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Extracorporeal blood purification (EBP) therapies traditionally aim to remove circulating mediators involved in this pathological response, although novel technologies that can remove cells and even living pathogens have recently been developed. Despite their growing clinical use, robust evidence supporting EBP in septic shock as an adjuvant therapy is lacking, and several knowledge gaps hinder their effective and safe application. This narrative review critically examines these gaps from both mechanistic and clinical perspectives. Key issues include the dynamic and compartmentalized nature of the immune response, the unclear roles of specific cytokines, and the potential removal of protective anti-inflammatory mediators. Broad-spectrum adsorption may induce unintended immunomodulatory effects, including desorption and altered leukocyte trafficking. Selective approaches, such as endotoxin removal with polymyxin B hemoadsorption, face challenges related to dose, patient stratification, and the limitations of endotoxin activity assays. Therapeutic plasma exchange offers the potential to restore homeostasis but raises questions regarding optimal regimens, replacement fluids, and the risk of unintended drug clearance. The heterogeneity of trial designs, insufficient patient phenotyping, and variability in treatment protocols have led to inconclusive or conflicting clinical outcomes, including some trials suggesting potential harm. This review underscores the need for better mechanistic understanding, real-time immune monitoring, and ideally targeted clinical trial designs to define which patients might benefit from EBP and when. Ultimately, the path to effective application of EBP in sepsis lies in individualized therapy guided by immune profiling, biomarker-driven stratification, and rigorous evaluation in high-quality randomized controlled trials.<\/jats:p>","DOI":"10.1186\/s40635-025-00819-8","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T03:00:00Z","timestamp":1763694000000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Knowledge gaps in extracorporeal blood purification: what would be required for its successful application in septic shock?"],"prefix":"10.1186","volume":"13","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":"Thomas","family":"Rimmel\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Joannidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Girardis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pickkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan D.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Buhlmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Molnar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Ostermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan T.","family":"Kielstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro David","family":"Wendel-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Stahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"819_CR1","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1056\/NEJMp1707170","volume":"377","author":"K Reinhart","year":"2017","unstructured":"Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S (2017) Recognizing sepsis as a global health priority - a WHO resolution. 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Sci Rep 15:17626","journal-title":"Sci Rep"}],"container-title":["Intensive Care Medicine Experimental"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-025-00819-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40635-025-00819-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40635-025-00819-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:04:27Z","timestamp":1763701467000},"score":1,"resource":{"primary":{"URL":"https:\/\/icm-experimental.springeropen.com\/articles\/10.1186\/s40635-025-00819-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":96,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["819"],"URL":"https:\/\/doi.org\/10.1186\/s40635-025-00819-8","relation":{},"ISSN":["2197-425X"],"issn-type":[{"value":"2197-425X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"assertion":[{"value":"13 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2025","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":"SD, CB and KS are principal investigators of EXCHANGE-2. This trial tests plasma exchange in septic shock and is supported by the German Research Foundation (DFG DA 1209\/7\u20131) and by Octapharma. SD and KS are supported with an unrestricted research grant from Cytosorbents. SD is an advisor for Santersus, Vantive and Octapharma. TR has recently received lecture fees at scientific conferences from Jafron, Vantive, Fresenius Medical Care, Cytosorbents, Estor and Nikkiso. MO has received research funding from Baxter and Biomerieux (paid to institution). MJ has received honoraria and\/or research support from Baxter Healthcare Corp, AM-Pharma, CLS Behring, Fresenius, Biomerieux, and Novartis. ZM has received lecture and consultation honoraria from CytoSorbents, ThermoFisher. MG has received honoraria for speaking at conferences from Estor and Fresenius.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"118"}}