Impact of early heparin therapy on mortality in critically ill patients with sepsis-related acute respiratory distress syndrome: a MIMIC-IV database analysis

Impact of early heparin therapy on mortality in critically ill patients with sepsis-related acute respiratory distress syndrome: a MIMIC-IV database analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of early heparin therapy on mortality in critically ill patients with sepsis-related acute respiratory distress syndrome: a MIMIC-IV database analysis Wenqian Lv, Xiao He, Haozhe Fan, Qianxin Lou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6980725/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Sepsis-associated acute respiratory distress syndrome (ARDS) is a life-threatening condition marked by significant thromboinflammation. Heparin, which has both anticoagulant and anti-inflammatory effects, may influence these pathways. However, its role in sepsis-related ARDS has not been fully explored. Methods Data for this retrospective cohort study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients were divided into two groups: those who received prophylactic heparin therapy at least once during their ICU stay and those who did not. The primary endpoint was intensive care unit (ICU) mortality, with secondary outcomes including 7-day, 14-day, 28-day, and in-hospital mortality. Propensity score matching (PSM), univariate Cox regression analysis, Kaplan-Meier curve analysis, multivariate Cox modeling, sensitivity analysis, and E-value analysis were performed. Results A total of 6,454 patients were included in this study: 2,528 received early heparin therapy, and 3,926 did not. Early heparin therapy was associated with a significant reduction in ICU mortality, 7-day, 14-day, 28-day, and in-hospital mortality in patients with sepsis-associated ARDS, and this effect remained significant following PSM ( P < 0.001). The association between early heparin therapy and reduced ICU mortality (HR = 0.72, 95% CI : 0.62–0.82, P < 0.01) persisted after adjusting for confounding variables and was more pronounced in patients aged < 60 years and those with a high body weight. E-value analyses demonstrated robustness to unmeasured confounders. Conclusion Early heparin therapy is correlated with decreased mortality in critically ill patients with sepsis-related ARDS. These findings provide a rationale for further exploring heparin as an adjunctive therapy. Heparin Sepsis Acute respiratory distress syndrome Mortality MIMIC-IV database Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Sepsis, a systemic inflammatory response syndrome resulting from severe infections, exhibits a high incidence rate of approximately 19 to 48.9 million cases annually across the globe [ 1 ]. Acute respiratory distress syndrome (ARDS) is the most common serious complication of sepsis, associated with a mortality rate of 20–50% [ 2 , 3 ]. Sepsis-related cytokine storms can damage to lung epithelial cells and endothelial cells [ 4 ]. Consequently, the prognosis of patients with sepsis-induced ARDS is worse than that of patients with sepsis or ARDS alone. Thromboinflammation plays a pivotal role in the progression of ARDS, where endothelial damage, neutrophil extracellular trap (NET) formation, and microvascular thrombosis exacerbate alveolar injury and multiorgan failure [ 5 – 8 ]. However, current clinical therapy prioritizes lung-protective ventilation and sepsis resuscitation but remains limited in targeted therapies that modulate inflammatory and coagulation pathways. Heparin, a sulfated polysaccharide polymer, is of particular interest due to its dual anticoagulant and anti-inflammatory properties. As an anticoagulant, heparin inhibits fibrinogen conversion and prevents microthrombosis, thereby alleviating microcirculatory disturbances [ 9 ]. Heparin can also suppress the release of pro-inflammatory mediators and attenuate the cytokine storm within the body. Furthermore, heparin can restore the integrity of the vascular endothelial glycocalyx, decrease capillary permeability, and preserve organ perfusion [ 10 ]. Clinical evidence has demonstrated that unfractionated heparin (UFH) reduces intensive care unit (ICU) mortality in septic patients [ 11 ]. The 2021 International Guidelines for the Management of Sepsis and Septic Shock advocate for the individualized initiation of heparin anticoagulation following adequate fluid resuscitation in patients with comorbid disseminated intravascular coagulation (DIC) and no hemorrhagic contraindications [ 12 ]. Considering the high incidence and mortality of sepsis-related ARDS, the exploration of effective therapeutic approaches is of paramount clinical importance. In this retrospective study, the Medical Information Marketplace for Intensive Care IV (MIMIC-IV) database was utilized to examine the association between early heparin therapy and mortality risk among patients with sepsis-related ARDS. Methods Data source and study design This retrospective cohort study employed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (version 3.0), which comprises electronic health records of patients admitted to ICU at Beth Israel Deaconess Medical Center, Boston, USA, between 2008 and 2022. The database documents complete medical information on patients, such as demographics, laboratory tests, therapeutic interventions, and additional comprehensive data. As the data are de-identified, no further ethical review is necessary. Study population All patients aged ≥ 18 years with sepsis combined with ARDS were included in this study. The diagnosis of sepsis was based on the Sepsis-3 guidelines: suspected infection combined with an acute increase in Sequential Organ Failure Assessment (SOFA) score of ≥ 2 [ 13 ]. The diagnosis of ARDS was established according to the Berlin criteria: acute onset, presence of bilateral infiltrates on chest radiograph, arterial oxygen partial pressure (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio ≤ 300 mmHg, positive end-expiratory pressure (PEEP) ≥ 5 cmH 2 O, and exclusion of heart failure [ 14 ]. Furthermore, the study excluded patients with ICU stays of less than 48 hours and those receiving warfarin, low molecular weight heparin (LMWH), therapeutic doses of heparin or heparin for dialysis. When patients had multiple admissions, only the data from their first ICU admission during the initial hospitalization were included for analysis. Data extraction and variables All data were systematically extracted from the MIMIC-IV database using structured query language (SQL) in conjunction with Navigate Premium (version 16). The collected data encompassed: (1) demographic characteristics (age, gender, weight, and ethnicity), and disease history (hypertension, diabetes mellitus, cardiac disease, and chronic obstructive pulmonary disease (COPD), among others); (2) vital signs within 24 hours of ICU admission (oxygenation index (PaO 2 /FiO 2 ), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and respiratory rate); (3) laboratory parameters within 24 hours of ICU admission, including white blood cell (WBC) count, platelet count, hemoglobin, international normalized ratio (INR), activated partial thromboplastin time (APTT), and prothrombin time (PT); (4) therapeutic interventions, such as vasoactive drug administration and mechanical ventilation use; (5) clinical scoring systems within 24 hours of ICU admission, including Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Glasgow Coma Score (GCS), and Oxford Acute Severity of Illness Score (OASIS); and (6) the duration of ICU stay. Exposure and outcomes The exposure group consisted of patients who received at least one prophylactic dose of subcutaneous heparin within 48 hours of ICU admission, whereas the control group received no heparin. The primary outcome in this study was ICU mortality, defined as death occurring during the ICU stay. Secondary outcomes included 7-day, 14-day, 28-day, and in-hospital mortality. Statistical analysis Continuous variables were presented as weighted mean ± standard deviation (SD), while categorical variables were presented as weighted percentage (%). Weighted t-tests and weighted chi-square tests were employed to assess between-group differences in variables. Probabilistic assessment of patients receiving early heparin therapy was conducted through calculation of the propensity score (PS). Subsequently, propensity score matching (PSM) was employed to generate a 1:1 matched cohort for baseline difference correction. Within the PSM analysis, the heparin group received continuous heparin therapy during the ICU stay. Patients in the treatment group were matched to untreated patients via nearest neighbor matching. The quality of matching was evaluated using the standardized mean difference (SMD), where SMD < 0.1 denoted a balanced distribution of baseline variables between the two groups. The association between early heparin therapy and ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality was analyzed using univariate Cox regression and Kaplan-Meier survival curves. Multivariate Cox regression models were used to adjust for confounding variables affecting ICU mortality: including sex, age, race, hypertension, diabetes mellitus, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy, heart rate, respiratory rate, PaO 2 /FiO 2 , SBP, DBP, SOFA, SAPS II, GCS, and OASIS. Subgroup analyses were conducted within multivariate Cox regression models post-PSM to investigate the impact of early heparin therapy on ICU mortality across different stratification factors, including age, sex, weight, ethnicity, hypertension, diabetes, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy, and PaO 2 /FiO 2 . Sensitivity and E-value analyses were additionally performed to evaluate the potential influence of both known and unmeasured confounders. All statistical analyses were conducted using R (version 4.4.3), with P < 0.05 considered statistically significant. Results Patient characteristics Following the analysis of 94,458 patients in the MIMIC-IV database, a total of 6,454 patients with sepsis-related ARDS were included in the study. Among these, 2,528 patients received prophylactic heparin therapy during their ICU stay, while 3,926 patients did not receive heparin therapy (Fig. 1 ). There were notable differences in baseline characteristics between the two groups (Supplementary Table S1 ). Compared with patients in the non-heparin group, patients in the heparin group had a comparatively higher proportion of females, whites, higher heart rate, higher SBP, greater prevalence of hypertension, higher platelet counts, higher OASIS scores, higher mechanical ventilation utilization, and higher PaO 2 /FiO 2 ( P < 0.05). However, MAP, DBP, prevalence of atrial fibrillation, prevalence of COPD, prevalence of coronary artery disease, urea nitrogen levels, INR, PT, APTT, PEEP, SOFA scores, and vasopressor utilization were higher in the non-heparin group ( P < 0.05). A total of 2528 patient pairs were matched subsequent to PSM. The SMD < 0.1 for all variables was indicative of a well-balanced baseline distribution of variables in both groups after PSM (Table 1 ). Table 1 Univariate Cox regression analysis of early heparin therapy and patient mortality Outcome Before PSM After PSM HR P -value HR P -value Primary ICU mortality, n (%) 0.60 (0.53–0.67) < 0.001 0.66 (0.59–0.75) < 0.001 Secondary 7-day mortality, n (%) 0.58 (0.49–0.69) < 0.001 0.59 (0.49–0.71) < 0.001 14-day mortality, n (%) 0.68 (0.60–0.78) < 0.001 0.69 (0.60–0.79) < 0.001 28-day mortality, n (%) 0.72 (0.66–0.82) 0.002 0.71 (0.63–0.80) < 0.001 In-hospital mortality, n (%) 0.73 (0.65–0.81) < 0.001 0.71 (0.63–0.81) < 0.001 Abbreviations: PSM, propensity score matching; ICU, intensive care unit; HR, hazard ratio. Effect of early heparin therapy on mortality in sepsis-related ARDS The association between prophylactic heparin therapy and mortality across various time points was analyzed using univariate Cox regression (Table 1 ). The results revealed that ICU mortality significantly decreased in the heparin-treated group compared with the control group (HR = 0.60, 95% CI: 0.53–0.67, P < 0.001). The correlation between heparin treatment and reduced ICU mortality remained stationary after the PSM (HR = 0.66, 95% CI: 0.59–0.75, P < 0.001). Furthermore, patients in the heparin group exhibited significantly lower 7-day (HR = 0.58, 95% CI: 0.49–0.69, P < 0.001), 14-day (HR = 0.68, 95% CI: 0.60–0.78, P < 0.001), 28-day (HR = 0.72, 95% CI: 0.66–0.82, P < 0.01), and in-hospital mortality (HR = 0.73, 95% CI: 0.65–0.81, P < 0.001) compared with patients who did not receive heparin. The post-PSM data further corroborate these findings. Kaplan-Meier curve analysis further validated the significant survival benefit of early heparin therapy ( P < 0.001). Survival curves for the heparin-treated group were consistently higher than those for the control group, exhibiting a more gradual downward trend (Fig. 2 ). This difference significantly persisted after PSM (Fig. 3 ). Correlation of early heparin therapy with ICU mortality Following PSM, the effect of heparin on ICU mortality was analyzed using a multivariable Cox proportional hazards models (Table 2 ). The results revealed that early heparin therapy was significantly associated with reduced ICU mortality in patients (HR = 0.71, 95% CI: 0.63–0.80, P < 0.001). The reduction in ICU death risk associated with early heparin therapy remained consistently significant across three models, even after adjusting for multiple covariates (HR range 0.72–0.73, all P < 0.00). Table 2 Multifactorial Cox modele analysis of heparin therapy and ICU mortality HR 95% CI P value No heparin therapy Reference Model 1 0.71 0.63–0.80 < 0.001 Model 2 0.73 0.65–0.82 < 0.001 Model 3 0.73 0.65–0.82 < 0.001 Model 4 0.72 0.62–0.82 0.002 Abbreviations: HR, hazard ratio; 95% CI, the 95% confidence interval of HR. Adjusted covariates: Model 1 = early heparin therapy. Model 2 = Model 1 + sex, age, race, and comorbidities (hypertension, diabetes mellitus, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy). Model 3 = Model 2 + vital signs at 24 hours of admission (MAP, SBP, DBP, heart rate, and respiratory rate) + all laboratory indicators (PaO 2 /FiO 2 , WBC, platelet count, hemoglobin, INR, APTT, and PT). Model 4 = Model 3 + clinical score at 24 hours of admission (SOFA, SAPS II, GCS, OASIS) Subgroup analysis Subgroup analysis was conducted to assess the effect of heparin therapy on ICU mortality across different populations (Fig. 4 ). The result revealed that in the fully adjusted model, early heparin therapy was significantly associated with reduced ICU mortality in patients younger than 60 years of age (HR = 0.566, 95% CI: 0.459–0.698, P < 0.001) and in those with high body weight (HR = 0.527, 95% CI: 0.423–0.656, P < 0.001) . Sensitivity analysis Risk factors for ICU mortality were assessed through sensitivity analysis, accounting for the complexity of patient conditions in the clinical setting. In the multivariate Cox proportional hazards model, significant risk factors for ICU mortality after PSM included age, race, glucose levels, WBC, APTT, SBP, SOFA, GCS, and SAPS II ( P < 0.05). The weight, atrial fibrillation, body temperature, and mechanical ventilation were protective factors ( P < 0.05) (Table 3 ). Table 3 Sensitivity analysis of heparin therapy and ICU mortality Variable HR 95% CI P Age 1.017 1.012–1.023 < 0.001 Gender 0.976 0.857–1.111 0.710 Weight 0.995 0.992–0.998 < 0.001 Race_Other 1.948 1.470–2.580 < 0.001 Race_White 1.277 0.963–1.694 0.090 Hypertension 0.924 0.814–1.0480 0.217 Glucose 1.003 1.002–1.005 < 0.001 Platelets 1.001 0.999-1.000 0.173 WBC 1.005 1.001–1.009 0.009 Diabetes 0.934 0.810–1.078 0.352 Atrial fibrillation 0.871 0.759–0.999 0.048 COPD 0.937 0.701–1.254 0.663 PaO 2 /FiO 2 0.999 0.999-1.000 0.171 Cardiomyopathy 0.950 0.734–1.228 0.694 Coronary heart 1.051 0.890–1.241 0.560 Heart rate 1.001 0.996–1.004 0.834 Respiratory rate 1.006 0.993–1.020 0.365 Temperature 0.911 0.870–0.953 < 0.001 SpO 2 1.006 0.998–1.014 0.147 BUN 0.999 0.996–1.002 0.436 INR 0.998 0.644–1.547 0.994 PT 1.040 0.997–1.085 0.070 APTT 1.006 1.002–1.011 0.009 MAP 0.998 0.993–1.004 0.563 DBP 1.002 0.994–1.010 0.683 SBP 1.008 1.002–1.013 0.005 SOFA 1.034 1.006–1.063 0.017 GCS 1.046 1.024–1.068 < 0.001 SAPS II 1.022 1.014–1.030 < 0.001 OASIS 1.007 0.995–1.019 0.261 Ventilation 0.610 0.500-0.743 < 0.001 Abbreviations: HR, hazard ratio; 95% CI, the 95% confidence interval of HR; WBC, white blood cell count; COPD, chronic obstructive pulmonary disease; PaO 2 , pressure of alveolar oxygen; FiO 2 , fraction of inspired oxygen; SpO 2 , pulse oxygen saturation; BUN, blood urine nitrogen; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; MAP, mean arterial pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure; SOFA, sequential organ failure assessment; GCS, glasgow coma score; SAPS II, simplified acute physiology score II; OASIS, oxford acute severity of illness score. E-value analysis demonstrated that the association between early heparin therapy and ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality was robust (Table 4 ). Only unmeasured confounders with an HR > 2 (upper limit of 95% CI: 1.74) would potentially affect the relationship between early heparin therapy and ICU mortality. Consequently, other unknown or unmeasured factors likely have a minimal impact on mortality relative to known risks. Table 4 E-value of the association between heparin therapy and mortality in sepsis-related ARDS Outcome E -value Upper limit of 95% CI Primary ICU mortality, n (%) 2 1.74 Secondary 7-day mortality, n (%) 2.24 1.85 14-day mortality, n (%) 1.91 1.63 28-day mortality, n (%) 1.85 1.61 In-hospital mortality, n (%) 1.85 1.58 Discussion The findings of this study indicate that early heparin therapy is effective in reducing the risk of mortality in critically ill patients with sepsis-related ARDS. After PSM, ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality were significantly decreased in the heparin-treated group. The correlation between heparin therapy and reduced ICU mortality was robust regardless various variables, including gender, age, comorbidities, vital signs, clinical indicators, and scores. Stratified analyses revealed that the effect of heparin therapy on ICU mortality was particularly pronounced in patients younger than 60 years of age and those with high body weight. These results are consistent with previous studies indicating heparin's therapeutic potential in managing sepsis-related ARDS. Researches have demonstrated that anticoagulation reduces the risk of death in patients with sepsis, particularly in those with DIC and high disease severity[ 15 , 16 ]. Heparin has been shown to reduce 28-day mortality in adults with sepsis without increasing the risk of bleeding [ 17 – 19 ]. Heparin therapy has demonstrated potential benefits in both sepsis and COVID-19 patients [ 20 – 22 ]. This positions heparin as a promising adjunctive treatment option for mechanically ventilated patients with sepsis in clinical practice. A retrospective study revealed a significant reduction in in-hospital, 60-day, and 90-day mortality among ARDS patients receiving prophylactic heparin therapy [ 23 ]. Furthermore, nebulized heparin therapy has been shown to reduce hospitalization time and duration of mechanical ventilation in patients with or at risk for ARDS [ 24 – 26 ]. This indicates that local anticoagulation may decrease alveolar fibrin deposition and mitigate lung injury. Heparin, despite its long-standing use, continues to be the first-line anticoagulant in clinical practice [ 27 ]. As per the aforementioned findings, the survival advantage observed in heparin-treated patients may be attributed