{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:17:04Z","timestamp":1764260224535},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Michael Locke Term Chair in Knowledge Translation and Rare Lung Disease Research"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease found in 10 to 32% of patients with cirrhosis and is characterized by intrapulmonary vascular dilatations and abnormal oxygenation. Liver transplantation is the only effective therapy for this disease. Patients with HPS have significant exercise limitations, impacting their quality of life and associated with poor liver transplant outcomes. Many patients with HPS exhibit orthodeoxia\u2014an 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We propose a randomized controlled crossover trial in patients with moderate HPS (PaO<jats:sub>2<\/jats:sub>&lt; 80\u2009mmHg) and orthodeoxia (supine to upright PaO<jats:sub>2<\/jats:sub>decrease &gt;\u20094\u2009mmHg) comparing the effect of supine vs upright position on exercise. Patients with pulmonary hypertension, FEV1\/FVC ratio &lt; 0.65, significant coronary artery disease, disorders preventing or contraindicating use of a cycle ergometer, and\/or moderate or severe ascites will be excluded. Participants will be randomized to cycle ergometry in either the supine or upright position. After a short washout period (a minimum of 1\u2009day to a maximum of 4\u2009weeks), participants will crossover and perform an exercise in the alternate position. Exercise will be performed at a constant work rate of 70\u201385% of the predicted peak work rate until the \u201cstopping time\u201d 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 the stopping time between exercise positions, compared with a repeated measures analysis of variance method with a mixed effects model approach. The model will be adjusted for period effects.<jats:italic>P<\/jats:italic>&lt; 0.05 will be considered statistically significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>HPS patients have hypoxemia leading to significant exercise limitations. 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>Protocol Registration and Results System (PRS)<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04004104\">NCT04004104<\/jats:ext-link>. Registered on 1 July 2019<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13063-021-05633-7","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T18:07:46Z","timestamp":1633889266000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Supine vs upright exercise in patients with hepatopulmonary syndrome and orthodeoxia: study protocol for a randomized controlled crossover trial"],"prefix":"10.1186","volume":"22","author":[{"given":"Harsh","family":"Parikh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Lui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie E.","family":"Faughnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul","family":"Al-Hesayen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Segovia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,9]]},"reference":[{"issue":"7","key":"5633_CR1","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1097\/TP.0000000000001229","volume":"100","author":"MJ Krowka","year":"2016","unstructured":"Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, et al. International Liver Transplant Society Practice Guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation. 2016;100(7):1440\u201352. https:\/\/doi.org\/10.1097\/TP.0000000000001229.","journal-title":"Transplantation."},{"issue":"2","key":"5633_CR2","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1002\/lt.20016","volume":"10","author":"MJ Krowka","year":"2004","unstructured":"Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, Manzarbeitia C, et al. Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database. Liver Transpl. 2004;10(2):174\u201382. https:\/\/doi.org\/10.1002\/lt.20016.","journal-title":"Liver Transpl."},{"issue":"5","key":"5633_CR3","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1002\/hep.20658","volume":"41","author":"KL Swanson","year":"2005","unstructured":"Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepatopulmonary syndrome: Impact of liver transplantation. Hepatology. 2005;41(5):1122\u20139. https:\/\/doi.org\/10.1002\/hep.20658.","journal-title":"Hepatology."},{"issue":"2","key":"5633_CR4","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1002\/lt.22472","volume":"18","author":"JC Jones","year":"2012","unstructured":"Jones JC, Coombes JS, Macdonald GA. Exercise capacity and muscle strength in patients with cirrhosis. Liver Transpl. 2012;18(2):146\u201351. https:\/\/doi.org\/10.1002\/lt.22472.","journal-title":"Liver Transpl."