{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:04:55Z","timestamp":1789538695480,"version":"build-2803163510"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Associations of chloride and bicarbonate abnormalities with sepsis outcomes have been studied separately, but whether a prespecified paired classification provides reproducible and interpretable risk characterization remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included adults with sepsis in MIMIC-IV v3.1 and eICU v2.0. Chloride (&amp;lt;98, 98\u2013107, &amp;gt;107\u2005mmol\/L) and bicarbonate (&amp;lt;22, 22\u201326, &amp;gt;26\u2005mmol\/L) defined a 3\u2009\u00d7\u20093 phenotype. In-hospital mortality was analyzed using multivariable logistic regression and predictive mean matching multiple imputation. Robustness was assessed through analyses of temporal ordering, threshold selection, cross-database heterogeneity, external transportability, and first-day changes in chloride and bicarbonate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The cohorts included 25,842 MIMIC-IV stays and 37,045 eICU stays, with mortality rates of 16.31% and 15.50%, respectively. In complete-case Model 3b, the phenotype was globally associated with mortality in both cohorts; the low-low contrast was individually significant in eICU but not MIMIC-IV. The low-low association was supported in multiple-imputation analyses (MIMIC-IV OR 1.276, 95% CI 1.066\u20131.527; eICU OR 1.507, 95% CI 1.277\u20131.779) and in strict pre-exposure analyses (OR 1.700 and 1.787, respectively). Formal 4-df categorical interaction tests were not significant (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.095 and\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.109). MIMIC-IV-derived data-driven cut points did not significantly outperform the clinical 3\u2009\u00d7\u20093 phenotype in eICU (CART vs. clinical \u0394AUROC 0.0009, 95% CI \u22120.0010 to 0.0029). In the main MIMIC-IV-to-eICU validation, adding the clinical phenotype left discrimination essentially unchanged (\u0394AUROC 0.0010, 95% CI \u22120.0013 to 0.0031), although the Brier score improved modestly (\u0394Brier \u22120.0011, 95% CI \u22120.0016 to \u22120.0006); NRI and IDI did not support improved discrimination or reclassification. Incident and persistent low-low states were both associated with higher subsequent mortality in 24\u2005h landmark analyses in both cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Prespecified chloride-bicarbonate phenotypes were associated with mortality in both databases, and persistence or incident development of the low-low state during the first ICU day was associated with higher subsequent mortality. The 3\u2009\u00d7\u20093 framework should therefore be interpreted primarily as a transparent, direction-preserving approach to descriptive risk characterization within a broader clinical assessment, rather than as a stand-alone prediction instrument, therapeutic threshold, or treatment guide.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1947296","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:32:34Z","timestamp":1789536754000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of early chloride-bicarbonate joint phenotypes with in-hospital mortality among intensive care unit patients with sepsis: a dual-database study"],"prefix":"10.3389","volume":"13","author":[{"given":"Liang","family":"Wang","sequence":"first","affiliation":[{"name":"School of Medicine, University of Electronic Science and Technology of China","place":["Chengdu, 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