{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:53:06Z","timestamp":1793386386446,"version":"4.5.0"},"reference-count":39,"publisher":"American Society of Hematology","issue":"8","license":[{"start":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T00:00:00Z","timestamp":1701648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,2,22]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>The volume of oxygen drawn from systemic capillaries down a partial pressure gradient is determined by the oxygen content of red blood cells (RBCs) and their oxygen-unloading kinetics, although the latter is assumed to be rapid and, therefore, not a meaningful factor. Under this paradigm, oxygen transfer to tissues is perfusion-limited. Consequently, clinical treatments to optimize oxygen delivery aim at improving blood flow and arterial oxygen content, rather than RBC oxygen handling. Although the oxygen-carrying capacity of blood is increased with transfusion, studies have shown that stored blood undergoes kinetic attrition of oxygen release, which may compromise overall oxygen delivery to tissues by causing transport to become diffusion-limited. We sought evidence for diffusion-limited oxygen release in viable human kidneys, normothermically perfused with stored blood. In a cohort of kidneys that went on to be transplanted, renal respiration correlated inversely with the time-constant of oxygen unloading from RBCs used for perfusion. Furthermore, the renal respiratory rate did not correlate with arterial O2 delivery unless this factored the rate of oxygen-release from RBCs, as expected from diffusion-limited transport. To test for a rescue effect, perfusion of kidneys deemed unsuitable for transplantation was alternated between stored and rejuvenated RBCs of the same donation. This experiment controlled oxygen-unloading, without intervening ischemia, holding all non-RBC parameters constant. Rejuvenated oxygen-unloading kinetics improved the kidney\u2019s oxygen diffusion capacity and increased cortical oxygen partial pressure by 60%. Thus, oxygen delivery to tissues can become diffusion-limited during perfusion with stored blood, which has implications in scenarios, such as ex\u00a0vivo organ perfusion, major hemorrhage, and pediatric transfusion. This trial was registered at www.clinicaltrials.gov as #ISRCTN13292277.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022385","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T22:01:59Z","timestamp":1701727319000},"page":"721-733","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":24,"title":["Impaired O2 unloading from stored blood results in diffusion-limited O2 release at tissues: evidence from human kidneys"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-4758","authenticated-orcid":false,"given":"Richard","family":"Dumbill","sequence":"first","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"3Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2367-4636","authenticated-orcid":false,"given":"Julija","family":"Rabcuka","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8644-9380","authenticated-orcid":false,"given":"John","family":"Fallon","sequence":"additional","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"3Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Knight","sequence":"additional","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"3Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Hunter","sequence":"additional","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"4University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Voyce","sequence":"additional","affiliation":[{"name":"5OrganOx Limited, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Barrett","sequence":"additional","affiliation":[{"name":"5OrganOx Limited, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Ellen","sequence":"additional","affiliation":[{"name":"5OrganOx Limited, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0582-1815","authenticated-orcid":false,"given":"Annemarie","family":"Weissenbacher","sequence":"additional","affiliation":[{"name":"6Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2227-8084","authenticated-orcid":false,"given":"Tetuko","family":"Kurniawan","sequence":"additional","affiliation":[{"name":"7Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland"},{"name":"9President University, Kota Jababeka, Bekasi, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6998-8198","authenticated-orcid":false,"given":"Slawomir","family":"Blonski","sequence":"additional","affiliation":[{"name":"7Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-7933","authenticated-orcid":false,"given":"Piotr Michal","family":"Korczyk","sequence":"additional","affiliation":[{"name":"7Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-665X","authenticated-orcid":false,"given":"Rutger","family":"Ploeg","sequence":"additional","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"3Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Coussios","sequence":"additional","affiliation":[{"name":"5OrganOx Limited, Oxford, United Kingdom"},{"name":"8Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0841-9685","authenticated-orcid":false,"given":"Peter","family":"Friend","sequence":"additional","affiliation":[{"name":"2Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom"},{"name":"3Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"name":"5OrganOx Limited, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9945-9473","authenticated-orcid":false,"given":"Pawel","family":"Swietach","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2024022216363356800_bib1","first-page":"690","volume-title":"Medical Physiology","author":"Boron","year":"2009"},{"issue":"1","key":"2024022216363356800_bib2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0034-5687(91)90090-6","article-title":"Diffusion and perfusion limitation in alveolar O2 exchange: shape of the blood O2 equilibrium curve","volume":"83","author":"Kobayashi","year":"1991","journal-title":"Respir