},{"issue":"3","key":"5633_CR5","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1590\/0103-5150.028.003.AR02","volume":"28","author":"RLTB Kr\u00fcger","year":"2015","unstructured":"Kr\u00fcger RLTB, Dias AS, Reischak-Oliveira \u00c1. The influence that hepatic cirrhosis provides in exercise capacity and muscle strength: a review. Fisioter em Mov. 2015;28(3):617\u201325. https:\/\/doi.org\/10.1590\/0103-5150.028.003.AR02.","journal-title":"Fisioter em Mov."},{"issue":"5","key":"5633_CR6","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.dld.2012.09.022","volume":"45","author":"M Lemyze","year":"2013","unstructured":"Lemyze M, Dharancy S, Wallaert B. Response to exercise in patients with liver cirrhosis: implications for liver transplantation. Dig Liver Dis. 2013;45(5):362\u20136. https:\/\/doi.org\/10.1016\/j.dld.2012.09.022.","journal-title":"Dig Liver Dis."},{"issue":"3","key":"5633_CR7","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1378\/chest.114.3.736","volume":"114","author":"SK Epstein","year":"1998","unstructured":"Epstein SK, Zilberberg MD, Jacoby C, Ciubotaru RL, Kaplan LM. Response to symptom-limited exercise in patients with the hepatopulmonary syndrome. Chest. 1998;114(3):736\u201341. https:\/\/doi.org\/10.1378\/chest.114.3.736.","journal-title":"Chest."},{"issue":"3","key":"5633_CR8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.ijcard.2004.06.011","volume":"102","author":"S Nusair","year":"2005","unstructured":"Nusair S, Eid A, Bardach E, Berkman N. Resolving impaired response to exercise in hepatopulmonary syndrome after liver transplantation. Int J Cardiol. 2005;102(3):533\u20135. https:\/\/doi.org\/10.1016\/j.ijcard.2004.06.011.","journal-title":"Int J Cardiol."},{"issue":"1","key":"5633_CR9","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0168-8278(98)80182-7","volume":"29","author":"MK Whyte","year":"1998","unstructured":"Whyte MK, Hughes JM, Peters AM, Ussov W, Patel S, Burroughs AK. Analysis of intrapulmonary right to left shunt in the hepatopulmonary syndrome. J Hepatol. 1998;29(1):85\u201393. https:\/\/doi.org\/10.1016\/S0168-8278(98)80182-7.","journal-title":"J Hepatol."},{"issue":"4","key":"5633_CR10","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1053\/j.gastro.2008.06.038","volume":"135","author":"MB Fallon","year":"2008","unstructured":"Fallon MB, Krowka MJ, Brown RS, Trotter JF, Zacks S, Roberts KE, et al. Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates. Gastroenterology. 2008;135(4):1168\u201375. https:\/\/doi.org\/10.1053\/j.gastro.2008.06.038.","journal-title":"Gastroenterology."},{"issue":"6","key":"5633_CR11","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1183\/09031936.93.05060754","volume":"5","author":"JB Thorens","year":"1992","unstructured":"Thorens JB, Junod AF. Hypoxaemia and liver cirrhosis: a new argument in favour of a \u201cdiffusion-perfusion defect\u201d. Eur Respir J. 1992;5(6):754\u20136.","journal-title":"Eur Respir J."},{"issue":"3","key":"5633_CR12","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/S1665-2681(19)31276-1","volume":"14","author":"JL Faustini-Pereira","year":"2015","unstructured":"Faustini-Pereira JL, Homercher-Galant L, Garcia E, de Mello Brandao AB, Marroni CA. Exercise capacity of cirrhotic patients with hepatopulmonary syndrome. Ann Hepatol. 2015;14(3):361\u20138. https:\/\/doi.org\/10.1016\/S1665-2681(19)31276-1.","journal-title":"Ann Hepatol."},{"issue":"25","key":"5633_CR13","doi-asserted-by":"publisher","first-page":"5728","DOI":"10.3748\/wjg.v22.i25.5728","volume":"22","author":"I Grilo-Bensusan","year":"2016","unstructured":"Grilo-Bensusan I, Pascasio-Acevedo JM. Hepatopulmonary syndrome: what we know and what we would like to know. World J Gastroenterol. 2016;22(25):5728\u201341. https:\/\/doi.org\/10.3748\/wjg.v22.i25.5728.","journal-title":"World J Gastroenterol."},{"issue":"10","key":"5633_CR14","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3390\/jcm5100085","volume":"5","author":"R De Vecchis","year":"2016","unstructured":"De Vecchis R, Baldi C, Ariano C. Platypnea-orthodeoxia syndrome: multiple pathophysiological interpretations of a clinical picture primarily consisting of orthostatic dyspnea. J Clin Med. 2016;5(10):85.","journal-title":"J Clin Med"},{"issue":"4","key":"5633_CR15","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1093\/bja\/aem036","volume":"98","author":"I Galvin","year":"2007","unstructured":"Galvin I, Drummond GB, Nirmalan M. Distribution of blood flow and ventilation in the lung: gravity is not the only factor. Br J Anaesth. 2007;98(4):420\u20138. https:\/\/doi.org\/10.1093\/bja\/aem036.","journal-title":"Br J Anaesth."