{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:36:49Z","timestamp":1785418609864,"version":"3.56.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007210","name":"RWTH Aachen University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007210","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis\/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan\u00ae 4% and Sterofundin\u00ae ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin\u00ae ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28\u2009days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits\/calls will be scheduled on day 28 and day 90.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>This study aims to generate evidence regarding which regimen\u2014a gelatine-crystalloid regimen or a pure crystalloid regimen\u2014is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>The European clinical trial database <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/trial\/2015-000057-20\/DE\">EudraCT 2015-000057-20<\/jats:ext-link> and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02715466?term=genius+1209&amp;recrs=ab&amp;cond=Sepsis&amp;draw=2&amp;rank=1\">NCT02715466<\/jats:ext-link>. Registered on 17 March 2016.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-021-05311-8","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:08:03Z","timestamp":1622628483000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis\/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial"],"prefix":"10.1186","volume":"22","author":[{"given":"Gernot","family":"Marx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zacharowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Ichai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Asehnoune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladim\u00edr","family":"\u010cern\u00fd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Dembinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricard","family":"Ferrer Roca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Fries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Molnar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rosenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Sanchez-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Sch\u00fcrholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Dehnhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Schmier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"von Kleist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Brauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim-Philipp","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"issue":"6","key":"5311_CR1","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1378\/chest.101.6.1644","volume":"101","author":"RC Bone","year":"1992","unstructured":"Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. 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BMJ. 2007;335(7625):879\u201383. https:\/\/doi.org\/10.1136\/bmj.39346.495880.AE.","journal-title":"BMJ"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05311-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-021-05311-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05311-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:16:09Z","timestamp":1622628969000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-021-05311-8"}},"subtitle":["GENIUS\u2014Gelatine use in ICU and sepsis"],"short-title":[],"issued":{"date-parts":[[2021,6,2]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["5311"],"URL":"https:\/\/doi.org\/10.1186\/s13063-021-05311-8","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,2]]},"assertion":[{"value":"27 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study protocol was initially approved in version 2.0, dated 30 November 2015, by the Ethics Committee of the Medical University of Innsbruck, Austria (AN2015-0179 352\/2.1), the Ethics Committee of the Institute of Clinical and Experimental Medicine and Thomayer Hospital with Multicentre Competence, Czech Republic (M-1544), the Ethics Committee at the RWTH Aachen Faculty of Medicine, Germany (EK 206\/15), the Comit\u00e9 de Protection des Personnes Sud M\u00e9diterran\u00e9e V, France (15.081), and the Ethics Committee for Clinical Pharmacology, Hungary (OGYI\/28863\/2015).After the study started, the protocol was amended three times via global protocol amendments. The first global protocol amendment aimed to improve patient recruitment (i.a. inclusion of three study sites in Spain and an additional site in Germany), to harmonize wording