Physiol"},{"issue":"3","key":"2024022216363356800_bib3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0034-5687(81)90121-3","article-title":"Model for capillary-alveolar equilibration with special reference to O2 uptake in hypoxia","volume":"46","author":"Piiper","year":"1981","journal-title":"Respir Physiol"},{"issue":"2","key":"2024022216363356800_bib4","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/thorax.57.2.170","article-title":"The pulmonary physician in critical care \u2217 2: oxygen delivery and consumption in the critically ill","volume":"57","author":"Leach","year":"2002","journal-title":"Thorax"},{"issue":"19","key":"2024022216363356800_bib5","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1056\/NEJMoa010307","article-title":"Early goal-directed therapy in the treatment of severe sepsis and septic shock","volume":"345","author":"Rivers","year":"2001","journal-title":"N\u00a0Engl J Med"},{"issue":"18","key":"2024022216363356800_bib6","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1056\/NEJMoa1401602","article-title":"A\u00a0randomized trial of protocol-based care for early septic shock","volume":"370","author":"Yealy","year":"2014","journal-title":"N\u00a0Engl J Med"},{"issue":"16","key":"2024022216363356800_bib7","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1056\/NEJMoa1404380","article-title":"Goal-directed resuscitation for patients with early septic shock","volume":"371","author":"Peake","year":"2014","journal-title":"N\u00a0Engl J Med"},{"issue":"14","key":"2024022216363356800_bib8","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1056\/NEJMoa1500896","article-title":"Trial of early, goal-directed resuscitation for septic shock","volume":"372","author":"Mouncey","year":"2015","journal-title":"N\u00a0Engl J Med"},{"issue":"1","key":"2024022216363356800_bib9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1161\/01.RES.72.1.187","article-title":"Regional myocardial capillary erythrocyte transit time in the normal\u00a0resting heart","volume":"72","author":"Allard","year":"1993","journal-title":"Circ Res"},{"issue":"18","key":"2024022216363356800_bib10","doi-asserted-by":"crossref","first-page":"10067","DOI":"10.1073\/pnas.1916641117","article-title":"Single-cell O(2) exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells","volume":"117","author":"Richardson","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"2024022216363356800_bib11","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1152\/japplphysiol.00469.2004","article-title":"Diffusing capacity reexamined: relative roles of diffusion and chemical reaction in red cell uptake of O2, CO, CO2, and NO","volume":"97","author":"Chakraborty","year":"2004","journal-title":"J\u00a0Appl Physiol (1985)"},{"issue":"2","key":"2024022216363356800_bib12","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1152\/physrev.2000.80.2.681","article-title":"Carbon dioxide transport and carbonic anhydrase in blood and muscle","volume":"80","author":"Geers","year":"2000","journal-title":"Physiol Rev"},{"issue":"3","key":"2024022216363356800_bib13","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF00586422","article-title":"The diffusion of carbon dioxide in erythrocytes and hemoglobin solutions","volume":"324","author":"Gros","year":"1971","journal-title":"Pflugers Arch"},{"issue":"20","key":"2024022216363356800_bib14","doi-asserted-by":"crossref","first-page":"12619","DOI":"10.1016\/S0021-9258(18)90791-X","article-title":"Morphological and physiological factors affecting oxygen uptake and release by red blood cells","volume":"259","author":"Vandegriff","year":"1984","journal-title":"J\u00a0Biol Chem"},{"issue":"20","key":"2024022216363356800_bib15","doi-asserted-by":"crossref","first-page":"12609","DOI":"10.1016\/S0021-9258(18)90790-8","article-title":"The kinetics of O2 release by human red blood cells in the presence of external sodium dithionite","volume":"259","author":"Vandegriff","year":"1984","journal-title":"J\u00a0Biol Chem"},{"issue":"43","key":"2024022216363356800_bib16","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1073\/pnas.0708160104","article-title":"Evolution of adverse changes in stored RBCs","volume":"104","author":"Bennett-Guerrero","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2024022216363356800_bib17","first-page":"27","article-title":"Red blood cell storage lesion: causes and potential clinical consequences","volume":"17","author":"Yoshida","year":"2019","journal-title":"Blood Transfus"},{"issue":"1","key":"2024022216363356800_bib18","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3324\/haematol.2021.279296","article-title":"Stored blood has compromised oxygen unloading kinetics that can be normalized with rejuvenation and predicted from corpuscular side-scatter","volume":"107","author":"Donovan","year":"2022","journal-title":"Haematologica"},{"issue":"20","key":"2024022216363356800_bib19","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1056\/NEJMoa1609014","article-title":"Effect of short-term vs. long-term blood storage on mortality after transfusion","volume":"375","author":"Heddle","year":"2016","journal-title":"N\u00a0Engl J Med"},{"issue":"19","key":"2024022216363356800_bib20","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1056\/NEJMoa1707572","article-title":"Age of red cells for transfusion and outcomes in critically ill adults","volume":"377","author":"Cooper","year":"2017","journal-title":"N\u00a0Engl J Med"},{"issue":"15","key":"2024022216363356800_bib21","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1056\/NEJMoa1500704","article-title":"Age of transfused blood in critically ill adults","volume":"372","author":"Lacroix","year":"2015","journal-title":"N\u00a0Engl J Med"},{"key":"2024022216363356800_bib22","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ahj.2018.04.007","article-title":"Clinical trials evaluating red blood cell transfusion thresholds: an updated systematic review and with additional focus on patients with cardiovascular