{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:06:57Z","timestamp":1789034817232,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012175","name":"Zhejiang Traditional Chinese Medicine Administration","doi-asserted-by":"publisher","award":["2025ZR124"],"award-info":[{"award-number":["2025ZR124"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>The classical concept of shunt confines the phenomenon to the pulmonary circulation, leaving microcirculatory flow maldistribution in distributive shock outside existing terminology. Tissue hypoxia can persist despite normal cardiac output; current hemodynamic stability criteria incorporate no microcirculatory dimension. This review addresses both gaps by proposing a unifying framework. We propose ineffective circulating volume (ICV) as blood flow that fails to achieve effective gas exchange, whether at the alveolar-blood interface (pulmonary shunt) or the blood-cell interface (systemic shunt). Pulmonary shunt and septic microcirculatory heterogeneity are established phenomena, whereas their unification as ICV\u2014particularly the term systemic \u201cfunctional shunt\u201d\u2014is a hypothesis requiring clinical validation. Anatomical shunt involves fixed structural bypasses correctable surgically; functional abnormalities reflect failure of active distribution mechanisms\u2014hypoxic pulmonary vasoconstriction suppressed by inflammatory mediators, and conducted responses disrupted by endothelial injury. Supportive interventions may improve their physiological consequences, whereas durable reversal depends on resolution or treatment of the underlying disease. The ICV framework subdivides circulatory hypoxia into a macrocirculatory sublayer (global oxygen delivery insufficiency) and a microcirculatory sublayer (flow maldistribution), the latter potentially persisting even when macrocirculatory parameters are normalised. Acute respiratory distress syndrome and distributive shock may share three upstream molecular mechanisms\u2014glycocalyx degradation, spatially heterogeneous inducible nitric oxide synthase overexpression, and neutrophil extracellular traps\u2014that could impair regulatory systems at both interfaces. Changes in sepsis resuscitation targets are compatible with, but do not validate, the ICV framework\u2019s emphasis on macro-microcirculatory uncoupling. No study has simultaneously quantified shunt at both interfaces in the same patient cohort, and no randomised trial targeting the shared upstream mechanisms has used dual-interface ICV as a combined primary endpoint. Translating the ICV framework into prospectively defined clinical endpoints remains an open methodological challenge.<\/jats:p>","DOI":"10.3389\/fphys.2026.1939745","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:14:11Z","timestamp":1789031651000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Shunt: pathophysiological mechanisms and clinical implications of ineffective circulating volume"],"prefix":"10.3389","volume":"17","author":[{"given":"Shenghui","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiatao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Data Science, Brown University","place":["Providence, RI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaokun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Gu","sequence":"additional","affiliation":[{"name":"The Third People\u2019s Hospital of Hangzhou Lin\u2019an District","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1002\/j.2040-4603.2012.tb00436.x","article-title":"Gas exchange in the respiratory distress syndromes","volume":"2","author":"Albert","year":"2012","journal-title":"Compr. Physiol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s40635-015-0040-7","article-title":"Cytocam-idf (incident dark field illumination) imaging for bedside monitoring of the microcirculation","volume":"3","author":"Aykut","year":"2015","journal-title":"Intensive Care Med. Exp."},{"key":"B3","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1186\/cc2353","article-title":"Bench-to-bedside review: microvascular dysfunction in sepsis, hemodynamics, oxygen transport, and nitric oxide","volume":"7","author":"Bateman","year":"2003","journal-title":"Crit. Care"},{"key":"B4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1097\/ccm.0b013e3181b02fc1","article-title":"Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis\/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial","volume":"38","author":"Boerma","year":"2010","journal-title":"Crit. Care Med."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1186\/s13613-015-0046-z","article-title":"Echocardiographic detection of transpulmonary bubble transit during acute respiratory distress syndrome","volume":"5","author":"Boissier","year":"2015","journal-title":"Ann. Intensive Care"},{"key":"B6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1097\/aln.0000000000004757","article-title":"Causes of hypoxemia in COVID-19 acute respiratory distress syndrome: a combined multiple inert gas elimination technique and dual-energy computed tomography study","volume":"140","author":"Busana","year":"2024","journal-title":"Anesthesiology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e191","DOI":"10.1016\/0140-6736(93)93067-b","article-title":"Almitrine infusion in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome: a single-center observational study","volume":"49","author":"Caplan","year":"2021","journal-title":"Crit. Care Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.ccm.2016.01.009","article-title":"Endothelial and microcirculatory function and dysfunction in sepsis","volume":"37","author":"Colbert","year":"2016","journal-title":"Clinics Chest Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1007\/s00134-010-1754-3","article-title":"Sildenafil