discrepancies and to clarify the documentation of some variables (protocol version 3.0, dated 2 May 2017). This amendment was approved by the ethics committees of the Medical University of Innsbruck (17 November 2017), the Institute of Clinical and Experimental Medicine and Thomayer Hospital (9 August 2017), the RWTH Aachen (26 July 2017), and the Ethics Committee for Clinical Pharmacology (6 September 2017). As study sites in France completed recruitment before the compilation of the first global amendment, this amendment was not submitted to the Comit\u00e9 de Protection des Personnes Sud M\u00e9diterran\u00e9e V. The Comit\u00e9s de \u00c9tica de la Investigaci\u00f3n de los Hospitales Universitarios Virgen Macarena \u2013 Virgen del Roc\u00edo de Sevilla, Spain; these institutions initially approved the version 3.0 protocol (Acta No. 09\/2017).The second global protocol amendment addressed changes to the protocol to reflect updates within the reference safety information (Summary of Product Characteristics) of the investigational test product (Gelaspan 4%) in addition to an update of the investigator list and editorial adaptions (protocol version 4.0, dated 20 July 2018). This amendment was approved by the ethics committees of the Medical University of Innsbruck (24 August 2018), the Institute of Clinical and Experimental Medicine and Thomayer Hospital (12 September 2018), the RWTH Aachen (14 September 2018), and the Comit\u00e9s de \u00c9tica de la Investigaci\u00f3n de los Hospitales Universitarios Virgen Macarena \u2013 Virgen del Roc\u00edo de Sevilla, Spain (23 August 2018). As the study was terminated in Hungary on 8 March 2018 (no patients enrolled), this amendment was not submitted to the Ethics Committee for Clinical Pharmacology.The third protocol amendment reflected the prolongation of the expected recruitment period from 3.5 to 5.5\u2009years, the replacement of the DSMB statistician and editorial changes (current protocol version 5.0, dated 10 January 2020). This protocol amendment was approved by the ethics committees of the Medical University of Innsbruck (21 February 2020), the Institute of Clinical and Experimental Medicine and Thomayer Hospital (11 March 2020), and the RWTH Aachen (18 March 2020). As changes reflected in the third global protocol amendment are considered nonsubstantial in Spain, this amendment was not submitted to the Comit\u00e9s de \u00c9tica de la Investigaci\u00f3n de los Hospitales Universitarios Virgen Macarena \u2013 Virgen del Roc\u00edo de Sevilla.The fourth protocol amendment addresses modifications within the inclusion and exclusion criteria to improve patient recruitment and to exclude patients with confirmed acute SARS-CoV-2 infection, changes within the secondary variables and corresponding visit schedule to reflect clinical routine, editorial and organizational modifications (current protocol version 6.0, dated 16 July 2020). This protocol amendment was approved by the ethics committees of the Medical University of Innsbruck (25 September 2020), the Institute of Clinical and Experimental Medicine and Thomayer Hospital (09 September 2020), Comit\u00e9s de \u00c9tica de la Investigaci\u00f3n de los Hospitales Universitarios Virgen Macarena \u2013 Virgen del Roc\u00edo de Sevilla (30 September 2020), and the RWTH Aachen (22 October 2020).Written informed consent will be obtained from all patients or their legal representatives, authorized persons, or relatives, depending on the local regulations. For details, refer to the \u201cMethods\/design\u201d section, specifically the \u201cInterventions and procedures\u201d or \u201cEnrolment\u201d subsection. The approvals by the ethic committees mentioned above include the deferred consent procedure used in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors:GM received grants\/research support and honouraria\/consultation fees from B. Braun Melsungen AG and Adrenomed and participated in company-sponsored speakers bureaus from B. Braun Melsungen AG, Edwards Life Sciences, Philips and Adrenomed. GM acted as coordinator of the S3 guideline on volume therapy for the Association of the Scientific Medical Societies in Germany (AWMF, see []).KZ received research grants, advisory and lecture honouraria, and financial support (education) for his department from Aesculap Akademie GmbH, Affinites Sante, Ashai Kasai Pharma, B. Braun Melsungen AG, B. Braun Avitum AG, Bayer AG, Biotest AG, Christian Doppler Stiftung, CSL Behring GmbH, Cyto Sorbents GmbH, Edward Lifescience Corporation, Executive Insight AG, Fresenius Kabi