{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T18:17:46Z","timestamp":1782152266360,"version":"3.54.5"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82360019"],"award-info":[{"award-number":["82360019"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Norepinephrine (NE) is a first line and effective vasopressor for septic shock management, but its impact on newonset acute kidney injury (AKI) in those patients remains controversial. This study sought to investigate the relationship between norepinephrine dose trajectories and the new occurrence of AKI during the management of septic shock by using NE.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>A retrospective cohort study was conducted using the MIMIC-IV database, which includes 3,462 patients diagnosed with septic shock during the initial 96 hours following their admission to the ICU. The unique patterns of trajectory analysis of NE were characterized by using group-based trajectory modeling (GBTM) during the initial four days of ICU admission. We employed multivariable logistic regression analysis and subgroup analysis to evaluate the association between NE dose trajectories and new-onset AKI in patients with septic shock.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Three NE dose trajectories were identified: low NE dose (47.3%), middle NE dose (41.5%), and high NE dose (11.2%). The high NE dose trajectory had significantly higher risks for new onset of AKI (OR 2.39, 95% CI 1.43\u20133.99), MAKE-30 (OR 3.82, 95% CI 2.97\u20134.91), and for 28-day mortality (HR 2.01, 95% CI 1.70\u20132.37) compared to the low NE dose trajectory. Despite over 90% of patients in the middle NE dose trajectory developing AKI, patients in this trajectory exhibited a lower risk of MAKE-30 and 28-day mortality. After comprehensive adjustment for demographic characteristics, comorbidities, acute physiological status, laboratory indicators, and fluid management, high NE dose trajectory remained independently associated with increased risk of new-onset AKI (OR 1.39, 95% CI 1.04\u20131.86, P\u2009=\u20090.024), this association persisted across multiple subgroup analyses.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>During the management of septic shock, high dose of NE trajectory was associated with high likelihood of new onset of AKI, high possibility of MAKE-30 and high 28-day mortality in patients with septic shock. High NE dose trajectory serves as an independent predictor for assessing the risk of new-onset AKI in patients with septic shock.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0323431","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T17:34:18Z","timestamp":1747157658000},"page":"e0323431","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["High NE dose trajectory is associated with new onset of acute kidney injury patients: A group-based trajectory modeling analysis"],"prefix":"10.1371","volume":"20","author":[{"given":"Jinfeng","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangzi","family":"Liujiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0807-8617","authenticated-orcid":true,"given":"Feng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"issue":"7","key":"pone.0323431.ref001","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1001\/jama.294.7.813","article-title":"Acute renal failure in critically ill patients: a multinational, multicenter study","volume":"294","author":"S Uchino","year":"2005","journal-title":"JAMA"},{"issue":"10","key":"pone.0323431.ref002","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41581-018-0052-0","article-title":"Global epidemiology and outcomes of acute kidney injury","volume":"14","author":"EAJ Hoste","year":"2018","journal-title":"Nat Rev Nephrol"},{"issue":"8","key":"pone.0323431.ref003","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"M Singer","year":"2016","journal-title":"JAMA"},{"issue":"1","key":"pone.0323431.ref004","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13613-019-0498-7","article-title":"Current use of vasopressors in septic shock","volume":"9","author":"TWL Scheeren","year":"2019","journal-title":"Ann Intensive Care"},{"issue":"3","key":"pone.0323431.ref005","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s00134-017-4683-6","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016","volume":"43","author":"A Rhodes","year":"2017","journal-title":"Intensive Care Med"},{"issue":"1","key":"pone.0323431.ref006","doi-asserted-by":"crossref","first-page":"22","DOI":"10.4037\/ajcc2013748","article-title":"High-dose norepinephrine treatment: determinants of mortality and futility in critically ill patients","volume":"22","author":"D D\u00f6pp-Zemel","year":"2013","journal-title":"Am J Crit Care"},{"issue":"5","key":"pone.0323431.ref007","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.jpainsymman.2016.12.333","article-title":"Intensity of Vasopressor Therapy for Septic Shock and the Risk of In-Hospital Death","volume":"53","author":"DA Brand","year":"2017","journal-title":"J Pain Symptom Manage"},{"issue":"5","key":"pone.0323431.ref008","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1378\/chest.07-0291","article-title":"Vasopressor support in septic shock","volume":"132","author":"SM Hollenberg","year":"2007","journal-title":"Chest"},{"issue":"1","key":"pone.0323431.ref009","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13613-017-0261-x","article-title":"Outcome of patients with septic shock and high-dose vasopressor therapy","volume":"7","author":"T Auchet","year":"2017","journal-title":"Ann Intensive Care"},{"key":"pone.0323431.