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This study explores the prerequisites for accumulation of infused crystalloid fluid in the remote slow-exchange space (\u201cthird fluid space\u00a8,\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    ). Volume kinetic analysis based on log likelihood mathematics was applied to retrospective data from 132 intravenous infusions in 85 healthy volunteers who received 0.6\u20132.5 L of crystalloid fluid over 30 min. Frequent measurements of the blood hemoglobin concentration during and after these infusions, together with the measured urine output, served as calculation inputs. Three substudies were set up to illustrate key issues regarding\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    filling. In the first of them, infusions were preceded by blood withdrawal, which is known to decrease the interstitial pressure (P\n                    <jats:sub>if<\/jats:sub>\n                    ). Blood withdrawal resulted in smaller volumes entering\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    , confirming that\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    filling is dependent on P\n                    <jats:sub>if<\/jats:sub>\n                    . In the second substudy, modeled and measured urine outputs were compared after varying the inclusion of\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    in kinetic analyses in which the infused volume was gradually increased. Consideration of\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    was deemed appropriate when &gt;\u20091.2 L of fluid was administered. In the third substudy, assessment of\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    filling during 7 time periods just before and after the 30 min infusions confirmed that uptake of fluid to\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    was initiated between 30 and 35 min. In conclusion, accumulation of fluid in\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>t2<\/jats:sub>\n                    is dependent on P\n                    <jats:sub>if<\/jats:sub>\n                    and occurs following infusion of &gt;\u20091.2 L of crystalloid fluid. Uptake is not gradual but is initiated at a specific point in time.\n                  <\/jats:p>","DOI":"10.1007\/s00424-025-03135-y","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T03:28:43Z","timestamp":1765942123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["When does the \u201cthird fluid space\u201d open?"],"prefix":"10.1007","volume":"478","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1528-3803","authenticated-orcid":false,"given":"Robert G.","family":"Hahn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"3135_CR1","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1097\/00000658-196111000-00005","volume":"154","author":"T Shires","year":"1961","unstructured":"Shires T, Williams J, Brown F (1961) Acute changes in extracellular fluids associated with major surgical procedures. 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