatively soon after diagnosis (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e), recruitment to prospective trials in HPS has previously proven very challenging (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e). Our recruitment will be further limited by the fact that only a subset of patients with HPS have orthodeoxia.\u003c/p\u003e\n\u003cp\u003eAccordingly, 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. To estimate feasible recruitment, we searched the literature for studies describing the prevalence of orthodeoxia in cohorts of \u0026ge;\u0026thinsp;10 HPS patients. However, we found only 4 small reports (14\u0026ndash;20 patients each) reporting a highly variable prevalence of orthodeoxia, ranging from 14\u0026ndash;88% of HPS participants (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of Orthodeoxia in Patients with Hepatopulmonary Syndrome\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr style=\"height: 54px;\"\u003e\n\u003cth style=\"height: 54px;\" align=\"left\"\u003e\n\u003cp\u003eAuthor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 54px;\" align=\"left\"\u003e\n\u003cp\u003eMean Upright \u0026dagger; PaO\u003csub\u003e2\u003c/sub\u003e (mmHg)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 54px;\" align=\"left\"\u003e\n\u003cp\u003ePrevalence of Orthodeoxia\u0026Dagger;, N (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 54px;\" align=\"left\"\u003e\n\u003cp\u003eMean Room air PaO\u003csub\u003e2\u003c/sub\u003e in patients with Orthodeoxia (mmHg) (SD)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 54px;\" align=\"left\"\u003e\n\u003cp\u003eOrthodeoxia (supine PaO\u003csub\u003e2\u003c/sub\u003e - upright PaO\u003csub\u003e2\u003c/sub\u003e; mmHg)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eKrowka, et al., 1993 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e44.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e14/16 (87.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eUpright: 44.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e\n\u003cp\u003eSupine: 62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e18.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eMartinez, et al., 1999 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e65.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e2/5 (40.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eUpright: 51.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e\n\u003cp\u003eSupine: 61.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e10.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eMartinez, et al., 2001 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e75.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e2/14 (14.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eUpright: 63.5\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e\n\u003cp\u003eSupine: 71.5\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e8.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eGomez, et al., 2004 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e69.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e5/20 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eUpright: 59.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n\u003cp\u003eSupine: 67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e8.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eCurrent Study\u003cstrong\u003e*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e51.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e37/56 (66.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"left\"\u003e\n\u003cp\u003eUpright: 48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n\u003cp\u003eSupine: 61.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e13.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr style=\"height: 29.1875px;\"\u003e\n\u003ctd style=\"height: 29.1875px;\" colspan=\"5\"\u003e\u003cstrong\u003e*\u003c/strong\u003e Analysis performed in patients at the Toronto site of the Canadian HPS Database with a PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;80 mmHg, absence of significant concurrent lung disease contributing to hypoxemia, and absence of concurrent portopulmonary hypertension.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13px;\"\u003e\n\u003ctd style=\"height: 13px;\" colspan=\"5\"\u003e\n\u003cp\u003e\u0026dagger;All studies defined \u0026ldquo;upright\u0026rdquo; as the sitting position, except Krowka 1993 (\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e) and the current study, which defined it as the standing position.\u003c/p\u003e\n\u003cp\u003e\u0026Dagger; All studies defined orthodeoxia as a drop in partial pressure of arterial oxygen (PaO\u003csub\u003e2\u003c/sub\u003e) of greater than 5% or 4 mmHg in the upright compared to the supine position, except Martinez 1999 (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e), which defined it as a drop in PaO\u003csub\u003e2\u003c/sub\u003e\u0026nbsp;greater than 10 mmHg in the upright compared to the supine position.