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41597-022-01899-x","article-title":"MIMIC-IV, a freely accessible electronic health record dataset","volume":"10","author":"A Johnson","year":"2023","journal-title":"Sci Data"},{"key":"pone.0323431.ref011","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1097\/00003246-199811000-00016","article-title":"Use of the SOFA score to assess the incidence of organ dysfunction\/failure in intensive care units: results of a multicenter, prospective studyWorking group on \u201csepsis-related problems\u201d of the European Society of Intensive Care Medicine","volume":"26","author":"JL Vincent","year":"1998","journal-title":"Crit Care Med"},{"key":"pone.0323431.ref012","doi-asserted-by":"crossref","first-page":"103653","DOI":"10.1016\/j.jbi.2020.103653","article-title":"A prediction and interpretation framework of acute kidney injury in critical care","volume":"113","author":"K Gong","year":"2021","journal-title":"J Biomed Inform"},{"key":"pone.0323431.ref013","article-title":"Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls","volume":"338","author":"JAC Sterne","year":"2009","journal-title":"BMJ"},{"issue":"2","key":"pone.0323431.ref014","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.chest.2017.12.021","article-title":"Management of Refractory Vasodilatory Shock","volume":"154","author":"JC Jentzer","year":"2018","journal-title":"Chest"},{"issue":"8","key":"pone.0323431.ref015","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1001\/jama.2016.0289","article-title":"Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"M Shankar-Hari","year":"2016","journal-title":"JAMA"},{"issue":"4","key":"pone.0323431.ref016","doi-asserted-by":"crossref","DOI":"10.1159\/000339789","article-title":"KDIGO clinical practice guidelines for acute kidney injury","volume":"120","author":"A Khwaja","year":"2012","journal-title":"Nephron Clin Pract"},{"issue":"10212","key":"pone.0323431.ref017","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(19)32563-2","article-title":"Acute kidney injury","volume":"394","author":"C Ronco","year":"2019","journal-title":"Lancet"},{"issue":"4","key":"pone.0323431.ref018","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1097\/MAT.0b013e3181de35e4","article-title":"Volume-related weight gain and subsequent mortality in acute renal failure patients treated with continuous renal replacement therapy","volume":"56","author":"T F\u00fcl\u00f6p","year":"2010","journal-title":"ASAIO J"},{"issue":"1","key":"pone.0323431.ref019","first-page":"40","article-title":"Association of fluid balance trajectories with clinical outcomes in patients with septic shock: a prospective multicenter cohort study","volume":"8","author":"M-P Wang","year":"2021","journal-title":"Mil Med Res"},{"key":"pone.0323431.ref020","first-page":"1","article-title":"Predicting Major Adverse Kidney Events among Critically Ill Adults Using the Electronic Health Record","volume":"41","author":"AC McKown","year":"2017","journal-title":"Med Syst"},{"key":"pone.0323431.ref021","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10916-016-0528-z","article-title":"Identification of Major Adverse Kidney Events Within the Electronic Health Record","volume":"40","author":"MW Semler","year":"2016","journal-title":"J Med Syst"},{"key":"pone.0323431.ref022","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1146\/annurev.clinpsy.121208.131413","article-title":"Group-based trajectory modeling in clinical research","volume":"6","author":"DS Nagin","year":"2010","journal-title":"Annu Rev Clin Psychol"},{"key":"pone.0323431.ref023","doi-asserted-by":"crossref","DOI":"10.4159\/9780674041318","volume-title":"Group-based modeling of development","author":"D Nagin","year":"2005"},{"key":"pone.0323431.ref024","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1037\/1082-989X.6.1.18","article-title":"Analyzing developmental trajectories of distinct but related behaviors: a group-based method","volume":"6","author":"D Nagin","year":"2001","journal-title":"Psychol Methods"},{"issue":"3","key":"pone.0323431.ref025","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2337\/dc16-1625","article-title":"Longitudinal Trajectories of Metabolic Control From Childhood to Young Adulthood in Type 1 Diabetes From a Large German\/Austrian Registry: A Group-Based Modeling Approach","volume":"40","author":"A Schwandt","year":"2017","journal-title":"Diabetes Care"},{"key":"pone.0323431.ref026","unstructured":"Jones L, Nagin D. A Stata plugin for estimating group-based trajectory models."