{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:35:08Z","timestamp":1791560108816,"version":"4.3.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":265,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzhen","doi-asserted-by":"publisher","award":["SZSM20162011"],"award-info":[{"award-number":["SZSM20162011"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010877","name":"Shenzhen Science and Technology Innovation Commission","doi-asserted-by":"publisher","award":["JCYJ20190806163603504"],"award-info":[{"award-number":["JCYJ20190806163603504"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shenzhen Second People\u2019s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Project","award":["20173357201815"],"award-info":[{"award-number":["20173357201815"]}]},{"name":"Shenzhen Second People\u2019s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Project","award":["20193357003"],"award-info":[{"award-number":["20193357003"]}]},{"name":"Shenzhen Second People\u2019s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Project","award":["20203357014"],"award-info":[{"award-number":["20203357014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68\u20130.87], p &amp;lt; 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68\u20130.89], p &amp;lt; 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p &amp;lt; 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71\u20130.78, p &amp;lt; 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56\u20130.87, p &amp;lt; 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score \u2265 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p &amp;lt;0.001). E-Value analysis suggested robustness to unmeasured confounding.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/burnst\/tkac029","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T08:57:56Z","timestamp":1663923476000},"source":"Crossref","is-referenced-by-count":32,"title":["Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database"],"prefix":"10.1093","volume":"10","author":[{"given":"Zhi-ye","family":"Zou","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-jia","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"},{"name":"Postgraduate Education, Shantou University Medical College , Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-yi","family":"Luan","sequence":"additional","affiliation":[{"name":"Capital Medical University Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, , Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-jia","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"},{"name":"Postgraduate Education, Shantou University Medical College , Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-peng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"},{"name":"Postgraduate Education, Shantou University Medical College , Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-ming","family":"Yao","sequence":"additional","affiliation":[{"name":"Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital , Beijing 100048, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0800-5506","authenticated-orcid":false,"given":"Ming","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People\u2019s Hospital & First Affiliated Hospital of Shenzhen University , Shenzhen 518035, China"},{"name":"Postgraduate Education, Shantou University Medical College , Shantou 515041, China"},{"name":"Guangxi University of Chinese Medicine , Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"2022092308573713500_ref1","article-title":"Inflammasome-Dependent Coagulation Activation in Sepsis","volume":"12","author":"Wu","year":"2021","journal-title":"Front Immunol"},{"key":"2022092308573713500_ref2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.ccm.2008.06.006","article-title":"The coagulant response in sepsis","volume":"29","author":"Levi","year":"2008","journal-title":"Clin Chest Med"},{"key":"2022092308573713500_ref3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/cc1854","article-title":"Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis","volume":"7","author":"Opal","year":"2003","journal-title":"Critical care (London, England)"},{"key":"2022092308573713500_ref4","doi-asserted-by":"crossref","first-page":"13995","DOI":"10.1038\/s41598-018-32275-8","article-title":"the clinical importance of a cytokine network in the acute phase of sepsis","volume":"8","author":"Matsumoto","year":"2018","journal-title":"Sci Rep"},{"key":"2022092308573713500_ref5","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/01.CCM.0000153520.31562.48","article-title":"Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure","volume":"33","author":"Dhainaut","year":"2005","journal-title":"Crit Care Med"},{"key":"2022092308573713500_ref6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.cyto.2012.06.008","article-title":"Unfractionated heparin inhibits lipopolysaccharide-induced inflammatory response through blocking p38 MAPK and NF-\u03baB activation on endothelial cell","volume":"60","author":"Li","year":"2012","journal-title":"Cytokine"},{"key":"2022092308573713500_ref7","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1097\/CCM.0b013e31819c06bc","article-title":"Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study)","volume":"37","author":"Jaimes","year":"2009","journal-title":"Crit