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eWe hypothesized that these variations in prevalence may have been due to 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 significant 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. Factors including baseline PaO\u003csub\u003e2\u003c/sub\u003e, etiology of liver disease, age, VO\u003csub\u003e2\u003c/sub\u003e, minute ventilation, and diffusion lung capacity of carbon monoxide (DLCO) were not significant predictors (\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eGiven 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. A priori, we identified the following candidate baseline predictors: age, sex, PaO\u003csub\u003e2\u003c/sub\u003e, MELD score, DLCO, macroaggregated albumin (MAA) shunt fraction, 6MWD, and presence of clubbing. We found that 37 out of 56 patients (66%) had orthodeoxia. In univariate analyses, lower baseline upright PaO\u003csub\u003e2\u003c/sub\u003e and DLCO were significant predictors of orthodeoxia in HPS (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDifferences in Baseline Clinical Characteristics Between Hepatopulmonary Syndrome Patients With and Without Orthodeoxia (Current Cohort)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo Orthodeoxia\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOrthodeoxia\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003cp\u003e63.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003cp\u003e60.4\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.302\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex \u0026ndash; male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (44.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (59.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.294\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMELD score\u003cstrong\u003e*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003cp\u003e14.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36\u003c/p\u003e\n\u003cp\u003e12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.144\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDLCO (% predicted)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003cp\u003e64.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003cp\u003e50.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMAA Shunt Fraction (%) (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e17.2\u0026thinsp;\u0026plusmn;\u0026thinsp;23.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003cp\u003e22.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.551\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eShunt Fraction on 100% FiO\u003csub\u003e2\u003c/sub\u003e (%) (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003cp\u003e14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.571\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6MWD (meters)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003cp\u003e418.6\u0026thinsp;\u0026plusmn;\u0026thinsp;109.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e441.8\u0026thinsp;\u0026plusmn;\u0026thinsp;147.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.715\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClubbing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (63.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (61.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.882\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e (upright) (mmHg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003cp\u003e59.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003cp\u003e48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003cstrong\u003e*\u003c/strong\u003e MELD score denotes model for end-stage liver disease score; DLCO denotes diffusion lung capacity for carbon monoxide; MAA denotes macroaggregated albumin; FiO\u003csub\u003e2\u003c/sub\u003e denotes fraction of inspired oxygen; 6MWD denotes 6-minute walk distance; PaO\u003csub\u003e2\u003c/sub\u003e denotes partial pressure of arterial oxygen. N denotes total number of participants; SD denotes standard deviation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u0026dagger; Univariate analyses are presented for each variable; continuous variables assessed with a 2-sample t- test and categorical variables with a chi-squared test; Variables were assessed on the same day as orthodeoxia, or within an interval of \u0026le;\u0026thinsp;1 year.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTo our knowledge, this is by far the largest analysis of both the prevalence and risk factors for orthodeoxia in HPS. Given that patients with orthodeoxia had more severe hypoxemia, it was not surprising that our more \u0026ldquo;severe\u0026rdquo; HPS cohort (compared to other reports) had a high observed orthodeoxia prevalence of 66.1% (Table 3). We complimented this with an analysis of our current active HPS database, revealing that six patients currently meet inclusion criteria. Additionally, a review of referrals in the last 3 years reveals that an average of 4 eligible patients are referred to our program each year. Based on a pessimistic recruitment target of 50%, this analysis of the Canadian HPS Program Database suggests that we will be able to recruit 10 eligible participants to this study in the 4-year recruitment window allowed by study funding.