Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database

Zhi-ye Zou; Jia-jia Huang; Ying-yi Luan; Zhen-jia Yang; Zhi-peng Zhou; Jing-jing Zhang; Yong-ming Yao; Ming Wu

doi:10.1093/burnst/tkac029

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Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database

更新时间：2023-09-05

- Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database
- Burns & Trauma Vol. 10, Issue 1, (2022)
- 作者机构：
  
  1. Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University
  2. Postgraduate Education, Shantou University Medical College
  3. Capital Medical University
  4. Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital
  5. Guangxi University of Chinese Medicine
- 作者简介：
- 基金信息：
- DOI：10.1093/burnst/tkac029
  CLC：
- Published：2022，
  
  Published Online：23 September 2022，
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Zhi-ye Zou, Jia-jia Huang, Ying-yi Luan, Zhen-jia Yang, Zhi-peng Zhou, Jing-jing Zhang, Yong-ming Yao, Ming Wu, Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database, Burns & Trauma, Volume 10, 2022, tkac029, https://doi.org/10.1093/burnst/tkac029
DOI：

Zhi-ye Zou, Jia-jia Huang, Ying-yi Luan, Zhen-jia Yang, Zhi-peng Zhou, Jing-jing Zhang, Yong-ming Yao, Ming Wu, Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database, Burns & Trauma, Volume 10, 2022, tkac029, https://doi.org/10.1093/burnst/tkac029 DOI：

摘要

Abstract

BackgroundMinimal 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.MethodsA 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.ResultsA 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) [0.68–0.87]

p < 0.001

and postmatched 14.9 vs 18.3%

HR 0.78

95% CI [0.68–0.89]

p < 0.001). Secondary endpoints

including 60-day mortality and length of ICU stay

differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71–0.78

p < 0.001)

and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70

95% CI 0.56–0.87

p < 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 ≥ 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 <0.001). E-Value analysis suggested robustness to unmeasured confounding.ConclusionsThis 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.

关键词

Keywords

Early prophylactic anticoagulationHeparinMortalitySepsisCritically ill patients

references

1.Wu R, Wang N, Comish PB, Tang D, Kang R. Inflammasome-Dependent Coagulation Activation in Sepsis. Front Immunol. 2021;12:641750.

2.Levi M. The coagulant response in sepsis. Clin Chest Med. 2008;29:627–42.

3.Opal SM, Esmon CT. Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Critical care (London, England). 2003;7:23–38.

4.Matsumoto H, Ogura H, Shimizu K, Ikeda M, Hirose T, Matsuura H, et al. the clinical importance of a cytokine network in the acute phase of sepsis. Sci Rep. 2018;8:13995.

5.Dhainaut JF, Shorr AF, Macias WL, Kollef MJ, Levi M, Reinhart K, et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med. 2005;33:341–8.

6.Li X, Zheng Z, Li X, Ma X. Unfractionated heparin inhibits lipopolysaccharide-induced inflammatory response through blocking p38 MAPK and NF-κB activation on endothelial cell. Cytokine. 2012;60:114–21.

7.Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, et al. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med. 2009;37:1185–96.

8.Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78.

9.Liu Z, Zhu H, Ma X. Heparin for treatment of sepsis: a systemic review. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2014;26:135–41.

10.Zarychanski R, Abou-Setta AM, Kanji S, Turgeon AF, Kumar A, Houston DS, et al. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2015;43:511–8.

11.Wang C, Chi C, Guo L, Wang X, Guo L, Sun J, et al. Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis. Crit Care. 2014;18:563.

12.Johnson A, Bulgarelli L, Pollard T, Horng S, Celi L A, Mark R. MIMIC-IV (version 1.0). PhysioNet In. 2021. https://doi.org/10.13026/s6n6-xd98.

13.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10.

14.Shen Y, Huang X, Zhang W. Platelet-to-lymphocyte ratio as a prognostic predictor of mortality for sepsis: interaction effect with disease severity—a retrospective study. BMJ Open. 2019;9:e022896. 10.1136/bmjopen-2018-022896.

15.Yoo MS, Zhu S, Lu Y, Greene JD, Hammer HL, Iberti CT, et al. Association of Positive Fluid Balance at Discharge After Sepsis Management With 30-Day Readmission. JAMA Netw Open. 2021;4:e216105.

16.Zhang Z, Kim HJ, Lonjon G, Zhu Y, written on behalf of AME Big-Data Clinical Trial Collaborative Group. Balance diagnostics after propensity score matching. Annals of translational medicine. 2019;7:16.