Care Med"},{"key":"2022092308573713500_ref8","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1001\/jama.286.15.1869","article-title":"Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial","volume":"286","author":"Warren","year":"2001","journal-title":"JAMA"},{"key":"2022092308573713500_ref9","first-page":"135","article-title":"Heparin for treatment of sepsis: a systemic review","volume":"26","author":"Liu","year":"2014","journal-title":"Zhonghua Wei Zhong Bing Ji Jiu Yi Xue"},{"key":"2022092308573713500_ref10","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1097\/CCM.0000000000000763","article-title":"The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis","volume":"43","author":"Zarychanski","year":"2015","journal-title":"Crit Care Med"},{"key":"2022092308573713500_ref11","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1186\/s13054-014-0563-4","article-title":"Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis","volume":"18","author":"Wang","year":"2014","journal-title":"Crit Care"},{"key":"2022092308573713500_ref12","article-title":"MIMIC-IV (version 1.0)","author":"Johnson","year":"2021","journal-title":"PhysioNet In"},{"key":"2022092308573713500_ref13","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":"2022092308573713500_ref14","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2018-022896","article-title":"Platelet-to-lymphocyte ratio as a prognostic predictor of mortality for sepsis: interaction effect with disease severity\u2014a retrospective study","volume":"9","author":"Shen","year":"2019","journal-title":"BMJ Open"},{"key":"2022092308573713500_ref15","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2021.6105","article-title":"Association of Positive Fluid Balance at Discharge After Sepsis Management With 30-Day Readmission","volume":"4","author":"Yoo","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2022092308573713500_ref16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.21037\/atm.2018.12.10","article-title":"Balance diagnostics after propensity score matching","volume":"7","author":"Zhang","year":"2019","journal-title":"Annals of translational medicine"},{"key":"2022092308573713500_ref17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1001\/jama.2018.21554","article-title":"Using the E-Value to Assess the Potential Effect of Unmeasured Confounding in Observational Studies","volume":"321","author":"Haneuse","year":"2019","journal-title":"JAMA"},{"key":"2022092308573713500_ref18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2147\/CLEP.S129785","article-title":"Missing data and multiple imputation in clinical epidemiological research","volume":"Volume 9","author":"Pedersen","year":"2017","journal-title":"Clin Epidemiol"},{"key":"2022092308573713500_ref19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1055\/s-0034-1398376","article-title":"Coagulation in patients with severe sepsis","volume":"41","author":"Levi","year":"2015","journal-title":"Semin Thromb Hemost"},{"key":"2022092308573713500_ref20","first-page":"1","article-title":"Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19","author":"","year":"2021","journal-title":"N Engl J Med"},{"key":"2022092308573713500_ref21","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1001\/jama.290.2.238","article-title":"Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial","volume":"290","author":"Abraham","year":"2003","journal-title":"JAMA"},{"key":"2022092308573713500_ref22","doi-asserted-by":"crossref","first-page":"00741","DOI":"10.1183\/23120541.00741-2020","article-title":"Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19","volume":"7","author":"Xue","year":"2021","journal-title":"ERJ Open Res"},{"key":"2022092308573713500_ref23","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s11239-020-02145-0","article-title":"Heparin resistance in COVID-19 patients in the intensive care unit","volume":"50","author":"White","year":"2020","journal-title":"J Thromb Thrombolysis"},{"key":"2022092308573713500_ref24","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.amjcard.2008.05.025","article-title":"Comparison of anticoagulant and anti-inflammatory responses using enoxaparin versus unfractionated heparin for transesophageal echocardiography-guided cardioversion of atrial fibrillation","volume":"102","author":"Hoppensteadt","year":"2008","journal-title":"Am J Cardiol"},{"key":"2022092308573713500_ref25","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1056\/NEJM200209263471316","article-title":"Low-dose heparin for severe sepsis","volume":"347","author":"Davidson","year":"2002","journal-title":"TN Engl J Med"},{"key":"2022092308573713500_ref26","first-page":"1","article-title":"Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19","author":"","year":"2021","journal-title":"N Engl J Med"},{"key":"2022092308573713500_ref27","article-title":"Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study","volume":"372","author":"Rentsch","year":"2021","journal-title":"BMJ"},{"key":"2022092308573713500_ref28","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1161\/01.CIR.100.25.2485","article-title":"Heparin blunts endotoxin-induced coagulation activation","volume":"100","author":"Pernerstorfer","year":"1999","journal-title":"Circulation"},{"key":"2022092308573713500_ref29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s40560-014-0065-0","article-title":"PAMPs