{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:43:41Z","timestamp":1784648621822,"version":"3.55.0"},"reference-count":91,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011924","name":"European Society of Anaesthesiology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2016T064"],"award-info":[{"award-number":["2016T064"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Microcirculation"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Microcirculatory perfusion disturbances following hemorrhagic shock and fluid resuscitation contribute to multiple organ dysfunction and mortality. Standard fluid resuscitation is insufficient to restore microcirculatory perfusion; however, additional therapies are lacking. We conducted a systematic search to provide an overview of potential non\u2010fluid\u2010based therapeutic interventions to restore microcirculatory perfusion following hemorrhagic shock.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A structured search of PubMed, EMBASE, and Cochrane Library was performed in March 2020. Animal studies needed to report at least one parameter of microcirculatory flow (perfusion, red blood cell velocity, functional capillary density).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The search identified 1269 records of which 48 fulfilled all eligibility criteria. In total, 62 drugs were tested of which 29 were able to restore microcirculatory perfusion. Particularly, complement inhibitors (75% of drugs tested successfully restored blood flow), endothelial barrier modulators (100% successful), antioxidants (66% successful), drugs targeting cell metabolism (83% successful), and sex hormones (75% successful) restored microcirculatory perfusion. Other drugs consisted of attenuation of inflammation (100% not successful), vasoactive agents (68% not successful), and steroid hormones (75% not successful).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Improving mitochondrial function, inhibition of complement inhibition, and reducing microvascular leakage via restoration of endothelial barrier function seem beneficial to restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/micc.12650","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T21:35:10Z","timestamp":1595280910000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Therapeutic interventions to restore microcirculatory perfusion following experimental hemorrhagic shock and fluid resuscitation: A systematic review"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6552-0830","authenticated-orcid":false,"given":"Anoek L. I.","family":"van Leeuwen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Experimental Laboratory for VItal Signs Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Physiology Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0300-3026","authenticated-orcid":false,"given":"Nicole A. M.","family":"Dekker","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Experimental Laboratory for VItal Signs Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Physiology Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1516-2171","authenticated-orcid":false,"given":"Elise P.","family":"Jansma","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Amsterdam UMC Vrije Universiteit Amsterdam Public Health research institute Amsterdam The Netherlands"},{"name":"Medical Library Vrije Universiteit Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-6951","authenticated-orcid":false,"given":"Christa","family":"Boer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Experimental Laboratory for VItal Signs Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0886-1388","authenticated-orcid":false,"given":"Charissa E.","family":"van den Brom","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Experimental Laboratory for VItal Signs Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"},{"name":"Department of Physiology Amsterdam UMC Vrije Universiteit Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003275"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1705649"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000000223"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000001695"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0000000000000335"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c170006"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570161114666151202210221"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00012.2005"},{"key":"e_1_2_8_10_1","article-title":"In vitro endothelial hyperpermeability occurs early following traumatic hemorrhagic shock","author":"Leeuwen ALI","year":"2020","journal-title":"Clin Hemorheol Microcirc"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000687"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc14726"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.08.024"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2017.11.074"},{"issue":"90","key":"e_1_2_8_15_1","first-page":"441","article-title":"Detrimental effects of complement activation in hemorrhagic shock","volume":"2001","author":"Younger JG","year":"1985","journal-title":"J Appl Physiol"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2741\/4347"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000097"},{"key":"e_1_2_8_18_1","unstructured":"van denBromCE TianS BorgdorffM.A review of new therapeutic targets for improvement of microvascular leakage and microcirculatory perfusion following hemorrhagic shock PROSPERO 2018 CRD42018095432.2018."},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-14-43"},{"key":"e_1_2_8_20_1","first-page":"1091","article-title":"Pharmacological effects of RA 642 on cerebrocortical perfusion in acute hemorrhagic shock in rats","volume":"308","author":"Hergenroder S","year":"1989","journal-title":"Prog Clin Biol Res"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.1969.01340170089021"},{"key":"e_1_2_8_22_1","first-page":"390","article-title":"Diltiazem administration after crystalloid resuscitation restores active hepatocellular function and hepatic blood flow after severe hemorrhagic shock","volume":"110","author":"Wang P","year":"1991","journal-title":"Surgery"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1997.273.6.G1246"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199710000-00010"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/jsre.1997.5016"},{"key":"e_1_2_8_26_1","first-page":"350","article-title":"Pentoxifylline restores intestinal microvascular blood flow during resuscitated hemorrhagic shock","volume":"110","author":"Flynn WJ","year":"1991","journal-title":"Surgery"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005373-199601000-00017"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-200005000-00047"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/153537020422900713"},{"key":"e_1_2_8_30_1","first-page":"115","article-title":"The