\u003c/p\u003e\n\u003cp\u003eA crossover design has previously been successfully employed in patients with HPS (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). The advantage of the crossover design 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 (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e). The crossover design is well-suited to an exercise intervention because there is no anticipated therapeutic carryover effect, obviating the need for a washout (we allowed for a 1 day minimum \u0026ldquo;washout\u0026rdquo; period for recovery from the prior exercise test). We established a 4-week maximum period between tests to minimize any possible period effect (i.e. to prevent significant disease progression by the time of the second test). The possibility of a period effect due to familiarity with the cycling exercise will be evaluated statistically.\u003c/p\u003e\n\u003cp\u003eCalculating 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 design, 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 design to evaluate the effect of hyperoxia (which has a similar physiologic impact to supine position in our cohort) on CWRET stopping time (\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e), 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 significantly with hyperoxia compared to room air (21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9 versus 11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0 minutes, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e), with a pooled standard deviation for change in exercise duration of 11.5 minutes. Applying this standard deviation, our crossover trial with a target sample size of 10 participants will be able to detect a difference of \u0026ge;\u0026thinsp;2.85 minutes between the two interventions with power of 80% and a two-sided alpha of 0.05.\u003c/p\u003e\n\u003cp\u003eAn increase in exercise time of 2.85 minutes is clinically meaningful in other hypoxemic diseases. In COPD, the minimal clinically important difference (MCID) for tLIM on CWRET is an increase of 33% or 105 seconds from baseline (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e). Bronchodilator trials suggest that clinical outcome improvements correspond to tLIM improvements of \u0026gt;\u0026thinsp;60 seconds (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e). Accordingly, an improvement of 2.85 minutes (171 seconds) would likely be clinically significant in our participants, who have more severe baseline exercise limitation than typical patients with COPD. With an estimated upright test duration of 3\u0026ndash;8 minutes in our design (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e), a change of 2.85 minutes would represent an improvement of between 36%-95%, which again suggests a clinically meaningful improvement.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eContinuous variables will be reported as mean (median) +/- standard deviation; and categorical variables will be reported as proportions or percentages. 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 account for the carry-over effect. Relationships between variables and between baseline characteristics and exercise test results will be explored with parametric or non-parametric tests of correlation, as appropriate. We will also test for period and carryover effects. The significance level (\u0026alpha;) will be set at \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eOur 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 use of a CWRET protocol in a cohort with this disease. Given the novelty of our research question and approach, development of this study posed a number of unique challenges and opportunities which merit discussion.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population and Design\u003c/h2\u003e \u003cp\u003eWe chose to include patients with at least moderate HPS (PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;80 mmHg), in order to ensure that the degree of observed orthodeoxia is both clinically and physiologically significant. Tissue oxygen delivery (DO\u003csub\u003e2\u003c/sub\u003e), which 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\u003csub\u003e2\u003c/sub\u003e through the sigmoidal oxyhemoglobin dissociation curve. Given the flat shape of this curve at higher PaO\u003csub\u003e2\u003c/sub\u003e levels, changes in PaO\u003csub\u003e2\u003c/sub\u003e of just over 4 mmHg (the definition of orthodeoxia) would not result in any significant changes in oxygen saturation in patients with a baseline PaO2\u0026thinsp;\u0026ge;\u0026thinsp;80 mmHg.\u003c/p\u003e \u003cp\u003eOur use of a CWRET protocol is novel in this population, as prior studies of exercise testing in HPS (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) have almost exclusively employed incremental exercise protocols (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Given the severe baseline disease in our expected patient population (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), with a predicted mean PaO\u003csub\u003e2\u003c/sub\u003e drop of 20 mmHg at peak exercise (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), we believe that an incremental exercise protocol would result in profound desaturation requiring cessation for safety reasons, with a high resulting likelihood of a submaximal test. Accordingly, the main variable of interest in an incremental exercise protocol - VO\u003csub\u003e2peak\u003c/sub\u003e, would not likely be achieved in most participants. To address this, we chose a high-intensity CWRET, which has been widely used to assess changes in exercise tolerance following interventions in other chronic hypoxemic lung diseases (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe constant work rate in a CWRET is typically set at 70\u0026ndash;85% of peak work rate measured on incremental exercise testing (IET) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). 