{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:31:12Z","timestamp":1793730672525,"version":"4.6.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Medizinische Hochschule Hannover (MHH)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["ICMx"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite extensive research, effective causal therapies for sepsis remain elusive, highlighting a persistent translational gap between biological understanding and clinical outcomes. Traditional randomised clinical trials (RCTs) have largely failed, likely due to profound patient heterogeneity, dynamic immune trajectories, and reliance on broad syndromic definitions coupled with mortality-centric endpoints. Such designs risk diluting treatment effects and obscuring biologically meaningful signals. Recent studies, however, suggest that precision medicine approaches may overcome these limitations. Trials such as ANDROMEDA-SHOCK-2, IMMUNOSEP, INSPIRE, and TIGRIS have operationalised patient stratification based on physiological or immunological phenotypes and employed novel endpoints or statistical frameworks. ANDROMEDA-SHOCK-2 used capillary refill time guided haemodynamic resuscitation and a hierarchical win-ratio composite endpoint to personalise treatment and enhance sensitivity to benefit. IMMUNOSEP stratified patients by macrophage activation-like syndrome or immunoparalysis, demonstrating improved organ function with targeted interventions using the SOFA score as a primary endpoint. Similarly, INSPIRE focused on progression to organ dysfunction in high-risk pneumonia patients, while TIGRIS employed Bayesian analysis to enrich patients by endotoxin activity, increasing trial efficiency. These studies illustrate that aligning interventions with biological pathways, incorporating adaptive trial designs, and moving beyond short-term mortality can reveal clinically meaningful benefits obscured in conventional trials. Collectively, they signal a conceptual shift in sepsis research towards precision-guided therapies, adaptive protocols, and biologically informed endpoints, suggesting that the era of universal failure may be giving way to more targeted, effective approaches in critical care.<\/jats:p>","DOI":"10.1186\/s40635-026-00911-7","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T03:45:44Z","timestamp":1780285544000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Innovation in sepsis trials: rethinking endpoints, statistics and patient stratification"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8231-0461","authenticated-orcid":false,"given":"Sascha","family":"David","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Leone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Girardis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia M.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srdjan","family":"Gavrilovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Domizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Damiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Martin-Loeches","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricard","family":"Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Chousterman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"911_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s00063-025-01317-1","volume":"120","author":"FM Brunkhorst","year":"2025","unstructured":"Brunkhorst FM, Adamzik M, Axer H, Bauer M, Bode C, Bone HG, Brenner T, Bucher M, David S, Dietrich M, Eckmann C, Elke G, Esser T, Felbinger T, Geffers C, Gerlach H, Grabein B, Grundling M, Gunther U, Hagel S, Hecker A, Henkel S, Janusan B, John S, Jorres A, Kaasch A, Kluge S, Kochanek M, Lajca A, Marx G, Mayer K, Meybohm P, Morer O, Oppert M, Patchev V, Pletz M, Putensen C, Rahmel T, Rosendahl J, Rossaint R, Salzberger B, Sander M, Schaller S, Scharf-Janssen C, Schmitt F, Unterberg M, Weigand M, Weimann A, Weis S, Weiss B, Wolf A, Zarbock A (2025) S3 guideline on sepsis-prevention, diagnosis, therapy, and follow-up care-update 2025. Med Klin Intensivmed Notfmed 120:163\u2013231","journal-title":"Med Klin Intensivmed Notfmed"},{"key":"911_CR2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000007089","author":"HC