{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:06:44Z","timestamp":1790186804844,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The optimal vasopressor-escalation strategy after norepinephrine in septic shock remains uncertain, with randomized trials showing no clear winner and observational data suggesting severity-dependent effects. We characterized severity-stratified heterogeneity for adding vasopressin or epinephrine to norepinephrine and tested external replicability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>We emulated a target trial in Medical Information Mart for Intensive Care IV (MIMIC-IV) (derivation) and eICU Collaborative Research Database (eICU-CRD) (external validation), enrolling adults with Sepsis-3 septic shock who started norepinephrine. Patients were classified as S1 (norepinephrine alone), S2 (plus vasopressin), or S3 (plus epinephrine) by the agent added in a baseline window. The primary outcome was 14-day administratively truncated in-hospital mortality. Average treatment effects were estimated with a cross-fitted doubly robust learner, anchored on a prespecified norepinephrine-equivalent dose below 0.25\u00a0\u03bcg\/kg\/min, with subgroups, sensitivity analyses, and E-values. A depth-2 policy tree summarized heterogeneity, not a decision rule.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      After trimming, 2,415 MIMIC-IV and 568 eICU-CRD patients were analyzed. Cohort-level effects were heterogeneous and did not replicate: in MIMIC-IV, S3\n                      <jats:italic>versus<\/jats:italic>\n                      S1 was \u22129.66 percentage points (95% confidence interval \u221219.36 to \u22120.11) and S2\n                      <jats:italic>versus<\/jats:italic>\n                      S1 was null (+1.60; \u22127.79 to +5.47), whereas in eICU-CRD the S3 contrast reversed (+0.73; \u221226.10 to +28.44). At the low-dose anchor, S3\n                      <jats:italic>versus<\/jats:italic>\n                      S1 was \u221210.87 pp (\u221219.66 to +2.97) in MIMIC-IV and directionally consistent but imprecise in eICU-CRD (\u221213.72; \u221248.24 to +9.47); the anchor E-value of 2.19 exceeded plausible unmeasured confounding. The S2 contrast was the one most exposed to confounding by indication (E-value 1.24).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Vasopressor-escalation effects were heterogeneous and concentrated at low baseline severity, with a directionally consistent but unconfirmed signal favoring epinephrine below the Surviving Sepsis Campaign dose threshold. These findings are hypothesis-generating and do not support changing first-line practice; future trials should stratify on baseline norepinephrine-equivalent dose rather than enroll uniform cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1876555","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:11:35Z","timestamp":1784819495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Severity-stratified vasopressor-escalation strategies in septic shock: a cross-fitted doubly robust analysis with external replication"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuhang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Zigong Fourth People\u2019s Hospital","place":["Zigong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Zigong Fourth People\u2019s Hospital","place":["Zigong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13613-022-01021-9","article-title":"Timing of vasoactive agents and corticosteroid initiation in septic shock","volume":"12","author":"Ammar","year":"2022","journal-title":"Ann. 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