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-minute walk distance (6MWD) in patients with COPD (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Given that peak work rate is affected by ventilatory impairment and dynamic hyperinflation in COPD, neither of which appear to play a role in HPS, this represents a vulnerability in our testing protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eThe primary outcome in our study is stopping time, as determined by either reaching tLim or experiencing desaturation to our pre-set safety stopping criterion, which is the lower of 80% or the nadir desaturation seen on room air 6MWT. There have been no reports of adverse events while performing CWRET (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). While there is no definitive threshold at which arterial desaturation becomes hazardous (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), cardiopulmonary exercise testing (CPET) guidelines from the American Thoracic Society and American College of Chest Physicians suggest a saturation of \u0026le;\u0026thinsp;80% (with accompanying signs and symptoms of severe hypoxemia) as one of the indications for exercise termination (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). However, patients with HPS are well adapted to hypoxemia (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These patients often present after a prolonged period of undiagnosed hypoxemia and are encouraged to exercise to preserve muscle mass despite significant exercise desaturation (which occurs even with oxygen supplementation) (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Furthermore, many patients who require oxygen do not use it at all times (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Accordingly, and because many patients in our severe population would desaturate to 80% at rest or with minimal exertion while upright, we added an individualized stopping criterion set at the nadir desaturation experienced on room air 6MWT. This novel approach will enable patients with severe disease to perform a sufficient amount of exercise for positional differences to be detectable and given that it likely reflects a level of desaturation that patients typically experience in their daily lives, will maintain a reasonable margin of safety.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eClinical relevance of the potential results\u003c/h2\u003e \u003cp\u003eExercise has been shown to have numerous health benefits, ranging from reducing the risk of heart disease, stroke, osteoporosis, diabetes, and cancer, to improving mental health (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). Unfortunately, patients with HPS are unable to realize the short- or long-term (training) benefits of exercise due to severe exercise limitation caused by hypoxemia. If our hypothesis proves correct, a supine exercise protocol would empower these patients to exercise for longer periods of time. Furthermore, supine exercise could enable a more effective long-term exercise training program. Exercise training results in improvements in exercise capacity, including maximum oxygen uptake (VO\u003csub\u003e2max\u003c/sub\u003e), VO\u003csub\u003e2peak\u003c/sub\u003e, and muscle mass in patients with cirrhosis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). This could be particularly impactful for patients with HPS awaiting liver transplant, given that this is the only treatment for HPS, and that pre-transplant exercise capacity predicts post-transplant survival (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Every 100- meter increase in baseline 6MWD is associated with a 52% reduction in 1-year post-transplant mortality (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e), and preoperative exercise capacity independently predicts respiratory complications post-liver transplant (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Furthermore, the median liver transplant wait time in severe HPS is 200 days (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e), and these patients experience progressive hypoxemia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), resulting in worsening exercise limitation while awaiting transplant. It is also of note that the HPS patients being targeted by this intervention \u0026ndash; those with orthodeoxia \u0026ndash; tend to have a lower baseline PaO\u003csub\u003e2\u003c/sub\u003e and are thus more likely to require a liver transplant for HPS.