GmbH, Fresenius Medical Care, Haemonetics Corporation, Hartmannbund Landesverband, Health Advances GmbH, Heinen+L\u00f6wenstein GmbH, Hexal AG, INC Research, Johnson & Johnson, Josef Gassner, Maquet GmbH, Markus L\u00fccke Kongress Organisation, Masimo International, med update GmbH, Medizin & Markt Gesundheitsnetzwerk, MSD Sharp & Dohme GmbH, Nordic Group, Nordic Pharma, Novo Nordisk Pharma GmbH, Pfizer Pharma GmbH, Pharmacosmos, Ratiopharm GmbH, Salvia Medical GmbH, Schering Stiftung, Sch\u00f6chl Medical \u00d6sterreich, Serumwerke, Verlag f\u00fcr Printmedien und PR, Forum Sanitas, Vifor Pharma GmbH, Wellington, Werfen.CI received reimbursement of registration fees and travel expenses for congress participation by B. Braun Melsungen AG and Baxter, as well as honouraria for participation in expert meetings by Fresenius.KA received lecture honouraria from Fresenius, Baxter, LFB and Boehringer.VC received lecture honouraria from Fresenius, B. Braun Melsungen AG, CSL Behring, AOP Orphan, Bard, AbbVie.RD received advisory fees from B. Braun Melsungen AG.RF received speaker fees and advisory fees from B. Braun Melsungen AG and Grifols.DF received honouraria for consulting, lecture fees, and sponsoring for academic studies from Baxter, B. Braun Melsungen AG, CSL Behring, Instrumental Laboratories, LFB, Mitsubishi Pharma, Octapharm, Takeda and Tem-Innovation.ZM was a member of the Pulsion medical advisory board and received lecture honouraria from Pulsion-Maquet (member of the Getinge Group), Biotest, CytoSorbents, and ThermoFisher. Currently, he is a member of the medical directors of CytoSorbents EuropePR declares that he has no competing interests.MS declares that he has no competing interests.TS received restricted grants from B. Braun Melsungen AG, Fresenius Kabi Deutschland GmbH and Fresenius Medical GmbH, Germany.TD (Director Clinical Development Plasma Volume Replacement), SSch (Senior Scientific Manager Clinical Development), EvK (Vice President Preclinical and Clinical Development), and UB (Chief Medical Officer) are employed by B. Braun Melsungen AG.TPS received research grants and lecture honouraria from B. Braun Melsungen AG.DSMB Members:The DRS academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland; the Swiss Society of Anaesthesiology and Reanimation (SGAR), Berne, Switzerland; the Swiss Foundation for Anaesthesia Research, Zurich, Switzerland; Vifor SA, Villars-sur-Gl\u00e2ne, Switzerland; and Vifor (International) AG, St. Gallen, Switzerland. DRS is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland; CSL Behring GmbH, Marburg, Germany; LFB Biom\u00e9dicaments, Courtaboeuf Cedex, France; and Octapharma AG, Lachen, Switzerland. DRS received honouraria\/travel support for consulting or lecturing from: Danube University of Krems, Austria; US Department of Defense, Washington, USA; European Society of Anaesthesiology, Brussels, BE; Korean Society for Patient Blood Management, Seoul, Korea; Korean Society of Anesthesiologists, Seoul, Korea; Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis, Paris, France; Baxalta Switzerland AG, Volketswil, Switzerland; Bayer AG, Z\u00fcrich, Switzerland; B. Braun Melsungen AG, Melsungen, Germany; Boehringer Ingelheim GmbH, Basel, Switzerland; Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland; CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland; Celgene International II S\u00e0rl, Couvet, Switzerland; Daiichi Sankyo AG, Thalwil, Switzerland; Haemonetics, Braintree, MA, USA; Instrumentation Laboratory (Werfen), Bedford, MA, USA; LFB Biom\u00e9dicaments, Courtaboeuf Cedex, France; Merck Sharp & Dohme, Kenilworth, New Jersey, USA; PAION Deutschland GmbH, Aachen, Germany; Pharmacosmos A\/S, Holbaek, Denmark; Pfizer AG, Z\u00fcrich, Switzerland; Pierre Fabre Pharma, Alschwil, Switzerland; Portola Schweiz GmbH, Aarau, Switzerland; Roche Diagnostics International Ltd, Reinach, Switzerland; Sarstedt AG & Co., Sevelen, Switzerland and N\u00fcmbrecht, Germany; Shire Switzerland GmbH, Zug, Switzerland; Tem International GmbH, Munich, Germany; Vifor Pharma, Munich, Germany; Neuilly sur Seine, France and Villars-sur-Gl\u00e2ne, Switzerland; Vifor (International) AG, St. Gallen, Switzerland; and Zuellig Pharma Holdings, Singapore, Singapore.PFL received honouraria consultation with B. Braun Melsungen AG, Melsungen, Germany.HS is employed by Pharmalog \u2013Institut f\u00fcr klinische Forschung and contracted by B. Braun Melsungen AG, Melsungen, Germany, for statistical consulting services.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"376"}}