},{"issue":"3","key":"5633_CR16","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1161\/01.CIR.62.3.528","volume":"62","author":"LR Poliner","year":"1980","unstructured":"Poliner LR, Dehmer GJ, Lewis SE, Parkey RW, Blomqvist CG, Willerson JT. Left ventricular performance in normal subjects: a comparison of the responses to exercise in the upright and supine positions. Circulation. 1980;62(3):528\u201334. https:\/\/doi.org\/10.1161\/01.CIR.62.3.528.","journal-title":"Circulation."},{"issue":"2","key":"5633_CR17","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1161\/01.RES.58.2.281","volume":"58","author":"MB Higginbotham","year":"1986","unstructured":"Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res. 1986;58(2):281\u201391. https:\/\/doi.org\/10.1161\/01.RES.58.2.281.","journal-title":"Circ Res."},{"issue":"1","key":"5633_CR18","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/0002-9149(78)90131-5","volume":"41","author":"U Thadani","year":"1978","unstructured":"Thadani U, Parker JO. Hemodynamics at rest and during supine and sitting bicycle exercise in normal subjects. Am J Cardiol. 1978;41(1):52\u20139. https:\/\/doi.org\/10.1016\/0002-9149(78)90131-5.","journal-title":"Am J Cardiol."},{"issue":"1","key":"5633_CR19","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1589\/jpts.7.33","volume":"7","author":"T Takahashi","year":"1995","unstructured":"Takahashi T, Tanabe K, Nakayama M, Osada N, Yamada S, Ishiguro T, et al. Cardiopulmonary response during supine and sitting bicycle exercise. J Phys Ther Sci. 1995;7(1):33\u20138. https:\/\/doi.org\/10.1589\/jpts.7.33.","journal-title":"J Phys Ther Sci"},{"issue":"2","key":"5633_CR20","first-page":"254","volume":"5","author":"R Denis","year":"2006","unstructured":"Denis R, Perrey S. Influence of posture on pulmonary O2 uptake kinetics, mucsle deoxygenation and myolectrical activity during heavy-intensity exercise. Journal of Sports Science and Medicine. 2006;5(2):254\u201365.","journal-title":"Journal of Sports Science and Medicine"},{"issue":"4","key":"5633_CR21","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1152\/japplphysiol.00890.2019","volume":"128","author":"BA Ross","year":"2020","unstructured":"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\u201333.","journal-title":"J Appl Physiol (1985)"},{"issue":"1","key":"5633_CR22","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0002-9149(99)80802-9","volume":"76","author":"DS Schulman","year":"1995","unstructured":"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\u20135. https:\/\/doi.org\/10.1016\/S0002-9149(99)80802-9.","journal-title":"Am J Cardiol."},{"issue":"2","key":"5633_CR23","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/0735-1097(88)90098-8","volume":"11","author":"JN Wetherbee","year":"1988","unstructured":"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\u20137. https:\/\/doi.org\/10.1016\/0735-1097(88)90098-8.","journal-title":"J Am Coll Cardiol."},{"issue":"8","key":"5633_CR24","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1161\/CIR.0b013e31829b5b44","volume":"128","author":"GFAP Fletcher","year":"2013","unstructured":"Fletcher GFAP, Kligfield P, et al. Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation. 2013;128(8):873\u2013934. https:\/\/doi.org\/10.1161\/CIR.0b013e31829b5b44.","journal-title":"Circulation."},{"issue":"2","key":"5633_CR25","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1183\/09031936.00078308","volume":"34","author":"L Puente-Maestu","year":"2009","unstructured":"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\u20135. https:\/\/doi.org\/10.1183\/09031936.00078308.","journal-title":"Eur Respir J."},{"issue":"2","key":"5633_CR26","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1183\/13993003.00745-2015","volume":"47","author":"L Puente-Maestu","year":"2016","unstructured":"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\u201360. https:\/\/doi.org\/10.1183\/13993003.00745-2015.","journal-title":"Eur Respir J."},{"issue":"4","key":"5633_CR27","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1111\/j.1440-1843.2010.01744.x","volume":"15","author":"R Kozu","year":"2010","unstructured":"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\u201313. https:\/\/doi.org\/10.1111\/j.1440-1843.2010.01744.x.","journal-title":"Respirology."},{"issue":"11","key":"5633_CR28","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1136\/thx.39.11.818","volume":"39","author":"GH Guyatt","year":"1984","unstructured":"Guyatt GH, Pugsley SO, Sullivan MJ, Thompson PJ, Berman L, Jones NL, et al. Effect of encouragement on walking test performance. Thorax. 1984;39(11):818\u201322. https:\/\/doi.org\/10.1136\/thx.39.11.818.","journal-title":"Thorax."