\u003c/p\u003e \u003cp\u003eIf positive, this study will establish the efficacy of supine exercise in this population, enabling this to become a routine part of HPS management, including in non-transplant and pre-transplant settings. This evidence would be required to justify the cost and complexity of a supine exercise prescription. Our results would warrant future studies investigating the long-term physiologic and clinical benefits of a supine exercise training program in HPS, including effects on patient-relevant outcomes such as quality of life, dyspnea, and liver transplant outcomes. Our data suggest that two thirds of patients with at least moderate HPS have orthodeoxia, representing a significant population of patients (particularly, those with the most severe disease) that could stand to benefit. We also believe that findings from our unique exercise protocol will advance understanding of the physiology of this disease and lay the foundations for larger future studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eIt is important to note that our findings will only be applicable to patients with HPS who have orthodeoxia. As noted, 66% of patients with at least moderate HPS had orthodeoxia in our cohort, but smaller studies have reported an orthodeoxia prevalence as low as 14% (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) in all-comers with HPS, and this requires further study. We also note that while orthodeoxia is measured in the supine versus the standing position, the upright bicycle exercise protocol more closely simulates sitting than standing, and prior reports have suggested that orthodeoxia is less pronounced in the sitting compared to the standing position (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). A smaller positional change in PaO\u003csub\u003e2\u003c/sub\u003e could reduce the predicted effect of position on exercise capacity.\u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eTrial Status\u003c/h2\u003e\n\u003cp\u003eProtocol version #3, version date 27 August 2019. Enrollment into the trial has started and is expected to be finalized by approximately December 1, 2022.\u003c/p\u003e "},{"header":"List Of Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHepatopulmonary syndrome; VO2\u003csub\u003epeak\u003c/sub\u003e:Peak oxygen consumption; IPVDs:Intrapulmonary vascular dilatations; PaO\u003csub\u003e2\u003c/sub\u003e:Partial pressure of arterial oxygen; COPD:Chronic obstructive pulmonary disease; FEV1/FVC:Forced expiratory volume in one second over forced vital capacity; AaDO2:Alveolar-arterial oxygen gradient; AO\u003csub\u003e2\u003c/sub\u003e:Partial pressure of alveolar oxygen; P\u003csub\u003eatm\u003c/sub\u003e:Atmosphere pressure; P\u003csub\u003eH2O\u003c/sub\u003e:Water vapor partial pressure; PaCO\u003csub\u003e2\u003c/sub\u003e:Arterial carbon dioxide pressure; CWRET:Constant work rate exercise test; 6MWT:Six minute walk test; RPM:Revolutions per minute; tLIM:Tolerable limit; VO\u003csub\u003e2\u003c/sub\u003e:Oxygen uptake; VE:Minute ventilation; HR:Heart rate; SpO\u003csub\u003e2\u003c/sub\u003e:Arterial oxygen saturation; VCO\u003csub\u003e2\u003c/sub\u003e:Carbon dioxide production; VE\u003csub\u003emax\u003c/sub\u003e:Maximum minute ventilation; AT:Anaerobic threshold; DLCO:Diffusion lung capacity of carbon monoxide; MELD:model for end-stage liver disease score; MAA:macroaggregated albumin; FiO\u003csub\u003e2\u003c/sub\u003e:fraction of inspired oxygen; 6MWD:Six minute walk distance; SD:Standard deviation; MCID:Minimal clinically important difference; DO\u003csub\u003e2\u003c/sub\u003e:Tissue oxygen delivery; IET:Incremental exercise testing; CPET:Cardiopulmonary exercise testing; VO\u003csub\u003e2max\u003c/sub\u003e:maximum oxygen uptake.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe study was reviewed and approved by the Research Ethics Board at Unity Health Toronto (REB #19-127).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eConsent for publication\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data will be presented as a mean or median. No individual data will be included in the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study will be made available by the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be funded by the Michael Locke Term Chair in Knowledge Translation and Rare Lung Disease Research. The funder had no role in the conception or design of this protocol and will have no role in data analysis or study publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAuthors\u0026rsquo; contributions\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHP, EL, SG, MEF, AAH: Study conception and design. HP, EL, SS, SG: Acquisition of data.\u003c/p\u003e\n\u003cp\u003eHP, EL, SG, MEF: Analysis and interpretation of data. HP, EL, SG: Drafting of the manuscript.\u003c/p\u003e\n\u003cp\u003eHP, EL, SS, MEF, AAH, SG: Critical revision of the manuscript for important intellectual content. HP, EL, SG: Statistical analysis. SG: Obtained funding. SS, SG: Administrative, technical, or material support. SG: Study supervision. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Jenna Sykes for statistical advice, and Eva Leek and Dejan Lukic for operational advice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAuthors\u0026rsquo; Information\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eLi Ka Shing Knowledge Institute, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. \u003csup\u003e2\u003c/sup\u003e Department of Medicine, University of Toronto, Canada. \u003csup\u003e3\u003c/sup\u003eDivision of Respirology, St. Michael's Hospital, Toronto, Canada. \u003csup\u003e4\u003c/sup\u003eDivision of Cardiology, St Michael's Hospital, Toronto, Canada. \u003csup\u003e*\u003c/sup\u003eThese authors contributed equally to this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKrowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, et al. 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J Hepatol. 2001;34(5):651-7.\u003c/li\u003e\n\u003cli\u003eGomez FP, Martinez-Palli G, Barbera JA, Roca J, Navasa M, Rodriguez-Roisin R. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology. 2004;40(3):660-6.