to its dual anticoagulant and anti-inflammatory properties. Central to the pathophysiology of sepsis and ARDS is a vicious cycle involving uncontrolled inflammatory responses and coagulation dysfunction [ 4 , 28 , 29 ]. Heparin mitigates microcirculatory thrombosis by binding to antithrombin III (ATIII), inhibiting coagulation factors Xa and IIa (thrombin), and blocking the coagulation cascade [ 10 , 30 ]. Furthermore, heparin downregulates tissue factor (TF) expression, reduces activation of exogenous coagulation pathways, enhances fibrinolytic activity, and ameliorates intra-alveolar fibrin deposition by inhibiting plasminogen activator inhibitor (PAI-1) [ 31 – 34 ]. Regarding oxidative stress, the reducing hydroxyl group of heparin binds to reactive oxygen species (ROS), inhibits lipid peroxidation, and increases the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) [ 35 ]. Collectively, these effects reduce alveolar-capillary leakage and enhance oxygenation, as evidenced by the higher PaO 2 /FiO 2 ratios observed in heparin-treated patients. Furthermore, heparin’s capacity to restore endothelial barrier function may reduce secondary organ injuries, which aligns with the reduced vasopressor requirements and lower SOFA scores observed in the treatment group [ 36 ]. Subgroup analyses revealed heterogeneity in treatment effects, with younger patients (< 60 years) and those with higher body weight exhibiting more pronounced reductions in mortality (HR = 0.566 and HR = 0.527). This may be attributed to age-related alterations in pharmacokinetics and hepatic and renal clearance, which can diminish the therapeutic efficacy of heparin in older adults. In obese patients, adipose tissue releases substantial quantities of pro-inflammatory mediators, intensifying the inflammatory cascade in sepsis. Moreover, obesity is associated with elevated platelet activity, increased production of coagulation factors, and a pre-thrombotic state. Obesity-related metabolic syndrome also contributes to endothelial cell glycocalyx damage, exacerbating vascular permeability. Consequently, the anti-inflammatory and anticoagulant effects of heparin, along with its role in protecting the endothelial barrier, are particularly obvious in these patients [ 37 ]. These findings highlight the necessity for personalized heparin regimens guided by pharmacodynamic monitoring. Although the current prophylactic dose of heparin therapy is standardized, individualized adjustments based on patient weight are also recommended. This study has critical implications for critical care practice. From a clinical standpoint, these results support considering prophylactic heparin as an adjunctive therapy for managing septic ARDS patients without bleeding contraindications. It is crucial to acknowledge that this study has certain limitations. First, as a retrospective study, it may be subject to measurement bias due to its extensive time span. Second, although PSM was used to adjust for baseline differences, some unmeasured confounding variables might still have exerted an impact. Future research should further investigate the effects of heparin administration timing and dosage on patients with sepsis-associated ARDS through larger prospective trials. Conclusions This study has demonstrated that early heparin therapy significantly reduces mortality at different stages in patients with sepsis-related ARDS. While heparin shows therapeutic potential in critically ill patients with sepsis-associated ARDS, individual bleeding risks must still be carefully weighed in clinical practice. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The data analyzed for this study were from the MIMIC-IV database, https://mimic.mit.edu/docs/iv/. Competing interests None declared. Funding This study is not supported by any sponsors. Authors' contributions W.L. and Q.L designed the study. W.L, X.H. and H.F. performed the data analysis. W.L. wrote the original draft. All authors reviewed the final manuscript. Acknowledgements None. Clinical Trial Number: Not applicable. References Chiu C, Legrand M: Epidemiology of sepsis and septic shock. Current opinion in anaesthesiology. 2021; 34:71-76; doi:10.1097/aco.0000000000000958 Xu C, Zheng L, Jiang Y, Jin L: A prediction model for predicting the risk of acute respiratory distress syndrome in sepsis patients: a retrospective cohort study. BMC pulmonary medicine. 2023; 23:78; doi:10.1186/s12890-023-02365-z Wang Q, Feng Q, Zhang Y, Zhou S, Chen H: Decreased microRNA 103 and microRNA 107 predict increased risks of acute respiratory distress syndrome and 28-day mortality in sepsis patients. Medicine. 2020; 99:e20729; doi:10.1097/md.0000000000020729 Qiao X, Yin J, Zheng Z, Li L, Feng X: Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications. Cell communication and signaling : CCS. 2024; 22:241; doi:10.1186/s12964-024-01620-y Scozzi D, Liao F, Krupnick AS, Kreisel D, Gelman AE: The role of neutrophil extracellular traps in acute lung injury. Frontiers in immunology. 2022; 13:953195; doi:10.3389/fimmu.2022.953195 Gando S, Wada T: Pathomechanisms Underlying Hypoxemia in Two COVID-19-Associated Acute Respiratory Distress Syndrome Phenotypes: Insights From Thrombosis and Hemostasis. Shock (Augusta, Ga). 2022; 57:1-6; doi:10.1097/shk.0000000000001825 Liu X, Li T, Chen H, Yuan L, Ao H: Role and intervention of PAD4 in NETs in acute respiratory distress syndrome. Respiratory research. 2024; 25:63; doi:10.1186/s12931-024-02676-7 Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S et al : Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature reviews Cardiology. 2021; 18:194-209; doi:10.1038/s41569-020-00469-1 Heestermans M, Poenou G, Hamzeh-Cognasse H, Cognasse F, Bertoletti L: Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications. Cells. 2022; 11; doi:10.3390/cells11203214 Hogwood J, Mulloy B, Lever R, Gray E, Page CP: Pharmacology of Heparin and Related Drugs: An Update. Pharmacological reviews. 2023; 75:328-379; doi:10.1124/pharmrev.122.000684 Huang JJ, Zou ZY, Zhou ZP, Liu Y, Yang ZJ, Zhang JJ, Luan YY, Yao YM, Wu M: Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy. Frontiers in pharmacology. 2023; 14:1173893; doi:10.3389/fphar.2023.1173893 Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC et al : Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive care medicine. 2021; 47:1181-1247; doi:10.1007/s00134-021-06506-y Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM et al : The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama. 2016; 315:801-810; doi:10.1001/jama.2016.0287 Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS: Acute respiratory distress syndrome: the Berlin Definition. Jama. 2012; 307:2526-2533; doi:10.1001/jama.2012.5669 Yu S, Chi Y, Ma X, Li X: Heparin in sepsis: current clinical findings and possible mechanisms. Frontiers in immunology. 2024; 15:1495260; doi:10.3389/fimmu.2024.1495260 Totoki T, Koami H, Makino Y, Wada T, Ito T, Yamakawa K, Iba T: Heparin therapy in sepsis and sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis. Thrombosis journal. 2024; 22:84; doi:10.1186/s12959-024-00653-0 Fu S, Yu S, Wang L, Ma X, Li X: Unfractionated heparin improves the clinical efficacy in adult sepsis patients: a systematic review and meta-analysis. BMC anesthesiology. 2022; 22:28; doi:10.1186/s12871-021-01545-w Peng JC, Nie F, Li YJ, Xu QY, Xing SP, Li W, Gao Y: Favorable Outcomes of Anticoagulation With Unfractioned Heparin in Sepsis-Induced Coagulopathy: A Retrospective Analysis of MIMIC-III Database. Frontiers in medicine. 2021; 8:773339; doi:10.3389/fmed.2021.773339 Zhang Z, Yan T, Ren D, Zhou J, Liu L, Li J, Fu S, Ni T, Xu W, Yang Y et al : Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy. Frontiers in medicine. 2023; 10:1157775; doi:10.3389/fmed.2023.1157775 Li X, Liu Z, Luo M, Xi Y, Li C, Wang S, Yang R: Therapeutic effect of low-molecular-weight heparin on adult sepsis: a meta-analysis. Annals of palliative medicine. 2021; 10:3115-3127; doi:10.21037/apm-21-169 Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G et al : Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA internal medicine. 2021; 181:1612-1620; doi:10.1001/jamainternmed.2021.6203 Billett HH, Reyes-Gil M, Szymanski J, Ikemura K, Stahl LR, Lo Y, Rahman S, Gonzalez-Lugo JD, Kushnir M, Barouqa M et al : Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality. Thrombosis and haemostasis. 2020; 120:1691-1699; doi:10.1055/s-0040-1720978 Xiao LX, Zhu L, Chen J, Lv J, Liu MJ, Dai X, Wang DX, Deng W: Exploring the therapeutic role of early heparin administration in ARDS management: a MIMIC-IV database analysis. Journal of intensive care. 2024; 12:9; doi:10.1186/s40560-024-00723-5 Dixon B, Smith RJ, Campbell DJ, Moran JL, Doig GS, Rechnitzer T, MacIsaac CM, Simpson N, van Haren FMP, Ghosh AN et al : Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. The Lancet Respiratory medicine. 2021; 9:360-372; doi:10.1016/s2213-2600(20)30470-7 van Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, Smith R, Shute J, Carroll M, Tree J et al : Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Critical care (London, England). 2020; 24:454; doi:10.1186/s13054-020-03148-2 Ball L, Schultz MJ, Pelosi P: Nebulised heparin for patients on ventilation: implications for COVID-19 pneumonia. The Lancet Respiratory medicine. 2021; 9:321-322; doi:10.1016/s2213-2600(20)30513-0 Wang P, Chi L, Zhang Z, Zhao H, Zhang F, Linhardt RJ: Heparin: An old drug for new clinical applications. Carbohydrate polymers. 2022; 295:119818; doi:10.1016/j.carbpol.2022.119818 Huang M, Cai S, Su J: The Pathogenesis of Sepsis and Potential Therapeutic Targets. International journal of molecular sciences. 2019; 20; doi:10.3390/ijms20215376 Xu H, Sheng S, Luo W, Xu X, Zhang Z: Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup. Frontiers in immunology. 