},{"key":"pone.0323431.ref027","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/biomet\/73.1.13","article-title":"Longitudinal data analysis using generalized linear models","volume":"73","author":"K Liang","year":"1986","journal-title":"Biometrics"},{"issue":"3","key":"pone.0323431.ref028","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10654-019-00494-6","article-title":"Principles of confounder selection","volume":"34","author":"TJ VanderWeele","year":"2019","journal-title":"Eur J Epidemiol"},{"issue":"9","key":"pone.0323431.ref029","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0307905","article-title":"Longitudinal trajectories of blood glucose and 30-day mortality in patients with diabetes mellitus combined with acute myocardial infarction: A retrospective cohort analysis of the MIMIC database","volume":"19","author":"B Deng","year":"2024","journal-title":"PLoS One"},{"issue":"1","key":"pone.0323431.ref030","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1186\/s13054-024-05186-6","article-title":"Lymphocyte count trajectories are associated with the prognosis of sepsis patients","volume":"28","author":"J Yang","year":"2024","journal-title":"Crit Care"},{"key":"pone.0323431.ref031","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.kint.2016.02.017","article-title":"Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury","volume":"90","author":"YR Lankadeva","year":"2016","journal-title":"Kidney Int"},{"issue":"5","key":"pone.0323431.ref032","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.kint.2019.06.013","article-title":"Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury","volume":"96","author":"YR Lankadeva","year":"2019","journal-title":"Kidney Int"},{"issue":"6","key":"pone.0323431.ref033","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1177\/0885066618768180","article-title":"Clinical Outcomes of Weight-Based Norepinephrine Dosing in Underweight and Morbidly Obese Patients: A Propensity-Matched Analysis","volume":"35","author":"AA Kotecha","year":"2020","journal-title":"J Intensive Care Med"},{"key":"pone.0323431.ref034","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jcrc.2019.05.024","article-title":"Optimal norepinephrine-equivalent dose to initiate epinephrine in patients with septic shock","volume":"53","author":"MA Ammar","year":"2019","journal-title":"J Crit Care"},{"issue":"5","key":"pone.0323431.ref035","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1001\/jama.2016.10485","article-title":"Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial","volume":"316","author":"AC Gordon","year":"2016","journal-title":"JAMA"},{"key":"pone.0323431.ref036","first-page":"139","article-title":"Mechanisms of vascular hyporesponsiveness in septic shock","volume":"11","author":"A Kimmoun","year":"2013","journal-title":"Curr Vasc Pharmacol"},{"issue":"7","key":"pone.0323431.ref037","first-page":"438","article-title":"Vasopressor and Inotropic Management Of Patients With Septic Shock","volume":"40","author":"S Pollard","year":"2015","journal-title":"P T"},{"issue":"2","key":"pone.0323431.ref038","article-title":"Sepsis-induced acute kidney injury: A disease of the microcirculation","volume":"26","author":"S Ma","year":"2019","journal-title":"Microcirculation"},{"key":"pone.0323431.ref039","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1097\/01.CCM.0000215834.48023.57","article-title":"Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis","volume":"34","author":"V Krejci","year":"2006","journal-title":"Crit Care Med"},{"issue":"2","key":"pone.0323431.ref040","doi-asserted-by":"crossref","DOI":"10.1186\/cc6823","article-title":"The histopathology of septic acute kidney injury: a systematic review","volume":"12","author":"C Langenberg","year":"2008","journal-title":"Crit Care"},{"key":"pone.0323431.ref041","doi-asserted-by":"crossref","DOI":"10.1097\/CCM.0b013e318187b8ac","article-title":"Vasoactive drugs and acute kidney injury","volume":"36","author":"R Bellomo","year":"2008","journal-title":"Crit Care Med"},{"key":"pone.0323431.ref042","doi-asserted-by":"crossref","first-page":"107499","DOI":"10.1016\/j.pharmthera.2020.107499","article-title":"Ion channels as effectors of cyclic nucleotide pathways: Functional relevance for arterial tone regulation","volume":"209","author":"B Manoury","year":"2020","journal-title":"Pharmacol Ther"},{"issue":"2","key":"pone.0323431.ref043","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/j.2040-4603.2017.tb00747.x","article-title":"Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles","volume":"7","author":"NR Tykocki","year":"2017","journal-title":"Compr Physiol"},{"issue":"1","key":"pone.0323431.ref044","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1097\/01.CCM.0000251127.45385.CD","article-title":"Vasopressin: mechanisms of action on the vasculature in health and in septic shock","volume":"35","author":"LK Barrett","year":"2007","journal-title":"Crit Care Med"},{"key":"pone.0323431.ref045","article-title":"Microcirculatory effects of norepinephrine in patients with septic shock: a microdialysis study","author":"A Fatnassi","year":"2020","journal-title":"Research Square Platform LLC"},{"issue":"6","key":"pone.0323431.ref046","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.semnephrol.2019.10.004","article-title":"Renal Medullary Hypoxia: A New Therapeutic Target for Septic Acute Kidney Injury?","volume":"39","author":"YR Lankadeva","year":"2019","journal-title":"Semin Nephrol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0323431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T17:34:34Z","timestamp":1747157674000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0323431"}},"subtitle":[],"editor":[{"given":"Chiara","family":"Lazzeri,","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0323431","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,13]]}}}