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Although emerging therapeutic strategies targeting pathways such as calcium signaling, TNF-\u03b1, the NLRP3 inflammasome, and HMGB1 have shown promise, their efficacy may be limited by the underlying biological heterogeneity of the disease. In this multinational retrospective cohort study across three large ICU databases (ICU-HAI, MIMIC-IV, and eICU-CRD), we used group-based trajectory modeling of early vital signs to identify four distinct AP subphenotypes: hyperinflammatory, hypertensive, hypotensive, and hypoinflammatory. These subtypes differed markedly in 30-day mortality, inflammatory burden, and hemodynamic stability. Compared to the hypertensive phenotype, hyperinflammatory and hypotensive patients had significantly higher 30-day mortality risks (HR\u2009=\u20093.38 and HR\u2009=\u20091.87, respectively), while the hypoinflammatory phenotype carried no excess risk. Fluid resuscitation responses were phenotype-specific: hyperinflammatory patients benefited from higher fluid volumes, whereas hypoinflammatory patients were at risk of fluid overload. Notably, distinct subphenotypes displayed unique responses to fluid intake over the first two ICU days. For hyperinflammatory phenotype, the algorithm-estimated lowest-risk fluid range was 4100\u20134300\u2009mL on day 1 and 3400\u20133600\u2009mL on day 2; for phenotype hypoinflammatory phenotype, the optimal ranges were 2800\u20133800\u2009mL and 1400\u20132600\u2009mL, respectively. Early use of lactated Ringer\u2019s solution, which inhibited NLRP3, was associated with reduced mortality in hypotensive phenotype. These findings underscore the clinical relevance of early physiological trajectories and support precision fluid resuscitation based on subtype. This study establishes the largest early-trajectory-based classification of AP to date, offering new insights into immune and vascular mechanisms that drive heterogeneity and therapeutic responsiveness.<\/jats:p>","DOI":"10.1038\/s41392-025-02261-4","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:32:34Z","timestamp":1749011554000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Development and validation of dynamic clinical subphenotypes in acute pancreatitis patients using vital sign trajectories in intensive care units: a multinational cohort study"],"prefix":"10.1038","volume":"10","author":[{"given":"Zichen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayue","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyi","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-7088","authenticated-orcid":false,"given":"Xin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"2261_CR1","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1001\/jama.2020.20317","volume":"325","author":"MA Mederos","year":"2021","unstructured":"Mederos, M. 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The author completed the required training (Collaborative Institutional Training Initiative ID: 37078282) and signed relevant agreements to access restricted public data. All data used in this study were retrospective, de-identified, and observational in nature; informed consent was formally waived by the ethics committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"180"}}