{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:49:12Z","timestamp":1782118152826,"version":"3.54.5"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"J\u00f6nk\u00f6ping University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["ICMx"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Septic shock is heterogeneous, and noradrenaline (NA) requirements evolve over time in ways that reflect vascular responsiveness and shock biology. Whether long-horizon NA dose-trajectory phenotypes are reproducible across healthcare systems and identifiable early in the clinical course remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed 1111 adults with septic shock at Sheba Medical Center (Israel) and 9343 adults from MIMIC-IV. Hourly NA infusion trajectories were reconstructed for 10\u00a0days. A fully prespecified clustering pipeline combining static-feature K-means with dynamic time warping refinement was derived in Sheba and applied unchanged to MIMIC-IV. The primary outcome was 90-day mortality; 30-day mortality was analyzed as a supportive secondary outcome. Secondary analyses included feature interpretability, multivariable landmark Cox models (24\u2013144\u00a0h), and early phenotype prediction using exposure features available at 24\u201396\u00a0h.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five stable phenotypes emerged in Sheba and six in MIMIC-IV. Despite this numerical difference and somewhat more prolonged high-dose exposure in Sheba sustained\/late-escalating patterns, both cohorts exhibited the same core families of trajectory shapes with preserved mortality gradients (90-day mortality 37\u201389% in Sheba; 16\u201369% in MIMIC-IV). Mortality gradients were preserved at both 30 and 90\u00a0days across cohorts. Across cohorts, exposure-persistence features\u2014particularly time to maximal NA dose and cumulative NA burden during days 2\u20134\u2014were key determinants of phenotype structure and mortality. Early-prediction models identified final phenotypes using 24-h data with 85% accuracy in Sheba and 86% in MIMIC-IV, improving by 48\u00a0h to 89% and 88%, respectively; high-confidence assignments achieved approximately 91%\u201395% accuracy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Long-horizon NA dose-trajectory phenotypes are clinically interpretable hemodynamic exposure\/response patterns, prognostically coherent, and externally reproducible. Their defining features were detectable within the first 24\u00a0h and showed stronger discrimination by 48\u00a0h. At present, these phenotypes should be interpreted as descriptive hemodynamic-response patterns that may support dynamic risk stratification, prognostic enrichment for future trials, and hypothesis generation; whether early phenotype identification can improve management or outcomes requires prospective evaluation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40635-026-00910-8","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:11:21Z","timestamp":1782115881000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Noradrenaline-trajectory phenotypes in septic shock: derivation and external validation in two independent cohorts"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5498-8513","authenticated-orcid":false,"given":"Gargi","family":"Yonatan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorit","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ori","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dor","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamutal S.","family":"Taube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Vine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Glebov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7851-8147","authenticated-orcid":false,"given":"Teddy","family":"Lazebnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mor","family":"Saban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Haviv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eran","family":"Segal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"issue":"8","key":"910_CR1","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 et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801\u2013810. https:\/\/doi.org\/10.1001\/jama.2016.0287","journal-title":"JAMA"},{"issue":"3","key":"910_CR2","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1007\/s00134-017-4683-6","volume":"43","author":"A Rhodes","year":"2017","unstructured":"Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43(3):304\u2013377. https:\/\/doi.org\/10.1007\/s00134-017-4683-6. (Epub 2017 Jan 18. PMID: 28101605)","journal-title":"Intensive Care Med"},{"issue":"1","key":"910_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-025-05717-9","volume":"29","author":"M Reinikainen","year":"2025","unstructured":"Reinikainen M, Delamarre L, Blaser AR, Hollenberg SM, Lobo SM, Rezende E, Moreno R, Rhodes A, Ranzani OT, Singer M, Lakbar I (2025) Association of noradrenaline dose with mortality in critically ill patients: a systematic review and dose-response meta-analysis. 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The requirement for informed consent was waived due to the retrospective design and use of anonymized data. All procedures were conducted in accordance with the ethical standards of the responsible committee and with the 1964 Declaration of Helsinki and its later amendments.MIMIC-IV is a publicly available, fully de-identified critical care database approved for research use with a waiver of informed consent. All analyses were conducted under the required data use agreement and did not require additional IRB approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The Sheba Hospital Research IRB provided a waiver for consent due to the retrospective and aggregative nature of the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All the authors declare that they have no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"77"}}