disease","volume":"200","author":"Carson","year":"2018","journal-title":"Am Heart J"},{"key":"2024022216363356800_bib23","doi-asserted-by":"crossref","first-page":"l2320","DOI":"10.1136\/bmj.l2320","article-title":"Can we be certain that storage duration of transfused red blood cells does not affect patient outcomes?","volume":"365","author":"Trivella","year":"2019","journal-title":"BMJ"},{"issue":"6","key":"2024022216363356800_bib24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1097\/MOT.0000000000000470","article-title":"Normothermic machine perfusion of the kidney","volume":"22","author":"Weissenbacher","year":"2017","journal-title":"Curr Opin Organ Transplant"},{"issue":"6","key":"2024022216363356800_bib25","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1111\/tri.13441","article-title":"The future of organ perfusion and re-conditioning","volume":"32","author":"Weissenbacher","year":"2019","journal-title":"Transpl Int"},{"issue":"18","key":"2024022216363356800_bib26","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1182\/bloodadvances.2022007774","article-title":"Metabolic reprogramming under hypoxic storage preserves faster oxygen unloading from stored red blood cells","volume":"6","author":"Rabcuka","year":"2022","journal-title":"Blood Adv"},{"issue":"2","key":"2024022216363356800_bib27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1152\/physrev.1977.57.2.257","article-title":"Diffusion and chemical reaction in pulmonary gas exchange","volume":"57","author":"Wagner","year":"1977","journal-title":"Physiol Rev"},{"key":"2024022216363356800_bib28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1172\/JCI101727","article-title":"An objective method for determining circulation time from pulmonary to systemic capillaries by the use of the oximeter","volume":"25","author":"Wexler","year":"1946","journal-title":"J\u00a0Clin Invest"},{"issue":"3","key":"2024022216363356800_bib29","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1537-2995.2008.02002.x","article-title":"Rejuvenation of stored human red blood cells reverses the renal microvascular oxygenation deficit in an isovolemic transfusion model in rats","volume":"49","author":"Raat","year":"2009","journal-title":"Transfusion"},{"issue":"pt\u00a02","key":"2024022216363356800_bib30","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/j.1469-7793.1998.619bt.x","article-title":"Exercise-induced arterial hypoxaemia in healthy young women","volume":"507","author":"Harms","year":"1998","journal-title":"J\u00a0Physiol"},{"issue":"1","key":"2024022216363356800_bib31","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40798-019-0204-1","article-title":"Autologous blood transfusion enhances exercise performance-strength of the evidence and physiological mechanisms","volume":"5","author":"Solheim","year":"2019","journal-title":"Sports Med Open"},{"issue":"3","key":"2024022216363356800_bib32","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1111\/trf.13918","article-title":"A\u00a0randomized controlled pilot study of VO(2) max testing: a potential model for measuring relative in\u00a0vivo efficacy of different red blood cell products","volume":"57","author":"Bennett-Guerrero","year":"2017","journal-title":"Transfusion"},{"issue":"3","key":"2024022216363356800_bib33","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1213\/ANE.0000000000001071","article-title":"2,3-Diphosphoglycerate concentrations in autologous salvaged versus stored red blood cells and in surgical patients after transfusion","volume":"122","author":"Scott","year":"2016","journal-title":"Anesth Analg"},{"issue":"6","key":"2024022216363356800_bib34","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1056\/NEJM199902113400601","article-title":"A\u00a0multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group","volume":"340","author":"H\u00e9bert","year":"1999","journal-title":"N\u00a0Engl J Med"},{"issue":"16","key":"2024022216363356800_bib35","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa066240","article-title":"Transfusion strategies for patients in pediatric intensive care units","volume":"356","author":"Lacroix","year":"2007","journal-title":"N\u00a0Engl J Med"},{"issue":"23","key":"2024022216363356800_bib36","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1056\/NEJMoa1701380","article-title":"Early, goal-directed therapy for septic shock - a patient-level meta-analysis","volume":"376","author":"Rowan","year":"2017","journal-title":"N\u00a0Engl J Med"},{"issue":"9","key":"2024022216363356800_bib37","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s00134-015-3822-1","article-title":"A\u00a0systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators","volume":"41","author":"Angus","year":"2015","journal-title":"Intensive Care Med"},{"issue":"1","key":"2024022216363356800_bib38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13613-016-0226-5","article-title":"Impact of transfusion on patients with sepsis admitted in intensive care unit: a systematic review and meta-analysis","volume":"7","author":"Dupuis","year":"2017","journal-title":"Ann Intensive Care"},{"issue":"11","key":"2024022216363356800_bib39","doi-asserted-by":"crossref","first-page":"e1063","DOI":"10.1097\/CCM.0000000000005337","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021","volume":"49","author":"Evans","year":"2021","journal-title":"Crit Care Med"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/143\/8\/721\/2215005\/blood_bld-2023-022385-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/143\/8\/721\/2215005\/blood_bld-2023-022385-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T16:37:00Z","timestamp":1708619820000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/143\/8\/721\/506501\/Impaired-O2-unloading-from-stored-blood-results-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,22]]},"references-count":39,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,2,22]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2023022385","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,22]]}}}