2023; 14:1277161; doi:10.3389/fimmu.2023.1277161 Beurskens DMH, Huckriede JP, Schrijver R, Hemker HC, Reutelingsperger CP, Nicolaes GAF: The Anticoagulant and Nonanticoagulant Properties of Heparin. Thrombosis and haemostasis. 2020; 120:1371-1383; doi:10.1055/s-0040-1715460 Shute JK: Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease. Pharmaceuticals (Basel, Switzerland). 2023; 16; doi:10.3390/ph16040584 Zang L, Zhu H, Wang K, Liu Y, Yu F, Zhao W: Not Just Anticoagulation-New and Old Applications of Heparin. Molecules (Basel, Switzerland). 2022; 27; doi:10.3390/molecules27206968 Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ: Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. Journal of thrombosis and haemostasis : JTH. 2020; 18:1548-1555; doi:10.1111/jth.14872 Li L, Yu S, Fu S, Ma X, Li X: Unfractionated heparin inhibits histone-mediated coagulation activation and thrombosis in mice. Thrombosis research. 2020; 193:122-129; doi:10.1016/j.thromres.2020.06.007 Lin L, Xie S, Zhao Y, Liang Z, Wu Q, Fang M, Teng X, Shi B, Yang Y, Chen B: Ultrasound-induced destruction of heparin-loaded microbubbles attenuates L-arginine-induced acute pancreatitis. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2023; 180:106318; doi:10.1016/j.ejps.2022.106318 Yang R, Zhang X: A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Frontiers in cellular and infection microbiology. 2022; 12:984835; doi:10.3389/fcimb.2022.984835 Schurr JW, Muske AM, Stevens CA, Culbreth SE, Sylvester KW, Connors JM: Derivation and Validation of Age- and Body Mass Index-Adjusted Weight-Based Unfractionated Heparin Dosing. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2019; 25:1076029619833480; doi:10.1177/1076029619833480 Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6980725","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":494962464,"identity":"868d5136-2e0f-4e2e-8249-4ecdd35246d9","order_by":0,"name":"Wenqian Lv","email":"","orcid":"","institution":"Yuyao People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenqian","middleName":"","lastName":"Lv","suffix":""},{"id":494962465,"identity":"a4a38816-daff-480a-b4eb-4771c0d13878","order_by":1,"name":"Xiao He","email":"","orcid":"","institution":"Jinhua Municipal Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"He","suffix":""},{"id":494962466,"identity":"1e56b641-2145-4450-8abb-e99ce98a2349","order_by":2,"name":"Haozhe Fan","email":"","orcid":"","institution":"Jinhua Municipal Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haozhe","middleName":"","lastName":"Fan","suffix":""},{"id":494962467,"identity":"9ae924d8-7c2a-4c1e-ac4e-9b5792572b39","order_by":3,"name":"Qianxin Lou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBAC+2bm4x8SKv7zMLY3EKnFgJ0tjeHDGWY55p4DxGrh5zFjnNnCbMw+I4FILebMDGaPeRvYEntnPt54g6HGJpqgFstmhnRj3h08iTNnpxVbMBxLy20gqOcwwwFp3jMSiRtn55hJMDYcJkYLY4M0b5tB4v6bZ4jUYnCYmU1yZluCMeMMHiK1SDazMRt8OHNAjrEH6JcEYvzCz3/+44OEigPAqDy88caHGhsi/ILsSIkEUpRDtJCqYxSMglEwCkYGAAAm70CWrbnVVQAAAABJRU5ErkJggg==","orcid":"","institution":"Yuyao People’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Qianxin","middleName":"","lastName":"Lou","suffix":""}],"badges":[],"createdAt":"2025-06-26 07:38:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6980725/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6980725/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88411103,"identity":"1253e726-e520-4ea4-9cb0-437c80eede46","added_by":"auto","created_at":"2025-08-06 08:24:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":784649,"visible":true,"origin":"","legend":"\u003cp\u003eThe process of patient selection.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/1905441383d9a33168363bd4.png"},{"id":88409073,"identity":"76d9ff3e-57b3-4be5-b1b3-cfb8fedea781","added_by":"auto","created_at":"2025-08-06 08:16:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":49168,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of heparin and non-heparin groups before PSM.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/19e3bff310969a60949c5200.png"},{"id":88409088,"identity":"2f1bd2f4-de15-4e9b-9826-76a19a761799","added_by":"auto","created_at":"2025-08-06 08:16:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":48915,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis of heparin and non-heparin groups after PSM\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/36e954dcabd4a167741a1058.png"},{"id":88409084,"identity":"a9b35523-ae2f-4756-94ac-a67582d949d9","added_by":"auto","created_at":"2025-08-06 08:16:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":86334,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of the effect of heparin on ICU mortality.\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio; 95% CI, the 95% confidence interval of HR; Weight Q1: 30.65-76 Kg, Q2: 76-95.65 Kg, Q3: 95.65-248 Kg; AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; CH, coronary heart; Severe: 200 mmHg \u0026lt; PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ≤ 300 mmHg; Moderate: 100 mmHg \u0026lt; PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ≤ 200 mmHg; Light: PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ≤ 100 mmHg.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/2dc7807ffe8b5e907b78d65e.png"},{"id":100237279,"identity":"f951375c-2c43-4ec2-926b-539d319b5058","added_by":"auto","created_at":"2026-01-14 12:41:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1308860,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/b7121d40-b32d-418a-b81f-9b6764b41542.pdf"},{"id":88411102,"identity":"184f91ba-d2c1-491d-88de-85c38556ae01","added_by":"auto","created_at":"2025-08-06 08:24:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35424,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6980725/v1/52334f33c1f6fcbb65a58e8e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of early heparin therapy on mortality in critically ill patients with sepsis-related acute respiratory distress syndrome: a MIMIC-IV database analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis, a systemic inflammatory response syndrome resulting from severe infections, exhibits a high incidence rate of approximately 19 to 48.9\u0026nbsp;million cases annually across the globe [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Acute respiratory distress syndrome (ARDS) is the most common serious complication of sepsis, associated with a mortality rate of 20\u0026ndash;50% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Sepsis-related cytokine storms can damage to lung epithelial cells and endothelial cells [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, the prognosis of patients with sepsis-induced ARDS is worse than that of patients with sepsis or ARDS alone. Thromboinflammation plays a pivotal role in the progression of ARDS, where endothelial damage, neutrophil extracellular trap (NET) formation, and microvascular thrombosis exacerbate alveolar injury and multiorgan failure [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, current clinical therapy prioritizes lung-protective ventilation and sepsis resuscitation but remains limited in targeted therapies that modulate inflammatory and coagulation pathways.\u003c/p\u003e\u003cp\u003eHeparin, a sulfated polysaccharide polymer, is of particular interest due to its dual anticoagulant and anti-inflammatory properties. As an anticoagulant, heparin inhibits fibrinogen conversion and prevents microthrombosis, thereby alleviating microcirculatory disturbances [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Heparin can also suppress the release of pro-inflammatory mediators and attenuate the cytokine storm within the body. Furthermore, heparin can restore the integrity of the vascular endothelial glycocalyx, decrease capillary permeability, and preserve organ perfusion [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Clinical evidence has demonstrated that unfractionated heparin (UFH) reduces intensive care unit (ICU) mortality in septic patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The 2021 International Guidelines for the Management of Sepsis and Septic Shock advocate for the individualized initiation of heparin anticoagulation following adequate fluid resuscitation in patients with comorbid disseminated intravascular coagulation (DIC) and no hemorrhagic contraindications [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eConsidering the high incidence and mortality of sepsis-related ARDS, the exploration of effective therapeutic approaches is of paramount clinical importance. In this retrospective study, the Medical Information Marketplace for Intensive Care IV (MIMIC-IV) database was utilized to examine the association between early heparin therapy and mortality risk among patients with sepsis-related ARDS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eData source and study design\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis retrospective cohort study employed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (version 3.0), which comprises electronic health records of patients admitted to ICU at Beth Israel Deaconess Medical Center, Boston, USA, between 2008 and 2022. The database documents complete medical information on patients, such as demographics, laboratory tests, therapeutic interventions, and additional comprehensive data. As the data are de-identified, no further ethical review is necessary.