Prescott","year":"2026","unstructured":"Prescott HC, Antonelli M, Alhazzani W, Moller MH, Alshamsi F, Azevedo LCP, Belley-Cote E, De Waele J, Derde L, Dionne JC, Evans L, Gershengorn HB, Hodgson CL, Honarmand K, Kesecioglu J, McIntyre L, Mer M, Nunnally ME, Oczkowski SJW, Rochwerg B, Akinola OO, Akuamoah-Boateng KA, Alberto L, Angus DC, Arabi YM, Azoulay E, Cecconi M, Convocar PF, De Pascale G, Doi K, Du B, Egi M, Elie-Turenne MC, Ferrer R, Fox-Robichaud A, French C, Freund Y, Gong MN, Hale CP, Hammond NE, Hashmi M, Heunks L, Iwashyna TJ, Jacob ST, Klompas M, Kwizera A, Leeies M, Lejnieks JD, Levy MM, Machado FR, Maia MO, Masur H, Maves RC, McGloughlin S, McPeake J, Mohr NM, Myatra SN, Ostermann M, Peake SL, Pletz MW, Roberts JA, Rosa RG, Sawyer RG, Schorr CA, Simpson SQ, Weng L, Wiersinga WJ, Rhodes A, Coopersmith CM (2026) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2026. Intensive Care Med. https:\/\/doi.org\/10.1097\/CCM.0000000000007089","journal-title":"Intensive Care Med"},{"key":"911_CR3","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1038\/s41591-022-01843-x","volume":"28","author":"DM Maslove","year":"2022","unstructured":"Maslove DM, Tang B, Shankar-Hari M, Lawler PR, Angus DC, Baillie JK, Baron RM, Bauer M, Buchman TG, Calfee CS, Dos Santos CC, Giamarellos-Bourboulis EJ, Gordon AC, Kellum JA, Knight JC, Leligdowicz A, McAuley DF, McLean AS, Menon DK, Meyer NJ, Moldawer LL, Reddy K, Reilly JP, Russell JA, Sevransky JE, Seymour CW, Shapiro NI, Singer M, Summers C, Sweeney TE, Thompson BT, van der Poll T, Venkatesh B, Walley KR, Walsh TS, Ware LB, Wong HR, Zador ZE, Marshall JC (2022) Redefining critical illness. Nat Med 28:1141\u20131148","journal-title":"Nat Med"},{"key":"911_CR4","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801\u2013810","journal-title":"JAMA"},{"key":"911_CR5","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s40635-026-00877-6","volume":"14","author":"S David","year":"2026","unstructured":"David S, Leone M, Girardis M, Muller MM, Gavrilovic S, Domizi R, Damiani E, Martin-Loeches I, Ferrer R, Chousterman B, Russell L (2026) Clinical practice in using corticosteroids and adjunctive sepsis therapies at the bedside among European ICUs: an ESICM-endorsed survey. Intensive Care Med Exp 14:33","journal-title":"Intensive Care Med Exp"},{"key":"911_CR6","doi-asserted-by":"publisher","first-page":"e2013","DOI":"10.1016\/S2214-109X(25)00356-0","volume":"13","author":"Collaborators GBDGS","year":"2025","unstructured":"Collaborators GBDGS (2025) Global, regional, and national sepsis incidence and mortality, 1990-2021: a systematic analysis. Lancet Glob Health 13:e2013\u2013e2026","journal-title":"Lancet Glob Health"},{"key":"911_CR7","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1186\/s13054-023-04762-6","volume":"27","author":"C Bode","year":"2023","unstructured":"Bode C, Weis S, Sauer A, Wendel-Garcia P, David S (2023) Targeting the host response in sepsis: current approaches and future evidence. Crit Care 27:478","journal-title":"Crit Care"},{"key":"911_CR8","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/S2213-2600(23)00330-2","volume":"12","author":"S Cajander","year":"2024","unstructured":"Cajander S, Kox M, Scicluna BP, Weigand MA, Mora RA, Flohe SB, Martin-Loeches I, Lachmann G, Girardis M, Garcia-Salido A, Brunkhorst FM, Bauer M, Torres A, Cossarizza A, Monneret G, Cavaillon JM, Shankar-Hari M, Giamarellos-Bourboulis EJ, Winkler MS, Skirecki T, Osuchowski M, Rubio I, Bermejo-Martin JF, Schefold JC, Venet F (2024) Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. Lancet Respir Med 12:305\u2013322","journal-title":"Lancet Respir Med"},{"key":"911_CR9","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1007\/s00134-024-07586-2","volume":"50","author":"M Girardis","year":"2024","unstructured":"Girardis M, David S, Ferrer R, Helms J, Juffermans NP, Martin-Loeches I, Povoa P, Russell L, Shankar-Hari M, Iba T, Coloretti I, Parchim N, Nielsen ND (2024) Understanding, assessing and treating immune, endothelial and haemostasis dysfunctions in bacterial sepsis. Intensive Care Med 