17.Haneuse S, VanderWeele TJ, Arterburn D. Using the E-Value to Assess the Potential Effect of Unmeasured Confounding in Observational Studies. JAMA. 2019;321:602–3.

18.Pedersen AB, Mikkelsen EM, Cronin-Fenton D, Kristensen N, Pham TM, Pedersen L, et al. Missing data and multiple imputation in clinical epidemiological research. Clin Epidemiol. 2017;Volume 9:157–66.

19.Levi M, Tvd P. Coagulation in patients with severe sepsis. Semin Thromb Hemost. 2015;41:9–16.

20.Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021;1–13.

21.Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238–47.

22.Xue M, Zeng Y, Qu H-Q, Zhang T, Li N, Huang H, et al. Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19. ERJ Open Res. 2021;7:00741–2020.

23.White D, MacDonald S, Bull T, Hayman M, de Monteverde-Robb R, Sapsford D, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50:287–91.

24.Hoppensteadt D, Fareed J, Klein AL, Jasper SE, Apperson-Hansen C, Lieber EA, et al. Comparison of anticoagulant and anti-inflammatory responses using enoxaparin versus unfractionated heparin for transesophageal echocardiography-guided cardioversion of atrial fibrillation. Am J Cardiol. 2008;102:842–6.

25.Davidson BL, Geerts WH, Lensing AWA. Low-dose heparin for severe sepsis. TN Engl J Med. 2002;347:1036–7.

26.Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021;1–13.

27.Rentsch CT, Beckman JA, Tomlinson L, Gellad WF, Alcorn C, Kidwai-Khan F, et al. Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ. 2021;372:n311.

28.Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, et al. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999;100:2485–90.

29.Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2:67.

30.Li X, Ma X. The role of heparin in sepsis: much more than just an anticoagulant. Br J Haematol. 2017;179:389–98.

31.Spyropoulos A, Northwell Health. Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients. https://www.clinicaltrials.gov/ct2/show/NCT04401293.

32.East JM, Cserti-Gazdewich CM, Granton JT. Heparin-Induced Thrombocytopenia in the Critically Ill Patient. Chest. 2018;154:678–90.

33.Liu Y, Mu S, Li X, Liang Y, Wang L, Ma X. Unfractionated Heparin Alleviates Sepsis-Induced Acute Lung Injury by Protecting Tight Junctions. J Surg Res. 2019;238:175–85.

34.Yuan C, Wu M, Xiao Q, Zhao W, Li H, Zhong Y, et al. Blocking Msr1 by berberine alkaloids inhibits caspase-11-dependent coagulation in bacterial sepsis. Signal Transduct Target Ther. 2021;6:92.

35.Tang Y, Wang X, Li Z, He Z, Yang X, Cheng X, et al. Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties. Immunity. 2021;54:454–467.e6.

36.Li L, Ling Y, Huang M, Yin T, Gou SM, Zhan NY, et al. Heparin inhibits the inflammatory response induced by LPS and HMGB1 by blocking the binding of HMGB1 to the surface of macrophages. Cytokine. 2015;72:36–42.

37.Li X, Zhao E, Li L, Ma X. Unfractionated Heparin Modulates Lipopolysaccharide-Induced Cytokine Production by Different Signaling Pathways in THP-1 Cells. J Interf Cytokine Res. 2018;38:283–9.

38.Wildhagen KCAA, García de Frutos P, Reutelingsperger CP, Schrijver R, Aresté C, Ortega-Gómez A, et al. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014;123:1098–101.

39.Hogwood J, Pitchford S, Mulloy B, Page C, Gray E. Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood. PLoS One. 2020;15(5):e0233644.

40.Beurskens DMH, Huckriede JP, Schrijver R, Hemker HC, Reutelingsperger CP, Nicolaes GAF. The Anticoagulant and Nonanticoagulant Properties of Heparin. Thromb Haemost. 2020;120:1371–83.

41.Li Y, Sun JF, Cui X, Mani H, Danner RL, Li X, et al. 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. Crit Care Med. 2011;39:1104–12.

42.Huang Y, Kong C. Low-molecular-weight heparin alleviates sepsis-induced renal inflammatory response and improves kidney function. Minerva Med. 2020;111:292–5.

43.Liu XL, Wang XZ, Liu XX, et al. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study. Experimental and therapeutic medicine. 2014;7:604–8.

44.Zarychanski R, Doucette S, Fergusson D, Roberts D, Houston DS, Sharma S, et al. Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med. 2008;36:2973–9.

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