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with sepsis combined with ARDS were included in this study. The diagnosis of sepsis was based on the Sepsis-3 guidelines: suspected infection combined with an acute increase in Sequential Organ Failure Assessment (SOFA) score of \u0026ge;\u0026thinsp;2 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The diagnosis of ARDS was established according to the Berlin criteria: acute onset, presence of bilateral infiltrates on chest radiograph, arterial oxygen partial pressure (PaO\u003csub\u003e2\u003c/sub\u003e)/fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) ratio\u0026thinsp;\u0026le;\u0026thinsp;300 mmHg, positive end-expiratory pressure (PEEP)\u0026thinsp;\u0026ge;\u0026thinsp;5 cmH\u003csub\u003e2\u003c/sub\u003eO, and exclusion of heart failure [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, the study excluded patients with ICU stays of less than 48 hours and those receiving warfarin, low molecular weight heparin (LMWH), therapeutic doses of heparin or heparin for dialysis. When patients had multiple admissions, only the data from their first ICU admission during the initial hospitalization were included for analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData extraction and variables\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll data were systematically extracted from the MIMIC-IV database using structured query language (SQL) in conjunction with Navigate Premium (version 16). The collected data encompassed: (1) demographic characteristics (age, gender, weight, and ethnicity), and disease history (hypertension, diabetes mellitus, cardiac disease, and chronic obstructive pulmonary disease (COPD), among others); (2) vital signs within 24 hours of ICU admission (oxygenation index (PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and respiratory rate); (3) laboratory parameters within 24 hours of ICU admission, including white blood cell (WBC) count, platelet count, hemoglobin, international normalized ratio (INR), activated partial thromboplastin time (APTT), and prothrombin time (PT); (4) therapeutic interventions, such as vasoactive drug administration and mechanical ventilation use; (5) clinical scoring systems within 24 hours of ICU admission, including Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Glasgow Coma Score (GCS), and Oxford Acute Severity of Illness Score (OASIS); and (6) the duration of ICU stay.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExposure and outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe exposure group consisted of patients who received at least one prophylactic dose of subcutaneous heparin within 48 hours of ICU admission, whereas the control group received no heparin. The primary outcome in this study was ICU mortality, defined as death occurring during the ICU stay. Secondary outcomes included 7-day, 14-day, 28-day, and in-hospital mortality.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were presented as weighted mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), while categorical variables were presented as weighted percentage (%). Weighted t-tests and weighted chi-square tests were employed to assess between-group differences in variables.\u003c/p\u003e\u003cp\u003eProbabilistic assessment of patients receiving early heparin therapy was conducted through calculation of the propensity score (PS). Subsequently, propensity score matching (PSM) was employed to generate a 1:1 matched cohort for baseline difference correction. Within the PSM analysis, the heparin group received continuous heparin therapy during the ICU stay. Patients in the treatment group were matched to untreated patients via nearest neighbor matching. The quality of matching was evaluated using the standardized mean difference (SMD), where \u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 denoted a balanced distribution of baseline variables between the two groups.\u003c/p\u003e\u003cp\u003eThe association between early heparin therapy and ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality was analyzed using univariate Cox regression and Kaplan-Meier survival curves.\u003c/p\u003e\u003cp\u003eMultivariate Cox regression models were used to adjust for confounding variables affecting ICU mortality: including sex, age, race, hypertension, diabetes mellitus, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy, heart rate, respiratory rate, PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, SBP, DBP, SOFA, SAPS II, GCS, and OASIS. Subgroup analyses were conducted within multivariate Cox regression models post-PSM to investigate the impact of early heparin therapy on ICU mortality across different stratification factors, including age, sex, weight, ethnicity, hypertension, diabetes, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy, and PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e. Sensitivity and E-value analyses were additionally performed to evaluate the potential influence of both known and unmeasured confounders. All statistical analyses were conducted using R (version 4.4.3), with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFollowing the analysis of 94,458 patients in the MIMIC-IV database, a total of 6,454 patients with sepsis-related ARDS were included in the study. Among these, 2,528 patients received prophylactic heparin therapy during their ICU stay, while 3,926 patients did not receive heparin therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were notable differences in baseline characteristics between the two groups (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCompared with patients in the non-heparin group, patients in the heparin group had a comparatively higher proportion of females, whites, higher heart rate, higher SBP, greater prevalence of hypertension, higher platelet counts, higher OASIS scores, higher mechanical ventilation utilization, and higher PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, MAP, DBP, prevalence of atrial fibrillation, prevalence of COPD, prevalence of coronary artery disease, urea nitrogen levels, INR, PT, APTT, PEEP, SOFA scores, and vasopressor utilization were higher in the non-heparin group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A total of 2528 patient pairs were matched subsequent to PSM. The \u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 for all variables was indicative of a well-balanced baseline distribution of variables in both groups after PSM (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eUnivariate Cox regression analysis of early heparin therapy and patient mortality\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eBefore PSM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eAfter PSM\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eICU mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.60\u003c/p\u003e\u003cp\u003e(0.53\u0026ndash;0.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003cp\u003e(0.59\u0026ndash;0.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecondary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003cp\u003e(0.49\u0026ndash;0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003cp\u003e(0.49\u0026ndash;0.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003cp\u003e(0.60\u0026ndash;0.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003cp\u003e(0.60\u0026ndash;0.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003cp\u003e(0.66\u0026ndash;0.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003cp\u003e(0.63\u0026ndash;0.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIn-hospital mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003cp\u003e(0.65\u0026ndash;0.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003cp\u003e(0.63\u0026ndash;0.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eAbbreviations: PSM, propensity score matching; ICU, intensive care unit; HR, hazard ratio.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect of early heparin therapy on mortality in sepsis-related ARDS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe association between prophylactic heparin therapy and mortality across various time points was analyzed using univariate Cox regression (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The results revealed that ICU mortality significantly decreased in the heparin-treated group compared with the control group (HR\u0026thinsp;=\u0026thinsp;0.60, 95% CI: 0.53\u0026ndash;0.67, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The correlation between heparin treatment and reduced ICU mortality remained stationary after the PSM (HR\u0026thinsp;=\u0026thinsp;0.66, 95% CI: 0.59\u0026ndash;0.75, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, patients in the heparin group exhibited significantly lower 7-day (HR\u0026thinsp;=\u0026thinsp;0.58, 95% CI: 0.49\u0026ndash;0.69, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), 14-day (HR\u0026thinsp;=\u0026thinsp;0.68, 95% CI: 0.60\u0026ndash;0.78, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), 28-day (HR\u0026thinsp;=\u0026thinsp;0.72, 95% CI: 0.66\u0026ndash;0.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and in-hospital mortality (HR\u0026thinsp;=\u0026thinsp;0.73, 95% CI: 0.65\u0026ndash;0.81, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared with patients who did not receive heparin. The post-PSM data further corroborate these findings.\u003c/p\u003e\u003cp\u003eKaplan-Meier curve analysis further validated the significant survival benefit of early heparin therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Survival curves for the heparin-treated group were consistently higher than those for the control group, exhibiting a more gradual downward trend (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This difference significantly persisted after PSM (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCorrelation of early heparin therapy with ICU mortality\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFollowing PSM, the effect of heparin on ICU mortality was analyzed using a multivariable Cox proportional hazards models (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The results revealed that early heparin therapy was significantly associated with reduced ICU mortality in patients (HR\u0026thinsp;=\u0026thinsp;0.71, 95% CI: 0.63\u0026ndash;0.80, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The reduction in ICU death risk associated with early heparin therapy remained consistently significant across three models, even after adjusting for multiple covariates (HR range 0.72\u0026ndash;0.73, all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.00).