50:1580\u20131592","journal-title":"Intensive Care Med"},{"key":"911_CR10","doi-asserted-by":"publisher","first-page":"S101","DOI":"10.21037\/jtd.2019.10.36","volume":"12","author":"ARJ Girbes","year":"2020","unstructured":"Girbes ARJ, de Grooth HJ (2020) Time to stop randomized and large pragmatic trials for intensive care medicine syndromes: the case of sepsis and acute respiratory distress syndrome. J Thorac Dis 12:S101\u2013S109","journal-title":"J Thorac Dis"},{"key":"911_CR11","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1001\/jama.2025.20402","volume":"334","author":"T Pain","year":"2025","unstructured":"Andromeda-Shock-2 Investigators for the Andromeda Research Network SSoAR, Pain T, Latin American Intensive Care N, Hernandez G, Ospina-Tascon GA, Kattan E, Ibarra-Estrada M, Ramasco F, Orozco N, Ramos K, Aldana JL, Ferri G, Hamzaoui O, De Backer D, Teboul JL, Vieillard-Baron A, Petri Damiani L, Garcia-Gallardo GA, Morales S, Carmona Garcia P, Mendez R, Hernandez-Gilsoul T, Perez-Nieto OR, Olea Vielba C, Ramos S, Dominguez D, Bruna M, David S, Wendel-Garcia PD, Galiana-Ivars M, Myatra SN, Messina A, Cecconi M, Pozo M, Amthauer M, Higuera E, Al Duhalib Z, Rico-Feijoo J, Ferrer-Gomez C, Perez-Carbonell A, Martinez-Castro S, Redondo Calvo FJ, Vives M, Sanchez HF, Bilbao I, Fernandez P, Al-Fares A, Benitez-Cano A, Gonzalez C, Reyes LF, Rodriguez-Guillen JH, Cristino AV, Pendino JC, Ortiz G, Alonso-Gonzalez MC, Murias G, Aguirre-Avalos G, Hernandez L, Calderon Barajas ZA, Zarragoikoetxea I, Monnet X, Goury A, Mendonca Dos Santos T, Vallecilla L, Martins de Lima L, Sady E, Alegria L, Ostermann M, Bakker J, Biasi Cavalcanti A (2025) Personalized hemodynamic resuscitation targeting capillary refill time in early septic shock: the ANDROMEDA-SHOCK-2 randomized clinical trial. JAMA 334:1988\u20131999","journal-title":"JAMA"},{"issue":"9","key":"911_CR12","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1001\/jama.2025.24175","volume":"335","author":"EJ Giamarellos-Bourboulis","year":"2025","unstructured":"Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, Efthymiou A, Koutsoukou V, Ehler J, Paridou A, Frantzeskaki F, Muller MCA, Pickkers P, Meylan S, Nikolopoulos I, Lupse M, Gavala A, Vlachogianni G, Solomonidi N, Alevizou A, Kondili E, Antoniadou E, Nakou M, Markou N, Hatziagelaki E, Prekates A, Komnos A, Bakkerus L, Slim MA, Dalekos GN, Karapanagiotou A, Ktena S, De Pascale G, Koulouras V, Psarrakis C, Massa E, Dakou K, Pazvanti C, Ioakeimidou A, Tsangaris I, Antonakos N, Vlaar APJ, Anisoglou S, Calandra T, Papaioannou V, Myrianthefs P, Patrani M, Alamanos I, Antonelli M, van der Meer JWM, van der Poll T, Wiersinga WJ, Ntaganou M, Gkeka E, Bauer M, Mouloudi E, Netea MG, ImmunoSep Study G (2025) Precision immunotherapy to improve sepsis outcomes: the immunosep randomized clinical trial. JAMA 335(9):775\u2013786","journal-title":"JAMA"},{"key":"911_CR13","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1001\/jama.2012.5833","volume":"307","author":"FM Brunkhorst","year":"2012","unstructured":"Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Grundling M, Moerer O, Riessen R, Seibel A, Ragaller M, Buchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bogatsch H, Engel C, Loeffler M, Kollef MH, Reinhart K, Welte T, German Study Group Competence Network S (2012) Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 307:2390\u20132399","journal-title":"JAMA"},{"key":"911_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2025.101573","volume":"62","author":"G Tavoulareas","year":"2026","unstructured":"Tavoulareas G, Kontakou-Zoniou O, Antonakos N, Tasouli E, Adamis G, Kakavoulis N, Michelakis E, Skopelitis I, Dakou K, Psarrakis C, Koufargyris P, Astriti M, Sympardi S, Giamarellos-Bourboulis EJ (2026) Efficacy of Anakinra in reducing progression to organ dysfunction in patients with pneumonia (INSPIRE): a randomised, double-blind, placebo-controlled, phase IIa trial. Lancet Reg Health Eur 62:101573","journal-title":"Lancet Reg Health Eur"},{"key":"911_CR15","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/S2213-2600(26)00047-0","volume":"14","author":"JA Neyra","year":"2026","unstructured":"Neyra