attenuates pulmonary arterial pressure but does not improve oxygenation during ards","volume":"36","author":"Cornet","year":"2010","journal-title":"Intensive Care Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1097\/01.ccm.0000198107.61493.5a","article-title":"The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects","volume":"34","author":"De Backer","year":"2006","journal-title":"Crit. Care Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1186\/s13054-016-1500-5","article-title":"Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study","volume":"20","author":"Donati","year":"2016","journal-title":"Crit. Care"},{"key":"B12","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/cc4969","article-title":"Mechanisms of critical illness: classifying microcirculatory flow abnormalities in distributive shock","volume":"10","author":"Elbers","year":"2006","journal-title":"Crit. Care"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1007\/s00134-021-06506-y","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021","volume":"47","author":"Evans","year":"2021","journal-title":"Intensive Care Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1097\/ccm.0000000000002017","article-title":"Evaluating pulmonary function: an assessment of pao2\/fio2","volume":"45","author":"Feiner","year":"2017","journal-title":"Crit. Care Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1136\/thoraxjnl-2016-208357","article-title":"Chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the TRanslational EIT developmeNt stuDy group","volume":"72","author":"Frerichs","year":"2017","journal-title":"Thorax"},{"key":"B16","doi-asserted-by":"publisher","first-page":"210059","DOI":"10.1183\/16000617.0059-2021","article-title":"Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome","volume":"30","author":"Gierhardt","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"B17","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1001\/jama.2019.0071","article-title":"Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial","volume":"321","author":"Hernandez","year":"2019","journal-title":"JAMA"},{"key":"B18","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1097\/01.ccm.0001102816.46938.cb","article-title":"Norepinephrine in septic shock","volume":"45","author":"Hernandez","year":"2019","journal-title":"Intensive Care Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1007\/s00134-016-4500-7","article-title":"Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial","volume":"42","author":"Hjortrup","year":"2016","journal-title":"Intensive Care Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"15086","DOI":"10.1002\/9781444306262.ch16","article-title":"Patent foramen ovale","volume":"2","author":"Homma","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B21","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1186\/cc3753","article-title":"The microcirculation is the motor of sepsis","volume":"9","author":"Ince","year":"2005","journal-title":"Crit. Care"},{"key":"B22","doi-asserted-by":"publisher","first-page":"S8","DOI":"10.1186\/cc14726","article-title":"Hemodynamic coherence and the rationale for monitoring the microcirculation","volume":"19","author":"Ince","year":"2015","journal-title":"Crit. Care"},{"key":"B23","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s00134-018-5070-7","article-title":"Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine","volume":"44","author":"Ince","year":"2018","journal-title":"Intensive Care Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1097\/00003246-199907000-00031","article-title":"Microcirculatory oxygenation and shunting in sepsis and shock","volume":"27","author":"Ince","year":"1999","journal-title":"Crit. Care Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1164\/rccm.201910-1911tr","article-title":"Endothelial responses in sepsis","volume":"202","author":"Joffre","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"S337","DOI":"10.1097\/01.ccm.0000057913.45273.1a","article-title":"Selective pulmonary vasodilation in acute respiratory distress syndrome","volume":"31","author":"Kaisers","year":"2003","journal-title":"Crit. Care Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1513\/annalsats.201509-606oc","article-title":"Similar microcirculatory alterations in patients with normodynamic and hyperdynamic septic shock","volume":"13","author":"Kanoore Edul","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"B28","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13054-020-2834-6","article-title":"Changes in shunt, ventilation\/perfusion mismatch, and lung aeration with peep in patients with ards: a prospective single-arm interventional study","volume":"24","author":"Karbing","year":"2020","journal-title":"Crit. Care"},{"key":"B29","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s13054-024-05033-8","article-title":"Absolute values of regional ventilation-perfusion mismatch in patients with ards monitored by electrical impedance tomography and the role of dead space and shunt compensation","volume":"28","author":"Leali","year":"2024","journal-title":"Crit. Care"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.98178","article-title":"Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury","volume":"3","author":"Lefranc\u00b8ais","year":"2018","journal-title":"JCI Insight"},{"key":"B31","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1186\/cc8011","article-title":"Low tissue oxygen saturation at the end of early goal-directed therapy is associated with worse outcome in critically ill patients","volume":"13","author":"Lima","year":"2009","journal-title":"Crit. Care"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1182\/blood-2016-09-741298","article-title":"Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice","volume":"129","author":"McDonald","year":"2017","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s13054-015-0858-0","article-title":"Central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference is associated with lactate evolution in the hemodynamic resuscitation process in early septic shock","volume":"19","author":"Mesquida","year":"2015","journal-title":"Crit. Care"},{"key":"B34","doi-asserted-by":"publisher","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. Engl. J. Med."