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultifactorial Cox modele analysis of heparin therapy and ICU mortality\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026nbsp;value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo heparin therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63\u0026ndash;0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.65\u0026ndash;0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.65\u0026ndash;0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.62\u0026ndash;0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: HR, hazard ratio; 95% CI, the 95% confidence interval of HR.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eAdjusted covariates: Model 1\u0026thinsp;=\u0026thinsp;early heparin therapy. Model 2\u0026thinsp;=\u0026thinsp;Model 1\u0026thinsp;+\u0026thinsp;sex, age, race, and comorbidities (hypertension, diabetes mellitus, atrial fibrillation, COPD, coronary heart disease, cardiomyopathy). Model 3\u0026thinsp;=\u0026thinsp;Model 2\u0026thinsp;+\u0026thinsp;vital signs at 24 hours of admission (MAP, SBP, DBP, heart rate, and respiratory rate)\u0026thinsp;+\u0026thinsp;all laboratory indicators (PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, WBC, platelet count, hemoglobin, INR, APTT, and PT). Model 4\u0026thinsp;=\u0026thinsp;Model 3\u0026thinsp;+\u0026thinsp;clinical score at 24 hours of admission (SOFA, SAPS II, GCS, OASIS)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSubgroup analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSubgroup analysis was conducted to assess the effect of heparin therapy on ICU mortality across different populations (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The result revealed that in the fully adjusted model, early heparin therapy was significantly associated with reduced ICU mortality in patients younger than 60 years of age (HR\u0026thinsp;=\u0026thinsp;0.566, 95% CI: 0.459\u0026ndash;0.698, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in those with high body weight (HR\u0026thinsp;=\u0026thinsp;0.527, 95% CI: 0.423\u0026ndash;0.656, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) .\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSensitivity analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRisk factors for ICU mortality were assessed through sensitivity analysis, accounting for the complexity of patient conditions in the clinical setting. In the multivariate Cox proportional hazards model, significant risk factors for ICU mortality after PSM included age, race, glucose levels, WBC, APTT, SBP, SOFA, GCS, and SAPS II (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The weight, atrial fibrillation, body temperature, and mechanical ventilation were protective factors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSensitivity analysis of heparin therapy and ICU mortality\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.012\u0026ndash;1.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.976\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.857\u0026ndash;1.111\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.710\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.995\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.992\u0026ndash;0.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace_Other\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.948\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.470\u0026ndash;2.580\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace_White\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.963\u0026ndash;1.694\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.090\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.924\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.814\u0026ndash;1.0480\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.217\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucose\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.002\u0026ndash;1.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelets\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.999-1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.173\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.001\u0026ndash;1.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.934\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.810\u0026ndash;1.078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.352\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAtrial fibrillation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.871\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.759\u0026ndash;0.999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCOPD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.937\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.701\u0026ndash;1.254\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.663\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.999-1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.171\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiomyopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.950\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.734\u0026ndash;1.228\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.694\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoronary heart\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.890\u0026ndash;1.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.560\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeart rate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.996\u0026ndash;1.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.834\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory rate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.993\u0026ndash;1.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.365\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTemperature\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.911\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.870\u0026ndash;0.953\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.998\u0026ndash;1.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.147\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBUN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.996\u0026ndash;1.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.436\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.644\u0026ndash;1.547\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.994\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.040\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.997\u0026ndash;1.085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.070\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.002\u0026ndash;1.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.993\u0026ndash;1.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.563\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.994\u0026ndash;1.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.683\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.002\u0026ndash;1.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.034\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.006\u0026ndash;1.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGCS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.046\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.024\u0026ndash;1.068\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSAPS II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.014\u0026ndash;1.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOASIS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.995\u0026ndash;1.019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.261\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVentilation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.610\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.500-0.743\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: HR, hazard ratio; 95% CI, the 95% confidence interval of HR; WBC, white blood cell count; COPD, chronic obstructive pulmonary disease; PaO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003epressure of alveolar oxygen; FiO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003efraction of inspired oxygen; SpO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003epulse oxygen saturation; BUN, blood urine nitrogen; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; MAP, mean arterial pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure; SOFA, sequential organ failure assessment; GCS, glasgow coma score; SAPS II, simplified acute physiology score II; OASIS, oxford acute severity of illness score.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eE-value analysis demonstrated that the association between early heparin therapy and ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality was robust (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Only unmeasured confounders with an HR\u0026thinsp;\u0026gt;\u0026thinsp;2 (upper limit of 95% CI: 1.74) would potentially affect the relationship between early heparin therapy and ICU mortality. Consequently, other unknown or unmeasured factors likely have a minimal impact on mortality relative to known risks.