{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:24:10Z","timestamp":1792027450151,"version":"4.4.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016224","name":"Univerzitetni Klini\u00c4ni Center Maribor","doi-asserted-by":"publisher","award":["Grant No.: OZRD-IRP-2023\/01; project code IRP-2023\/01-03"],"award-info":[{"award-number":["Grant No.: OZRD-IRP-2023\/01; project code IRP-2023\/01-03"]}],"id":[{"id":"10.13039\/501100016224","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>The main mechanism of hypotension in septic shock is persistent vasodilation secondary to vascular hyporeactivity despite high endogenous catecholamine levels and despite endogenous activation of the renin-angiotensin-aldosterone system. The classic stepwise approach involves initiation of norepinephrine, up-titration of the dosage to achieve a specified mean arterial pressure and moving to a second-line vasopressor if the patient remains refractory to norepinephrine. This approach often leads to prolonged states of hypoperfusion and high dose catecholamine exposure and is associated with poor clinical outcomes. Given the multifactorial basis of vasodilation in septic shock there is a strong physiological rationale for the early introduction of a multimodal vasopressor strategy that would provide a more physiologically guided approach. This study will compare the effects of a classic stepwise vs. an early balanced multimodal vasopressor strategy in septic shock.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This is a single blind randomized Phase II study. Patients with septic shock will be randomly assigned to control (classic stepwise vasopressor administration, n\u2009=\u200940) versus interventional (balanced multimodal vasopressor administration, n\u2009=\u200940) groups. The study employs a superiority trial design. Patients in the control group will be started on norepinephrine followed by vasopressin. Additional vasoactive drugs will be added as per the clinical team\u2019s decision. In the interventional group, patients will simultaneously receive norepinephrine, angiotensin II and vasopressin at equipotent starting doses. We hypothesize that balanced multimodal vasopressor administration will result in a significant decrease in renin levels compared to the conventional stepwise strategy. Several secondary and exploratory outcome measures will be investigated. Univariate statistical tests with generalized linear modeling will be used to test for significant differences between the groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>The goal of this randomized controlled trial is to test the clinical efficacy of an early multimodal vasopressor strategy in septic shock. It aims to provide new insights and contribute to improved management of vasodilatory states.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>ClinicalTrials.gov NCT06155812.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0331304","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T17:29:51Z","timestamp":1756488591000},"page":"e0331304","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Early multimodal vasopressor strategy in septic shock (TRICYCLE)\u2014Study protocol for a randomized controlled clinical 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