{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T14:11:48Z","timestamp":1791727908157,"version":"4.3.4"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:00:00Z","timestamp":1632355200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient\u2019s mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU \u00b7 kg<jats:sup>-1<\/jats:sup> \u00b7 h<jats:sup>-1<\/jats:sup> (therapeutic)) or vehicle. Microcirculatory oxygenation (\u03bcHBO<jats:sub>2<\/jats:sub>) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm\/mm<jats:sup>2<\/jats:sup>) and perfused vessel density (PVD; mm\/mm<jats:sup>2<\/jats:sup>)) were measured using incident dark field-Imaging at baseline and after 60 min.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In mild as well as in moderate septic animals with vehicle-infusion intestinal \u03bcHbO<jats:sub>2<\/jats:sub>, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU \u00b7 kg<jats:sup>-1<\/jats:sup> \u00b7 h<jats:sup>-1<\/jats:sup> elevated intestinal \u03bcHBO<jats:sub>2<\/jats:sub> (+ 6.1 \u00b1 5.3%; p &lt; 0.05 vs. baseline) and TVD (+ 5.2 \u00b1 3.0 mm\/mm<jats:sup>2<\/jats:sup>; p &lt; 0.05 vs. baseline). \u03bcHBO<jats:sub>2<\/jats:sub>, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0257034","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T22:07:19Z","timestamp":1632434839000},"page":"e0257034","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sub-therapeutic vasopressin but not therapeutic vasopressin improves gastrointestinal microcirculation in septic rats: A randomized, placebo-controlled, blinded 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Landry","year":"1997","journal-title":"Circulation"},{"issue":"3","key":"pone.0257034.ref017","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/CCM.0000000000002255","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016","volume":"45","author":"A Rhodes","year":"2017","journal-title":"Crit Care Med."},{"key":"pone.0257034.ref018","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.bpa.2008.02.009","article-title":"Impact of vasopressin analogues on the gut mucosal microcirculation","volume":"22","author":"P Asfar","year":"2008","journal-title":"Best Practice & Research Clinical Anaesthesiology"},{"issue":"1","key":"pone.0257034.ref019","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1097\/01.CCM.0000104201.62736.12","article-title":"Arginine vasopressin compromises gut mucosal microcirculation in septic rats","volume":"32","author":"M Westphal","year":"2004","journal-title":"Crit Care 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