cardiovascular effects of gamma\u2010hydroxybutyrate following hemorrhage","volume":"38","author":"Boyd AJ","year":"1992","journal-title":"Circ Shock"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1139\/y92-044"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2005.06.009"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4804(91)90205-Z"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1997.273.6.G1297"},{"key":"e_1_2_8_35_1","first-page":"R645","article-title":"Preheparinization improves organ function after hemorrhage and resuscitation","volume":"259","author":"Wang P","year":"1990","journal-title":"Am J Physiol"},{"key":"e_1_2_8_36_1","first-page":"169","article-title":"Chemically modified heparin improves hepatocellular function, cardiac output, and microcirculation after trauma\u2010hemorrhage and resuscitation","volume":"116","author":"Wang P","year":"1994","journal-title":"Surgery"},{"key":"e_1_2_8_37_1","first-page":"H1294","article-title":"Effects of nonanticoagulant heparin on cardiovascular and hepatocellular function after hemorrhagic shock","volume":"270","author":"Wang P","year":"1996","journal-title":"Am J Physiol"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2010.12.001"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1067\/msy.1998.91489"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1549-8719.2001.tb00189.x"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00006.2014"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000001907"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00437.2004"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.136.10.1158"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/10739680490425930"},{"key":"e_1_2_8_46_1","first-page":"H2919","article-title":"Testosterone receptor blockade after trauma\u2010hemorrhage improves cardiac and hepatic functions in males","volume":"273","author":"Remmers DE","year":"1997","journal-title":"Am J Physiol"},{"key":"e_1_2_8_47_1","first-page":"489","article-title":"Steroids and severe hemorrhagic shock","volume":"82","author":"Pinilla J","year":"1977","journal-title":"Surgery"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12345"},{"key":"e_1_2_8_49_1","first-page":"268","article-title":"Persistent gastric mucosal hypoxia and interstitial edema after hemorrhagic shock: prevention with steroid therapy","volume":"85","author":"Bowen JC","year":"1979","journal-title":"Surgery"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199506000-00016"},{"key":"e_1_2_8_51_1","first-page":"105","article-title":"Leukocyte\u2010endothelial cell interactions in the liver after hemorrhagic shock in the rat","volume":"40","author":"Marzi I","year":"1993","journal-title":"Circ Shock"},{"key":"e_1_2_8_52_1","first-page":"27","article-title":"Effect of anti\u2010tumor necrosis factor alpha on leukocyte adhesion in the liver after hemorrhagic shock: an intravital microscopic study in the rat","volume":"3","author":"Marzi I","year":"1995","journal-title":"Shock"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.1.C145"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.shk.0000107442.26299.fb"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.4103\/0973-6247.150952"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(94)90758-7"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resuscitation.2009.09.005"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31826b64e5"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000202205.93372.7C"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200404000-00006"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2019.103909"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13017-018-0172-7"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e318157e526"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-006-0335-y"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199611000-00013"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000895"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199712000-00019"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199410000-00012"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00543"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e318236edb8"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0b013e31825b5c10"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000854"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.148.10.3210"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186339"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0624com"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00139.2004"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc9387"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e318162d616"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136205"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000002008"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-009-0011-0"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcrc.2009.05.003"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-010-1970-x"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201006-0972CI"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200204000-00015"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199500252-00006"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.36"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1807-59322006000500017"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-200209000-00002"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.jvca.2018.04.017"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13049-019-0589-3"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002689900067"}],"container-title":["Microcirculation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fmicc.12650","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/micc.12650","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/micc.12650","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/micc.12650","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T09:19:45Z","timestamp":1693819185000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/micc.12650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,20]]},"references-count":91,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["10.1111\/micc.12650"],"URL":"https:\/\/doi.org\/10.1111\/micc.12650","archive":["Portico"],"relation":{},"ISSN":["1073-9688","1549-8719"],"issn-type":[{"value":"1073-9688","type":"print"},{"value":"1549-8719","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,20]]},"assertion":[{"value":"2020-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12650"}}