{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:59:31Z","timestamp":1780901971178,"version":"3.54.1"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008431","name":"Regional Health Management of the Government of Castile and Le\u00f3n, Spain","doi-asserted-by":"publisher","award":["GRS 2826\/A2\/2023"],"award-info":[{"award-number":["GRS 2826\/A2\/2023"]}],"id":[{"id":"10.13039\/501100008431","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Sepsis remains one of the leading causes of hospital morbidity and mortality worldwide. While its epidemiology has been extensively investigated, the chronobiology of sepsis\u2014the temporal patterns underlying its occurrence and outcomes\u2014has received comparatively little attention, despite its potential relevance for anticipating clinical demand and optimizing healthcare resource allocation. Objective: To analyze trends in the epidemiology and chronobiology of hospital admissions for sepsis across a large healthcare region in Spain over a 21-year period. Design: Retrospective observational study based on clinical\u2013administrative records. We included all patients \u2265 18 years who had a principal diagnosis of sepsis or septic shock admitted between 2001 and 2021, identified through ICD-9-CM and ICD-10-CM coding in the Spanish National Hospital Discharge Records Database. Annual incidence, in-hospital mortality, and temporal distribution of admissions and deaths were assessed. Joinpoint regression was used to evaluate trends, Fourier spectral analysis to identify dominant rhythms, and multi-harmonic cosinor models to test for circannual rhythmicity. Results: We identified 39,622 sepsis admissions. Hospital incidence increased significantly over time (annual percent change [APC]: +9.6%; p &lt; 0.001), with two inflection points (2008 and 2014). In-hospital mortality decreased linearly from 42.1% in 2001 to 31.9% in 2021 (p &lt; 0.001), despite a progressive increase in patient age. Chronobiological analyses revealed no significant circannual rhythm in incidence or mortality (cosinor p = 0.14), although mortality was disproportionately clustered in winter months (p &lt; 0.001). In multivariable analyses, clinical and epidemiological variables were independent predictors of in-hospital mortality. Conclusions: Over the last two decades, sepsis incidence has risen steadily, whereas hospital mortality has declined. Although no regular biological rhythm was demonstrated, excess winter mortality suggests extrinsic seasonal influences. This study provides novel evidence by jointly examining the epidemiology and chronobiology of sepsis, and supports their integration into healthcare planning strategies.<\/jats:p>","DOI":"10.3390\/antibiotics15060579","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:43:46Z","timestamp":1780897426000},"page":"579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Temporal Trends in the Chronobiology and Epidemiology of Sepsis Admissions over 21 Years: A Nationwide Study in Northwestern Spain"],"prefix":"10.3390","volume":"15","author":[{"given":"David","family":"Andaluz Ojeda","sequence":"first","affiliation":[{"name":"Department of Intensive Care Medicine, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain"},{"name":"BioCritic, Group for Biomedical Research in Critical Care Medicine, Universidad de Valladolid, 47005 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6688-7243","authenticated-orcid":false,"given":"Mar\u00eda Paz","family":"Barrio Alonso","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Hospital Cl\u00ednico Universitario de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-0639","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Cus\u00e1covich Torres","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Cl\u00ednico Universitario de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ram\u00f3n","family":"Garmendia Leiza","sequence":"additional","affiliation":[{"name":"Health Centre Jardinillos, Gerencia de Salud de \u00c1rea de Palencia, 34001 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngela","family":"Gonz\u00e1lez Salamanca","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Manuel Merino","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"P\u00e9rez Bastida","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"P\u00e9rez Rubio","sequence":"additional","affiliation":[{"name":"Hospital Nuestra Se\u00f1ora de Sonsoles de \u00c1vila, 05004 \u00c1vila, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9357-3219","authenticated-orcid":false,"given":"Laura","family":"Sanz Rueda","sequence":"additional","affiliation":[{"name":"Health Centre Villamuriel de Cerrato, Gerencia de Salud de \u00c1rea de Palencia, 34190 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9989-4996","authenticated-orcid":false,"given":"Jes\u00fas Mar\u00eda","family":"Andr\u00e9s de Llano","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"ref_1","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":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/ACO.0000000000000958","article-title":"Epidemiology of sepsis and septic shock","volume":"34","author":"Chiu","year":"2021","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/S1473-3099(17)30322-5","article-title":"The epidemiology of sepsis in Brazilian intensive care units (the Sepsis PREvalence Assessment Database, SPREAD): An observational study","volume":"17","author":"Machado","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13613-019-0495-x","article-title":"Risk factors for mortality in elderly and very elderly critically ill patients with sepsis: A prospective, observational, multicenter cohort study","volume":"9","author":"Guia","year":"2019","journal-title":"Ann. Intensive Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/jech-2018-210501","article-title":"Clinical and epidemiological variability in severe sepsis: An ecological study","volume":"72","author":"Vakkalanka","year":"2018","journal-title":"J. Epidemiol. Community Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"154096","DOI":"10.1016\/j.jcrc.2022.154096","article-title":"Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis","volume":"71","author":"Bouma","year":"2022","journal-title":"J. Crit. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s00134-019-05908-3","article-title":"Rate and risk factors for rehospitalisation in sepsis survivors: Systematic review and meta-analysis","volume":"46","author":"Saha","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1097\/01.CCM.0000117317.18092.E4","article-title":"Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock","volume":"32","author":"Dellinger","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/CCM.0000000000002255","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016","volume":"45","author":"Rhodes","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1063","DOI":"10.1097\/CCM.0000000000005337","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021","volume":"49","author":"Rhodes","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_12","first-page":"12","article-title":"Impact of the implementation of a Sepsis Code hospital protocol on antibiotic prescription and clinical outcomes in an intensive care unit","volume":"41","author":"Lamo","year":"2017","journal-title":"Med. Intensiv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1097\/01.CCM.0000050454.01978.3B","article-title":"2001 SCCM\/ESICM\/ACCP\/ATS\/SIS International Sepsis Definitions Conference","volume":"31","author":"Levy","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1007\/s15010-025-02601-0","article-title":"Rising rates of sepsis in England: An ecological study","volume":"53","author":"Allen","year":"2025","journal-title":"Infection"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1097\/01.CCM.0000298158.12101.41","article-title":"Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008","volume":"36","author":"Dellinger","year":"2008","journal-title":"Crit. Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.medin.2016.09.004","article-title":"Declining mortality due to severe sepsis and septic shock in Spanish intensive care units: A two-cohort study in 2005 and 2011","volume":"41","author":"Ferrer","year":"2017","journal-title":"Med. Intensiv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1186\/s13054-022-04176-w","article-title":"Trends in mortality in septic patients according to the different organ failure during 15 years","volume":"26","author":"Vela","year":"2022","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1007\/s15010-023-02082-z","article-title":"Trends in mortality after a sepsis hospitalization: A nationwide prospective registry study from 2008 to 2021","volume":"51","author":"Skei","year":"2023","journal-title":"Infection"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13613-023-01233-7","article-title":"The critically ill older patient with sepsis: A narrative review","volume":"14","author":"Ibarz","year":"2024","journal-title":"Ann. Intensive Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1097\/01.CCM.0000253405.17038.43","article-title":"Seasonal variation in the incidence of sepsis: Analysis of hospital discharge data","volume":"35","author":"Danai","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1097\/CCM.0000000000005973","article-title":"The Relationship Between Hospital Capability and Mortality in Sepsis: Development of a Sepsis-Related Hospital Capability Index","volume":"51","author":"Ofoma","year":"2023","journal-title":"Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Philippou, C., Tsioutis, C., Tsiappari, M., Spernovasilis, N., Papadopoulos, D., and Agouridis, A.P. (2025). The Impact of Statin Use on Sepsis Mortality: A Systematic Review and Meta-Analysis. Medicina, 61.","DOI":"10.3390\/medicina61091563"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pieroni, M., Olier, I., Ortega-Martorell, S., Johnston, B.W., and Welters, I.D. (2022). In-Hospital Mortality of sepsis differs depending on the origin of infection: An investigation of predisposing factors. Front. Med., 9.","DOI":"10.3389\/fmed.2022.915224"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/SHK.0000000000002151","article-title":"Clinical characteristics and predictors of mortality differ between pulmonary and abdominal sepsis","volume":"60","author":"Ren","year":"2023","journal-title":"Shock"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.medin.2024.04.010","article-title":"Sepsis mortality prediction with machine learning techniques","volume":"48","year":"2024","journal-title":"Med. Intensiv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2331168","DOI":"10.1001\/jamanetworkopen.2023.31168","article-title":"Estimating Sepsis Incidence Using Administrative Data and Clinical Medical Record Review","volume":"6","author":"Mellhammar","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1097\/CCM.0000000000004577","article-title":"Sepsis epidemiology across the International Classification of Diseases, 9th Edition to International Classification of Diseases, 10th Edition chasm: A direct application of the Institute for Health Metrics and Evaluation case definition to hospital discharge data","volume":"48","author":"Kempker","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1001\/jama.2017.13836","article-title":"Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009\u20132014","volume":"318","author":"Rhee","year":"2017","journal-title":"JAMA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bouza, C., L\u00f3pez-Cuadrado, T., Saz-Parkinson, Z., and Amate-Blanco, J.M. (2014). Epidemiology and Recent Trends of Severe Sepsis in Spain: A Nationwide Population-Based Analysis (2006\u20132011), BMC Infectious Diseases.","DOI":"10.1186\/s12879-014-0717-7"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/S0165-1684(03)00018-5","article-title":"A simple test of equality of time series","volume":"83","year":"2003","journal-title":"Signal. Proc."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/6\/579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:26:11Z","timestamp":1780899971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/6\/579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,7]]},"references-count":30,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["antibiotics15060579"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15060579","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,7]]}}}