and DAMPs as triggers for DIC","volume":"2","author":"Ito","year":"2014","journal-title":"J Intensive Care"},{"key":"2022092308573713500_ref30","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/bjh.14885","article-title":"The role of heparin in sepsis: much more than just an anticoagulant","volume":"179","author":"Li","year":"2017","journal-title":"Br J Haematol"},{"key":"2022092308573713500_ref31","article-title":"Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients","author":"Spyropoulos"},{"key":"2022092308573713500_ref32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.chest.2017.11.039","article-title":"Heparin-Induced Thrombocytopenia in the Critically Ill Patient","volume":"154","author":"East","year":"2018","journal-title":"Chest"},{"key":"2022092308573713500_ref33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.jss.2019.01.020","article-title":"Unfractionated Heparin Alleviates Sepsis-Induced Acute Lung Injury by Protecting Tight Junctions","volume":"238","author":"Liu","year":"2019","journal-title":"J Surg Res"},{"key":"2022092308573713500_ref34","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-021-00483-w","article-title":"Blocking Msr1 by berberine alkaloids inhibits caspase-11-dependent coagulation in bacterial sepsis","volume":"6","author":"Yuan","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"2022092308573713500_ref35","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.immuni.2021.01.007","article-title":"Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties","volume":"54","author":"Tang","year":"2021","journal-title":"Immunity"},{"key":"2022092308573713500_ref36","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cyto.2014.12.010","article-title":"Heparin inhibits the inflammatory response induced by LPS and HMGB1 by blocking the binding of HMGB1 to the surface of macrophages","volume":"72","author":"Li","year":"2015","journal-title":"Cytokine"},{"key":"2022092308573713500_ref37","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1089\/jir.2018.0042","article-title":"Unfractionated Heparin Modulates Lipopolysaccharide-Induced Cytokine Production by Different Signaling Pathways in THP-1 Cells","volume":"38","author":"Li","year":"2018","journal-title":"J Interf Cytokine Res"},{"key":"2022092308573713500_ref38","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1182\/blood-2013-07-514984","article-title":"Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis","volume":"123","author":"Wildhagen","year":"2014","journal-title":"Blood"},{"key":"2022092308573713500_ref39","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0233644","article-title":"Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood","volume":"15","author":"Hogwood","year":"2020","journal-title":"PLoS One"},{"key":"2022092308573713500_ref40","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1055\/s-0040-1715460","article-title":"The Anticoagulant and Nonanticoagulant Properties of Heparin","volume":"120","author":"Beurskens","year":"2020","journal-title":"Thromb Haemost"},{"key":"2022092308573713500_ref41","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1097\/CCM.0b013e31820eb718","article-title":"The effect of heparin administration in animal models of sepsis: a prospective study in Escherichia coli-challenged mice and a systematic review and metaregression analysis of published studies","volume":"39","author":"Li","year":"2011","journal-title":"Crit Care Med"},{"key":"2022092308573713500_ref42","doi-asserted-by":"crossref","first-page":"292","DOI":"10.23736\/S0026-4806.19.06188-3","article-title":"Low-molecular-weight heparin alleviates sepsis-induced renal inflammatory response and improves kidney function","volume":"111","author":"Huang","year":"2020","journal-title":"Minerva Med"},{"key":"2022092308573713500_ref43","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3892\/etm.2013.1466","article-title":"Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study","volume":"7","author":"Liu","year":"2014","journal-title":"Experimental and therapeutic medicine"},{"key":"2022092308573713500_ref44","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1097\/CCM.0b013e31818b8c6b","article-title":"Early intravenous unfractionated heparin and mortality in septic shock","volume":"36","author":"Zarychanski","year":"2008","journal-title":"Crit Care Med"}],"container-title":["Burns &amp; Trauma"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/burnstrauma\/article-pdf\/doi\/10.1093\/burnst\/tkac029\/45978111\/tkac029.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/burnstrauma\/article-pdf\/doi\/10.1093\/burnst\/tkac029\/45978111\/tkac029.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T08:58:39Z","timestamp":1663923519000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/burnstrauma\/article\/doi\/10.1093\/burnst\/tkac029\/6711718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,1]]},"references-count":44,"URL":"https:\/\/doi.org\/10.1093\/burnst\/tkac029","relation":{},"ISSN":["2321-3876"],"issn-type":[{"value":"2321-3876","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022]]},"published":{"date-parts":[[2022,1,1]]},"article-number":"tkac029"}}