JA, Legrand M, Tidswell MA, Al-Khafaji A, Galphin C, Rains R, Davison D, Tolwani A, Chen JT, Bender WS, Busse LW, Meena NK, DellaVolpe J, Williams GW, Kashani KB, Gunnerson KJ, McMahon BA, Eaton J, Khan S, Kohli-Seth R, Jagpal S, Klein D, Kamaluddin E, Foster DM, Walker PM, Tomlinson G, Kellum JA (2026) Polymyxin B haemoadsorption in endotoxic septic shock (Tigris): a multicentre, open-label, Bayesian, randomised, controlled, phase 3 trial. Lancet Respir Med 14:443\u2013452","journal-title":"Lancet Respir Med"},{"key":"911_CR16","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1007\/s00134-018-5463-7","volume":"44","author":"DJ Klein","year":"2018","unstructured":"Klein DJ, Foster D, Walker PM, Bagshaw SM, Mekonnen H, Antonelli M (2018) Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive Care Med 44:2205\u20132212","journal-title":"Intensive Care Med"},{"key":"911_CR17","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1001\/jama.2018.14618","volume":"320","author":"RP Dellinger","year":"2018","unstructured":"Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, Palevsky PM, Weisberg LS, Schorr CA, Trzeciak S, Walker PM, Investigators ET (2018) Effect of targeted Polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level: The EUPHRATES randomized clinical trial. JAMA 320:1455\u20131463","journal-title":"JAMA"},{"key":"911_CR18","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1093\/eurheartj\/ehr352","volume":"33","author":"SJ Pocock","year":"2012","unstructured":"Pocock SJ, Ariti CA, Collier TJ, Wang D (2012) The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J 33:176\u2013182","journal-title":"Eur Heart J"},{"key":"911_CR19","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1161\/CIRCULATIONAHA.123.067786","volume":"149","author":"J Butler","year":"2024","unstructured":"Butler J, Stockbridge N, Packer M (2024) Win ratio: a seductive but potentially misleading method for evaluating evidence from clinical trials. Circulation 149:1546\u20131548","journal-title":"Circulation"},{"key":"911_CR20","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1093\/ageing\/afab036","volume":"50","author":"LEM Haas","year":"2021","unstructured":"Haas LEM, Boumendil A, Flaatten H, Guidet B, Ibarz M, Jung C, Moreno R, Morandi A, Andersen FH, Zafeiridis T, Walther S, Oeyen S, Leaver S, Watson X, Boulanger C, Szczeklik W, Schefold JC, Cecconi M, Marsh B, Joannidis M, Nalapko Y, Elhadi M, Fjolner J, Artigas A, de Lange DW, group VIPs (2021) Frailty is associated with long-term outcome in patients with sepsis who are over 80 years old: results from an observational study in 241 European ICUs. Age Ageing 50:1719\u20131727","journal-title":"Age Ageing"},{"key":"911_CR21","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s40121-024-01106-x","volume":"14","author":"S Basu","year":"2025","unstructured":"Basu S, Wei ZJ, Laor A, Bennetts L, Ahmad N, El Khoury AC, Geurtsen J, Neary MP (2025) Health-related quality of life among patients who have survived an episode of sepsis in the United States: a systematic review. Infect Dis Ther 14:385\u2013400","journal-title":"Infect Dis Ther"}],"container-title":["Intensive Care Medicine Experimental"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-026-00911-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40635-026-00911-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-026-00911-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T03:45:49Z","timestamp":1780285549000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s40635-026-00911-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":21,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["911"],"URL":"https:\/\/doi.org\/10.1186\/s40635-026-00911-7","relation":{},"ISSN":["2197-425X"],"issn-type":[{"value":"2197-425X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"assertion":[{"value":"22 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","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":"All authors have no competing interest related to the topic of this review article. SD is a co-author of the Andromeda-Shock 2 trial.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"65"}}