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eE-value of the association between heparin therapy and mortality in sepsis-related ARDS\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eE\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eUpper limit of 95% CI\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eICU mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecondary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIn-hospital mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this study indicate that early heparin therapy is effective in reducing the risk of mortality in critically ill patients with sepsis-related ARDS. After PSM, ICU mortality, 7-day mortality, 14-day mortality, 28-day mortality, and in-hospital mortality were significantly decreased in the heparin-treated group. The correlation between heparin therapy and reduced ICU mortality was robust regardless various variables, including gender, age, comorbidities, vital signs, clinical indicators, and scores. Stratified analyses revealed that the effect of heparin therapy on ICU mortality was particularly pronounced in patients younger than 60 years of age and those with high body weight.\u003c/p\u003e\u003cp\u003eThese results are consistent with previous studies indicating heparin's therapeutic potential in managing sepsis-related ARDS. Researches have demonstrated that anticoagulation reduces the risk of death in patients with sepsis, particularly in those with DIC and high disease severity[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Heparin has been shown to reduce 28-day mortality in adults with sepsis without increasing the risk of bleeding [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Heparin therapy has demonstrated potential benefits in both sepsis and COVID-19 patients [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This positions heparin as a promising adjunctive treatment option for mechanically ventilated patients with sepsis in clinical practice. A retrospective study revealed a significant reduction in in-hospital, 60-day, and 90-day mortality among ARDS patients receiving prophylactic heparin therapy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Furthermore, nebulized heparin therapy has been shown to reduce hospitalization time and duration of mechanical ventilation in patients with or at risk for ARDS [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This indicates that local anticoagulation may decrease alveolar fibrin deposition and mitigate lung injury.\u003c/p\u003e\u003cp\u003eHeparin, despite its long-standing use, continues to be the first-line anticoagulant in clinical practice [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. As per the aforementioned findings, the survival advantage observed in heparin-treated patients may be attributed to its dual anticoagulant and anti-inflammatory properties. Central to the pathophysiology of sepsis and ARDS is a vicious cycle involving uncontrolled inflammatory responses and coagulation dysfunction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Heparin mitigates microcirculatory thrombosis by binding to antithrombin III (ATIII), inhibiting coagulation factors Xa and IIa (thrombin), and blocking the coagulation cascade [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Furthermore, heparin downregulates tissue factor (TF) expression, reduces activation of exogenous coagulation pathways, enhances fibrinolytic activity, and ameliorates intra-alveolar fibrin deposition by inhibiting plasminogen activator inhibitor (PAI-1) [\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Regarding oxidative stress, the reducing hydroxyl group of heparin binds to reactive oxygen species (ROS), inhibits lipid peroxidation, and increases the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Collectively, these effects reduce alveolar-capillary leakage and enhance oxygenation, as evidenced by the higher PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratios observed in heparin-treated patients. Furthermore, heparin\u0026rsquo;s capacity to restore endothelial barrier function may reduce secondary organ injuries, which aligns with the reduced vasopressor requirements and lower SOFA scores observed in the treatment group [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSubgroup analyses revealed heterogeneity in treatment effects, with younger patients (\u0026lt;\u0026thinsp;60 years) and those with higher body weight exhibiting more pronounced reductions in mortality (HR\u0026thinsp;=\u0026thinsp;0.566 and HR\u0026thinsp;=\u0026thinsp;0.527). This may be attributed to age-related alterations in pharmacokinetics and hepatic and renal clearance, which can diminish the therapeutic efficacy of heparin in older adults. In obese patients, adipose tissue releases substantial quantities of pro-inflammatory mediators, intensifying the inflammatory cascade in sepsis. Moreover, obesity is associated with elevated platelet activity, increased production of coagulation factors, and a pre-thrombotic state. Obesity-related metabolic syndrome also contributes to endothelial cell glycocalyx damage, exacerbating vascular permeability. Consequently, the anti-inflammatory and anticoagulant effects of heparin, along with its role in protecting the endothelial barrier, are particularly obvious in these patients [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These findings highlight the necessity for personalized heparin regimens guided by pharmacodynamic monitoring. Although the current prophylactic dose of heparin therapy is standardized, individualized adjustments based on patient weight are also recommended.\u003c/p\u003e\u003cp\u003eThis study has critical implications for critical care practice. From a clinical standpoint, these results support considering prophylactic heparin as an adjunctive therapy for managing septic ARDS patients without bleeding contraindications.\u003c/p\u003e\u003cp\u003eIt is crucial to acknowledge that this study has certain limitations. First, as a retrospective study, it may be subject to measurement bias due to its extensive time span. Second, although PSM was used to adjust for baseline differences, some unmeasured confounding variables might still have exerted an impact. Future research should further investigate the effects of heparin administration timing and dosage on patients with sepsis-associated ARDS through larger prospective trials.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study has demonstrated that early heparin therapy significantly reduces mortality at different stages in patients with sepsis-related ARDS. While heparin shows therapeutic potential in critically ill patients with sepsis-associated ARDS, individual bleeding risks must still be carefully weighed in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data analyzed for this study were from the MIMIC-IV database, https://mimic.mit.edu/docs/iv/.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is not supported by any sponsors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.L. and Q.L designed the study. W.L, X.H. and H.F. performed the data analysis. W.L. wrote the original draft. All authors reviewed the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChiu C, Legrand M: Epidemiology of sepsis and septic shock. Current opinion in anaesthesiology.\u003cem\u003e \u003c/em\u003e2021; 34:71-76; doi:10.1097/aco.0000000000000958\u003c/li\u003e\n\u003cli\u003eXu C, Zheng L, Jiang Y, Jin L: A prediction model for predicting the risk of acute respiratory distress syndrome in sepsis patients: a retrospective cohort study. BMC pulmonary medicine.\u003cem\u003e \u003c/em\u003e2023; 23:78; doi:10.1186/s12890-023-02365-z\u003c/li\u003e\n\u003cli\u003eWang Q, Feng Q, Zhang Y, Zhou S, Chen H: Decreased microRNA 103 and microRNA 107 predict increased risks of acute respiratory distress syndrome and 28-day mortality in sepsis patients. Medicine.\u003cem\u003e \u003c/em\u003e2020; 99:e20729; doi:10.1097/md.0000000000020729\u003c/li\u003e\n\u003cli\u003eQiao X, Yin J, Zheng Z, Li L, Feng X: Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications. Cell communication and signaling : CCS.\u003cem\u003e \u003c/em\u003e2024; 22:241; doi:10.1186/s12964-024-01620-y\u003c/li\u003e\n\u003cli\u003eScozzi D, Liao F, Krupnick AS, Kreisel D, Gelman AE: The role of neutrophil extracellular traps in acute lung injury. Frontiers in immunology.\u003cem\u003e \u003c/em\u003e2022; 13:953195; doi:10.3389/fimmu.2022.953195\u003c/li\u003e\n\u003cli\u003eGando S, Wada T: Pathomechanisms Underlying Hypoxemia in Two COVID-19-Associated Acute Respiratory Distress Syndrome Phenotypes: Insights From Thrombosis and Hemostasis. Shock (Augusta, Ga).\u003cem\u003e \u003c/em\u003e2022; 57:1-6; doi:10.1097/shk.0000000000001825\u003c/li\u003e\n\u003cli\u003eLiu X, Li T, Chen H, Yuan L, Ao H: Role and intervention of PAD4 in NETs in acute respiratory distress syndrome. Respiratory research.\u003cem\u003e \u003c/em\u003e2024; 25:63; doi:10.1186/s12931-024-02676-7\u003c/li\u003e\n\u003cli\u003eGu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S\u003cem\u003e et al\u003c/em\u003e: Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature reviews Cardiology.\u003cem\u003e \u003c/em\u003e2021; 18:194-209; doi:10.1038/s41569-020-00469-1\u003c/li\u003e\n\u003cli\u003eHeestermans M, Poenou G, Hamzeh-Cognasse H, Cognasse F, Bertoletti L: Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications. Cells.\u003cem\u003e \u003c/em\u003e2022; 11; doi:10.3390/cells11203214\u003c/li\u003e\n\u003cli\u003eHogwood J, Mulloy B, Lever R, Gray E, Page CP: Pharmacology of Heparin and Related Drugs: An Update. Pharmacological reviews.\u003cem\u003e \u003c/em\u003e2023; 75:328-379; doi:10.1124/pharmrev.122.000684\u003c/li\u003e\n\u003cli\u003eHuang JJ, Zou ZY, Zhou ZP, Liu Y, Yang ZJ, Zhang JJ, Luan YY, Yao YM, Wu M: Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy. Frontiers in pharmacology.\u003cem\u003e \u003c/em\u003e2023; 14:1173893; doi:10.3389/fphar.2023.1173893\u003c/li\u003e\n\u003cli\u003eEvans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC\u003cem\u003e et al\u003c/em\u003e: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive care medicine.