},{"issue":"5","key":"5633_CR29","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1249\/00005768-198205000-00012","volume":"14","author":"GA Borg","year":"1982","unstructured":"Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377\u201381. https:\/\/doi.org\/10.1249\/00005768-198205000-00012.","journal-title":"Med Sci Sports Exerc."},{"issue":"12","key":"5633_CR30","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1016\/j.cgh.2010.08.011","volume":"8","author":"S Gupta","year":"2010","unstructured":"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\u20138. https:\/\/doi.org\/10.1016\/j.cgh.2010.08.011.","journal-title":"Clin Gastroenterol Hepatol."},{"issue":"8","key":"5633_CR31","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1002\/lt.25438","volume":"25","author":"SM Kawut","year":"2019","unstructured":"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\u201364. https:\/\/doi.org\/10.1002\/lt.25438.","journal-title":"Liver Transpl."},{"issue":"2","key":"5633_CR32","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1378\/chest.104.2.515","volume":"104","author":"MJ Krowka","year":"1993","unstructured":"Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue. Chest. 1993;104(2):515\u201321. https:\/\/doi.org\/10.1378\/chest.104.2.515.","journal-title":"Chest."},{"issue":"5","key":"5633_CR33","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/S0168-8278(99)80143-3","volume":"30","author":"G Martinez","year":"1999","unstructured":"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\u20139. https:\/\/doi.org\/10.1016\/S0168-8278(99)80143-3.","journal-title":"J Hepatol."},{"issue":"5","key":"5633_CR34","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/S0168-8278(00)00108-2","volume":"34","author":"GP Martinez","year":"2001","unstructured":"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\u20137. https:\/\/doi.org\/10.1016\/S0168-8278(00)00108-2.","journal-title":"J Hepatol."},{"issue":"3","key":"5633_CR35","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1002\/hep.20358","volume":"40","author":"FP Gomez","year":"2004","unstructured":"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\u20136. https:\/\/doi.org\/10.1002\/hep.20358.","journal-title":"Hepatology."},{"issue":"2","key":"5633_CR36","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/S0016-5085(98)70481-0","volume":"114","author":"GA Abrams","year":"1998","unstructured":"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\u201310. https:\/\/doi.org\/10.1016\/S0016-5085(98)70481-0.","journal-title":"Gastroenterology."},{"issue":"1","key":"5633_CR37","doi-asserted-by":"publisher","first-page":"47","DOI":"10.4103\/0970-2113.197116","volume":"34","author":"M Sarkar","year":"2017","unstructured":"Sarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017;34(1):47\u201360. https:\/\/doi.org\/10.4103\/0970-2113.197116.","journal-title":"Lung India."},{"issue":"10","key":"5633_CR38","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/j.jclinepi.2010.12.019","volume":"64","author":"S Gupta","year":"2011","unstructured":"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\u201394. https:\/\/doi.org\/10.1016\/j.jclinepi.2010.12.019.","journal-title":"J Clin Epidemiol."},{"issue":"5","key":"5633_CR39","doi-asserted-by":"publisher","first-page":"1602494","DOI":"10.1183\/13993003.02494-2016","volume":"49","author":"MR Schaeffer","year":"2017","unstructured":"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):1602494.","journal-title":"Eur Respir J"},{"key":"5633_CR40","volume-title":"R: a language and environment for statistical computing","author":"R Core Team","year":"2020","unstructured":"R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2020."},{"issue":"6","key":"5633_CR41","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/HCR.0000000000000129","volume":"35","author":"AA Kirkham","year":"2015","unstructured":"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\u20138. https:\/\/doi.org\/10.1097\/HCR.0000000000000129.","journal-title":"J Cardiopulm Rehabil Prev."},{"issue":"8","key":"5633_CR42","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1016\/S0735-1097(02)02164-2","volume":"40","author":"RJ Gibbons","year":"2002","unstructured":"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\u201340. https:\/\/doi.org\/10.1016\/S0735-1097(02)02164-2.","journal-title":"J Am Coll Cardiol."},{"issue":"2","key":"5633_CR43","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1164\/rccm.167.2.211","volume":"167","author":"S American Thoracic","year":"2003","unstructured":"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\u201377. https:\/\/doi.org\/10.1164\/rccm.167.2.211.","journal-title":"Am J Respir Crit Care Med."},{"issue":"2","key":"5633_CR44","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1111\/j.1600-6143.2009.02822.x","volume":"10","author":"S Gupta","year":"2010","unstructured":"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\u201363. https:\/\/doi.org\/10.1111\/j.1600-6143.2009.02822.x.","journal-title":"Am J Transplant."