\u003c/li\u003e\n\u003cli\u003eAbrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB. Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology. 1998;114(2):305-10.\u003c/li\u003e\n\u003cli\u003eSarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017;34(1):47-60.\u003c/li\u003e\n\u003cli\u003eGupta S, Faughnan ME, Tomlinson GA, Bayoumi AM. A framework for applying unfamiliar trial designs in studies of rare diseases. J Clin Epidemiol. 2011;64(10):1085-94.\u003c/li\u003e\n\u003cli\u003eSchaeffer MR, Ryerson CJ, Ramsook AH, Molgat-Seon Y, Wilkie SS, Dhillon SS, et al. Effects of hyperoxia on dyspnoea and exercise endurance in fibrotic interstitial lung disease. Eur Respir J. 2017;49(5).\u003c/li\u003e\n\u003cli\u003eKirkham AA, Pauhl KE, Elliott RM, Scott JA, Doria SC, Davidson HK, et al. Utility of Equations to Estimate Peak Oxygen Uptake and Work Rate From a 6-Minute Walk Test in Patients With COPD in a Clinical Setting. J Cardiopulm Rehabil Prev. 2015;35(6):431-8.\u003c/li\u003e\n\u003cli\u003eGibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8):1531-40.\u003c/li\u003e\n\u003cli\u003eAmerican Thoracic S, American College of Chest P. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003;167(2):211-77.\u003c/li\u003e\n\u003cli\u003eGupta S, Castel H, Rao RV, Picard M, Lilly L, Faughnan ME, et al. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am J Transplant. 2010;10(2):354-63.\u003c/li\u003e\n\u003cli\u003eKhan AN, Al-Jahdali H, Abdullah K, Irion KL, Sabih Q, Gouda A. Pulmonary vascular complications of chronic liver disease: Pathophysiology, imaging, and treatment. Ann Thorac Med. 2011;6(2):57-65.\u003c/li\u003e\n\u003cli\u003eBender BG. Nonadherence in chronic obstructive pulmonary disease patients: what do we know and what should we do next? Curr Opin Pulm Med. 2014;20(2):132-7.\u003c/li\u003e\n\u003cli\u003eFentem PH. ABC of sports medicine. Benefits of exercise in health and disease. BMJ. 1994;308(6939):1291-5.\u003c/li\u003e\n\u003cli\u003eCampillo B FP, Bonnet JC, Atlan G. Submaximal oxygen consumption in liver cirrhosis. Evidence of severe functional aerobic impairment. J Hepatol 1990:163-7.\u003c/li\u003e\n\u003cli\u003eRitland S PC, Knudsen T, Skrede S. 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Am Rev Respir Dis. 1989;140(6):1631-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hepatopulmonary syndrome, Orthodeoxia, Exercise limitation, Randomized crossover control study, Tolerable limit, Liver transplantation. ","lastPublishedDoi":"10.21203/rs.3.rs-308658/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-308658/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis and characterized by intrapulmonary vascular dilatations and abnormal oxygenation. Liver transplantation is the only effective therapy for this disease. Patients with HPS have significant exercise limitation, 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.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We propose a randomized controlled cross-over trial in patients with HPS and orthodeoxia, comparing the effect of supine versus upright position on exercise. Participants will be randomized to cycle ergometry in either the supine or upright position, followed by a crossover to the alternate position after a minimum of 1 day to a maximum of 4 weeks. Exercise will be performed at a constant work rate of 70-85% of the predicted peak work rate until the “stopping time” is reached, defined by exhaustion, profound desaturation, or safety concerns (drop in systolic blood pressure or life-threatening arrhythmia). The primary outcome will be the difference in stopping time between exercise positions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e: HPS patients have hypoxemia leading to significant exercise limitation. 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.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: The ClinicalTrials.gov Protocol Registration and Results System (PRS): NCT04004104. Registered on 1\u003csup\u003est\u003c/sup\u003e July 2019. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04004104\" rel=\"noopener noreferrer\" target=\"_blank\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04004104\u003c/a\u003e\u003c/p\u003e","manuscriptTitle":"Supine Versus Upright Exercise in Patients With Hepatopulmonary Syndrome and Orthodeoxia: Study Protocol for a Randomized Controlled Crossover Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-10 13:56:10","doi":"10.21203/rs.3.rs-308658/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2021-05-07T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-05-07T00:00:00+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2021-04-28T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2021-03-08T00:27:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83bbc05b-7cd5-46c0-8e4c-a046cd48b9b1","owner":[],"postedDate":"May 10th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":4187461,"name":"Translational Medicine"},{"id":4187462,"name":"Internal Medicine"},{"id":4187463,"name":"Integrative \u0026 Complementary Medicine"}],"tags":[],"updatedAt":"2021-08-26T06:59:55+00:00","versionOfRecord":[],"versionCreatedAt":"2021-05-10 13:56:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-308658","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-308658","identity":"rs-308658","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}