\u003cem\u003e \u003c/em\u003e2021; 47:1181-1247; doi:10.1007/s00134-021-06506-y\u003c/li\u003e\n\u003cli\u003eSinger M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM\u003cem\u003e et al\u003c/em\u003e: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama.\u003cem\u003e \u003c/em\u003e2016; 315:801-810; doi:10.1001/jama.2016.0287\u003c/li\u003e\n\u003cli\u003eRanieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS: Acute respiratory distress syndrome: the Berlin Definition. Jama.\u003cem\u003e \u003c/em\u003e2012; 307:2526-2533; doi:10.1001/jama.2012.5669\u003c/li\u003e\n\u003cli\u003eYu S, Chi Y, Ma X, Li X: Heparin in sepsis: current clinical findings and possible mechanisms. Frontiers in immunology.\u003cem\u003e \u003c/em\u003e2024; 15:1495260; doi:10.3389/fimmu.2024.1495260\u003c/li\u003e\n\u003cli\u003eTotoki T, Koami H, Makino Y, Wada T, Ito T, Yamakawa K, Iba T: Heparin therapy in sepsis and sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis. Thrombosis journal.\u003cem\u003e \u003c/em\u003e2024; 22:84; doi:10.1186/s12959-024-00653-0\u003c/li\u003e\n\u003cli\u003eFu S, Yu S, Wang L, Ma X, Li X: Unfractionated heparin improves the clinical efficacy in adult sepsis patients: a systematic review and meta-analysis. BMC anesthesiology.\u003cem\u003e \u003c/em\u003e2022; 22:28; doi:10.1186/s12871-021-01545-w\u003c/li\u003e\n\u003cli\u003ePeng JC, Nie F, Li YJ, Xu QY, Xing SP, Li W, Gao Y: Favorable Outcomes of Anticoagulation With Unfractioned Heparin in Sepsis-Induced Coagulopathy: A Retrospective Analysis of MIMIC-III Database. Frontiers in medicine.\u003cem\u003e \u003c/em\u003e2021; 8:773339; doi:10.3389/fmed.2021.773339\u003c/li\u003e\n\u003cli\u003eZhang Z, Yan T, Ren D, Zhou J, Liu L, Li J, Fu S, Ni T, Xu W, Yang Y\u003cem\u003e et al\u003c/em\u003e: Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy. Frontiers in medicine.\u003cem\u003e \u003c/em\u003e2023; 10:1157775; doi:10.3389/fmed.2023.1157775\u003c/li\u003e\n\u003cli\u003eLi X, Liu Z, Luo M, Xi Y, Li C, Wang S, Yang R: Therapeutic effect of low-molecular-weight heparin on adult sepsis: a meta-analysis. Annals of palliative medicine.\u003cem\u003e \u003c/em\u003e2021; 10:3115-3127; doi:10.21037/apm-21-169\u003c/li\u003e\n\u003cli\u003eSpyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G\u003cem\u003e et al\u003c/em\u003e: Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA internal medicine.\u003cem\u003e \u003c/em\u003e2021; 181:1612-1620; doi:10.1001/jamainternmed.2021.6203\u003c/li\u003e\n\u003cli\u003eBillett HH, Reyes-Gil M, Szymanski J, Ikemura K, Stahl LR, Lo Y, Rahman S, Gonzalez-Lugo JD, Kushnir M, Barouqa M\u003cem\u003e et al\u003c/em\u003e: Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality. Thrombosis and haemostasis.\u003cem\u003e \u003c/em\u003e2020; 120:1691-1699; doi:10.1055/s-0040-1720978\u003c/li\u003e\n\u003cli\u003eXiao LX, Zhu L, Chen J, Lv J, Liu MJ, Dai X, Wang DX, Deng W: Exploring the therapeutic role of early heparin administration in ARDS management: a MIMIC-IV database analysis. Journal of intensive care.\u003cem\u003e \u003c/em\u003e2024; 12:9; doi:10.1186/s40560-024-00723-5\u003c/li\u003e\n\u003cli\u003eDixon B, Smith RJ, Campbell DJ, Moran JL, Doig GS, Rechnitzer T, MacIsaac CM, Simpson N, van Haren FMP, Ghosh AN\u003cem\u003e et al\u003c/em\u003e: Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. The Lancet Respiratory medicine.\u003cem\u003e \u003c/em\u003e2021; 9:360-372; doi:10.1016/s2213-2600(20)30470-7\u003c/li\u003e\n\u003cli\u003evan Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, Smith R, Shute J, Carroll M, Tree J\u003cem\u003e et al\u003c/em\u003e: Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Critical care (London, England).\u003cem\u003e \u003c/em\u003e2020; 24:454; doi:10.1186/s13054-020-03148-2\u003c/li\u003e\n\u003cli\u003eBall L, Schultz MJ, Pelosi P: Nebulised heparin for patients on ventilation: implications for COVID-19 pneumonia. The Lancet Respiratory medicine.\u003cem\u003e \u003c/em\u003e2021; 9:321-322; doi:10.1016/s2213-2600(20)30513-0\u003c/li\u003e\n\u003cli\u003eWang P, Chi L, Zhang Z, Zhao H, Zhang F, Linhardt RJ: Heparin: An old drug for new clinical applications. Carbohydrate polymers.\u003cem\u003e \u003c/em\u003e2022; 295:119818; doi:10.1016/j.carbpol.2022.119818\u003c/li\u003e\n\u003cli\u003eHuang M, Cai S, Su J: The Pathogenesis of Sepsis and Potential Therapeutic Targets. International journal of molecular sciences.\u003cem\u003e \u003c/em\u003e2019; 20; doi:10.3390/ijms20215376\u003c/li\u003e\n\u003cli\u003eXu H, Sheng S, Luo W, Xu X, Zhang Z: Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup. Frontiers in immunology.\u003cem\u003e \u003c/em\u003e2023; 14:1277161; doi:10.3389/fimmu.2023.1277161\u003c/li\u003e\n\u003cli\u003eBeurskens DMH, Huckriede JP, Schrijver R, Hemker HC, Reutelingsperger CP, Nicolaes GAF: The Anticoagulant and Nonanticoagulant Properties of Heparin. Thrombosis and haemostasis.\u003cem\u003e \u003c/em\u003e2020; 120:1371-1383; doi:10.1055/s-0040-1715460\u003c/li\u003e\n\u003cli\u003eShute JK: Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease. Pharmaceuticals (Basel, Switzerland).\u003cem\u003e \u003c/em\u003e2023; 16; doi:10.3390/ph16040584\u003c/li\u003e\n\u003cli\u003eZang L, Zhu H, Wang K, Liu Y, Yu F, Zhao W: Not Just Anticoagulation-New and Old Applications of Heparin. Molecules (Basel, Switzerland).\u003cem\u003e \u003c/em\u003e2022; 27; doi:10.3390/molecules27206968\u003c/li\u003e\n\u003cli\u003eWhyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ: Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. Journal of thrombosis and haemostasis : JTH.\u003cem\u003e \u003c/em\u003e2020; 18:1548-1555; doi:10.1111/jth.14872\u003c/li\u003e\n\u003cli\u003eLi L, Yu S, Fu S, Ma X, Li X: Unfractionated heparin inhibits histone-mediated coagulation activation and thrombosis in mice. Thrombosis research.\u003cem\u003e \u003c/em\u003e2020; 193:122-129; doi:10.1016/j.thromres.2020.06.007\u003c/li\u003e\n\u003cli\u003eLin L, Xie S, Zhao Y, Liang Z, Wu Q, Fang M, Teng X, Shi B, Yang Y, Chen B: Ultrasound-induced destruction of heparin-loaded microbubbles attenuates L-arginine-induced acute pancreatitis. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.\u003cem\u003e \u003c/em\u003e2023; 180:106318; doi:10.1016/j.ejps.2022.106318\u003c/li\u003e\n\u003cli\u003eYang R, Zhang X: A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Frontiers in cellular and infection microbiology.\u003cem\u003e \u003c/em\u003e2022; 12:984835; doi:10.3389/fcimb.2022.984835\u003c/li\u003e\n\u003cli\u003eSchurr JW, Muske AM, Stevens CA, Culbreth SE, Sylvester KW, Connors JM: Derivation and Validation of Age- and Body Mass Index-Adjusted Weight-Based Unfractionated Heparin Dosing. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.\u003cem\u003e \u003c/em\u003e2019; 25:1076029619833480; doi:10.1177/1076029619833480\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Heparin, Sepsis, Acute respiratory distress syndrome, Mortality, MIMIC-IV database","lastPublishedDoi":"10.21203/rs.3.rs-6980725/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6980725/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eSepsis-associated acute respiratory distress syndrome (ARDS) is a life-threatening condition marked by significant thromboinflammation. Heparin, which has both anticoagulant and anti-inflammatory effects, may influence these pathways. However, its role in sepsis-related ARDS has not been fully explored.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eData for this retrospective cohort study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients were divided into two groups: those who received prophylactic heparin therapy at least once during their ICU stay and those who did not. The primary endpoint was intensive care unit (ICU) mortality, with secondary outcomes including 7-day, 14-day, 28-day, and in-hospital mortality. Propensity score matching (PSM), univariate Cox regression analysis, Kaplan-Meier curve analysis, multivariate Cox modeling, sensitivity analysis, and E-value analysis were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 6,454 patients were included in this study: 2,528 received early heparin therapy, and 3,926 did not. Early heparin therapy was associated with a significant reduction in ICU mortality, 7-day, 14-day, 28-day, and in-hospital mortality in patients with sepsis-associated ARDS, and this effect remained significant following PSM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The association between early heparin therapy and reduced ICU mortality (HR\u0026thinsp;=\u0026thinsp;0.72, \u003cem\u003e95% CI\u003c/em\u003e: 0.62\u0026ndash;0.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) persisted after adjusting for confounding variables and was more pronounced in patients aged\u0026thinsp;\u0026lt;\u0026thinsp;60 years and those with a high body weight. E-value analyses demonstrated robustness to unmeasured confounders.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eEarly heparin therapy is correlated with decreased mortality in critically ill patients with sepsis-related ARDS. These findings provide a rationale for further exploring heparin as an adjunctive therapy.\u003c/p\u003e","manuscriptTitle":"Impact of early heparin therapy on mortality in critically ill patients with sepsis-related acute respiratory distress syndrome: a MIMIC-IV database analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 08:15:55","doi":"10.21203/rs.3.rs-6980725/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"584fb999-3c04-4bbf-a7e7-27bf77ae1539","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-14T12:40:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-06 08:15:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6980725","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6980725","identity":"rs-6980725","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}