},{"key":"B35","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. Engl. J. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s00134-026-08361-1","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2026","volume":"52","author":"Prescott","year":"2026","journal-title":"Intensive Care Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nrc2895","article-title":"The shunt problem: control of functional shunting in normal and tumour vasculature","volume":"10","author":"Pries","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1097\/aln.0000000000003221","article-title":"Extracorporeal membrane oxygenation for respiratory failure","volume":"132","author":"Quintel","year":"2020","journal-title":"Anesthesiology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1007\/978-3-642-83010-5_21","article-title":"Gas exchange in acute respiratory distress syndrome","volume":"196","author":"Radermacher","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1186\/s13054-019-2542-2","article-title":"Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions with illness severity and outcome in icu patients: a prospective observational study","volume":"23","author":"Rovas","year":"2019","journal-title":"Crit. Care"},{"key":"B41","first-page":"1049","article-title":"A systematic review and meta-analysis of the association of sublingual microcirculation and poor outcome in septic patients","volume":"48","author":"Sanfilippo","year":"2022","journal-title":"Intensive Care Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1080\/10739680590895028","article-title":"Regulation of blood flow in the microcirculation","volume":"12","author":"Segal","year":"2005","journal-title":"Microcirculation"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1016\/s0140-6736(02)11393-6","article-title":"Nitroglycerin in septic shock after intravascular volume resuscitation","volume":"360","author":"Spronk","year":"2002","journal-title":"Lancet"},{"key":"B44","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13054-018-2292-6","article-title":"The glycocalyx: a novel diagnostic and therapeutic target in sepsis","volume":"23","author":"Uchimido","year":"2019","journal-title":"Crit. Care"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1007\/s00134-013-2998-5","article-title":"Resuscitation of patients with septic shock: please \u201cmind the gap\u201d","volume":"39","author":"Vallet","year":"2013","journal-title":"Intensive Care Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.echo.2014.12.008","article-title":"Clinical implications of pulmonary shunting on saline contrast echocardiography","volume":"28","author":"Velthuis","year":"2015","journal-title":"J. Am. Soc. Echocardiography"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.1056\/nejmra1208943","article-title":"Circulatory shock","volume":"369","author":"Vincent","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13613-025-01489-1","article-title":"Association between ventilationperfusion matching improvement during initial prone positioning and icu mortality in patients with moderate to severe ards: a prospective two-center study","volume":"15","author":"Wang","year":"2025","journal-title":"Ann. Intensive Care"},{"key":"B49","doi-asserted-by":"publisher","first-page":"154","DOI":"10.21203\/rs.3.rs-1388270\/v1","article-title":"Prone positioning improves ventilation-perfusion matching assessed by electrical impedance tomography in patients with ards: a prospective physiological study","volume":"26","author":"Wang","year":"2022","journal-title":"Crit. Care"},{"key":"B50","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s13054-025-05778-w","article-title":"Predicting early prone position ventilation responsiveness in patients with acute respiratory distress syndrome based on electrical impedance tomography: a prospective study","volume":"30","author":"Wu","year":"2025","journal-title":"Crit. Care"},{"key":"B51","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1056\/NEJMoa1401602","article-title":"A randomized trial of protocol-based care for early septic shock","volume":"370","author":"Yealy","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1186\/s13054-023-04749-3","article-title":"Effects of early versus delayed application of prone position on ventilation-perfusion mismatch in patients with acute respiratory distress syndrome: a prospective observational study","volume":"27","author":"Yuan","year":"2023","journal-title":"Crit. Care"},{"key":"B53","first-page":"e653","article-title":"Plasma syndecan-1 protein concentrations in pediatric acute respiratory distress syndrome: effects of the primary diagnosis and association with secondary outcomes","volume":"46","author":"Zinter","year":"2018","journal-title":"Crit. Care Med."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1939745\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:14:13Z","timestamp":1789031653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1939745\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":53,"alternative-id":["10.3389\/fphys.2026.1939745"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2026.1939745","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]},"article-number":"1939745"}}