},{"issue":"2","key":"5633_CR45","doi-asserted-by":"publisher","first-page":"57","DOI":"10.4103\/1817-1737.78412","volume":"6","author":"AN Khan","year":"2011","unstructured":"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\u201365. https:\/\/doi.org\/10.4103\/1817-1737.78412.","journal-title":"Ann Thorac Med."},{"issue":"2","key":"5633_CR46","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1097\/MCP.0000000000000027","volume":"20","author":"BG Bender","year":"2014","unstructured":"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\u20137. https:\/\/doi.org\/10.1097\/MCP.0000000000000027.","journal-title":"Curr Opin Pulm Med."},{"issue":"6939","key":"5633_CR47","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1136\/bmj.308.6939.1291","volume":"308","author":"PH Fentem","year":"1994","unstructured":"Fentem PH. ABC of sports medicine. Benefits of exercise in health and disease. BMJ. 1994;308(6939):1291\u20135. https:\/\/doi.org\/10.1136\/bmj.308.6939.1291.","journal-title":"BMJ."},{"key":"5633_CR48","doi-asserted-by":"publisher","unstructured":"Campillo B FP, Bonnet JC, Atlan G. Submaximal oxygen consumption in liver cirrhosis. Evidence of severe functional aerobic impairment. J Hepatol 1990:163-167, 10, 2, DOI: https:\/\/doi.org\/10.1016\/0168-8278(90)90046-T.","DOI":"10.1016\/0168-8278(90)90046-T"},{"issue":"8","key":"5633_CR49","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.3109\/00365528309181845","volume":"18","author":"SPC Ritland","year":"1983","unstructured":"Ritland SPC, Knudsen T, Skrede S. Improvement of physical capacity after long-term training in patients with chronic active hepatitis. Scand J Gastroenterol. 1983;18(8):1083\u20137. https:\/\/doi.org\/10.3109\/00365528309181845.","journal-title":"Scand J Gastroenterol."},{"issue":"8","key":"5633_CR50","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1097\/TP.0b013e318187758b","volume":"86","author":"S Dharancy","year":"2008","unstructured":"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\u201383. https:\/\/doi.org\/10.1097\/TP.0b013e318187758b.","journal-title":"Transplantation."},{"issue":"3","key":"5633_CR51","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/lt.20088","volume":"10","author":"SK Epstein","year":"2004","unstructured":"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\u201324. https:\/\/doi.org\/10.1002\/lt.20088.","journal-title":"Liver Transpl."},{"issue":"12","key":"5633_CR52","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1002\/lt.22167","volume":"16","author":"EJ Carey","year":"2010","unstructured":"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\u20138. https:\/\/doi.org\/10.1002\/lt.22167.","journal-title":"Liver Transpl."},{"issue":"3","key":"5633_CR53","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1159\/000479008","volume":"94","author":"CBA Magalhaes","year":"2017","unstructured":"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\u20138. https:\/\/doi.org\/10.1159\/000479008.","journal-title":"Respiration."},{"issue":"5","key":"5633_CR54","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1111\/j.1600-6143.2007.02124.x","volume":"8","author":"BM Sulieman","year":"2008","unstructured":"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\u201364. https:\/\/doi.org\/10.1111\/j.1600-6143.2007.02124.x.","journal-title":"Am J Transplant."},{"issue":"6","key":"5633_CR55","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1164\/ajrccm\/140.6.1631","volume":"140","author":"ES Edell","year":"1989","unstructured":"Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis. 1989;140(6):1631\u20135. https:\/\/doi.org\/10.1164\/ajrccm\/140.6.1631.","journal-title":"Am Rev Respir Dis."}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05633-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-021-05633-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05633-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T16:37:59Z","timestamp":1673455079000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-021-05633-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,9]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["5633"],"URL":"https:\/\/doi.org\/10.1186\/s13063-021-05633-7","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,9]]},"assertion":[{"value":"8 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was reviewed and approved by the Research Ethics Board at Unity Health Toronto (REB #19-127).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All data will be presented as a mean or median. No individual data will be included in the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"683"}}