Abstract
Background
Due to age-related immunosenescence, the efficacy of unfractionated heparin (UFH) in geriatric sepsis populations remains unclear. The aim of this study was to investigate the efficacy of UFH in geriatric sepsis patients, providing a basis for the design of interventional randomized controlled trials.
Methods
We identified geriatric sepsis patients (aged ≥65 years) from the Medical Information Mart for Intensive Care (MIMIC-IV) database, Propensity score matching (PSM) and marginal structural Cox model (MSCM) were used to adjust for both baseline and time varying confounding. The primary endpoint was intensive care unit (ICU) mortality, while secondary outcomes included 28-day, 90-day, and in-hospital mortality, along with haemorrhage occurrence.
Results
A total of 3866 geriatric sepsis patients were enrolled in the study, with 1434 patients receiving UFH therapy. UFH therapy significantly reduced in-ICU mortality (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.48-0.81) and haemorrhage occurrence (HR 0.43, 95% CI 0.33-0.56) with PSM. However,UFH therapy did not significantly improve 28-day, 90-day, or in-hospital mortality. MSCMs further confirmed that UFH administration reduced ICU mortality (HR 0.58, 95% CI: 0.44-0.75) in the general population. Stratification analysis using MSCMs indicated that UFH administration was associated with a reduced ICU mortality rate among patients on ventilation (HR 0.55, 95% CI 0.41-0.74) and with acute kidney injury (AKI) (HR 0.59, 95% CI 0.45-0.78) (P < .001).
Conclusions
Early administration UFH to geriatric patients with sepsis was associated with reducing ICU mortality, without increasing the risk of bleeding. Subgroup analysis further suggested that UFH therapy conferred organ protective effects, particularly pronounced in patients requiring mechanical ventilation and those with AKI.
Introduction
Sepsis is a life-threatening condition caused by an imbalance in the host multiple system in response to infection. 1 The latest research indicates that the global mortality for sepsis, encompassing both middle-income and low-income countries, ranges from 22.9% to 30.7%. 2 The overall incidence of sepsis is increasing, and the aging of the population appears to be an important factor, more than 60% of sepsis cases are diagnosed in adults aged ≥65 years, and it is the primary cause of admission of geriatric to ICU.3–6 Despite advances in antibiotic therapy, fluid resuscitation, and extracorporeal life support, sepsis continues to contribute significantly to mortality in ICUs, particularly among geriatric patients. In-hospital mortality among patients with sepsis aged 65 years and above range from 30%-60%, with rates approaching 40%-80% among those aged 80 years and above.6–8
An extensive interaction between inflammation and coagulation contributes to the development of sepsis.9,10 Inhibiting the production of inflammatory mediators and disrupting microthrombus formation are crucial for mitigating inflammatory response and tissue ischaemia in sepsis.1,11 UFH is a mammalian polysaccharide with anticoagulant properties, in addition to thrombotic diseases, accumulated evidence from basic research and clinical practice implicate that UFH treatment improves the outcome of sepsis.12–15 Groundbreaking study has demonstrated that UFH prevents caspase-11 dependent septic lethality independent of anticoagulant properties. 16 The most recent studies also demonstrate that UFH enhances sepsis prognosis through inhibiting Drp1 mediated mitochondrial quality imbalance. 17
As geriatric patients with sepsis constitute the majority of ICU admissions, the mortality rates are highest in such population. Whether UFH therapy confers a survival advantage to geriatric critically ill patients with sepsis remains unknown. Therefore, we conducted a retrospective cohort study leveraging data from the Medical Information Mart for Intensive Care (MIMIC-IV) database to assess the efficacy and safety of UFH therapy in geriatric patients with sepsis, laying the groundwork for future prospective clinical studies.
Methods
Data Source and Study Design
Data were extracted from the MIMIC-IV database (version 2.2) in August 2023 - December 2023 ，for a retrospective cohort study. The dataset comprised three types of data: basic clinical information on patients obtained from electronic health records (EHRs); bedside clinical information obtained from systems utilised primarily within critical care units, particularly from the IMD Soft MetaVision system; and mortality follow-up data collected at Beth Israel Deaconess Medical Center in Boston between 2008 and 2019. Only individuals who successfully completed the Collaborative Institutional Training Initiative examination (certification number 38995627 for author Huang) were granted access to the database.
A total of 34 678 patients were admitted to the ICU for sepsis between 2008 and 2019, with 33 773 patients receiving a diagnosis within the initial 48 h of ICU admission. The inclusion criteria were as follows: (1) diagnosis of sepsis, defined according to the Sepsis-3 criteria; (2) patient age ≥ 65 years; (3) diagnosis of sepsis within the first 48 h of admission; The exclusion criteria were as follows: (1) ICU stay < 24 h; (2) multiple admissions to the ICU; (3) patients with thrombotic disease or a high risk of thrombosis; (4)patients who used anticoagulants (LMWH or Warfarin etc); (5)UFH usage not in the first 48 h after lCU admission; (6) patients with missing data.
Research Strategy and Definitions
Structured Query Language (SQL) was used to extract data from the MIMIC-IV database. Patient characteristics, including age, sex, race, and year of admission, were collected. During hospitalisation, data on other parameters, including anion gap, blood urea nitrogen (BUN), creatinine, international normalised ratio (INR), partial thromboplastin time (PTT), prothrombin time (PT), haemoglobin, platelet count, white blood cell (WBC) count, urine output, ventilation time, haemorrhage, vasopressors (norepinephrine, phenylephrine, epinephrine), anamnesis (chronic pulmonary disease, congestive heart failure, diabetes, hypertension), Sequential Organ Failure Assessment (SOFA) score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology Score (APS III), Charlson Comorbidity Index, in-ICU mortality, 28-day mortality, and 90-day mortality, were collected.
Exposure and Outcome
The enrolled patients were divided into two groups. In the UFH group, treatment was initiated within 48 h of sepsis diagnosis. UFH was administered subcutaneously at an initial dose of 5000 units once daily. Subsequent doses were adjusted dynamically and individually, guided by close monitoring of the patient's clinical status and APTT (activated partial thromboplastin time), to ensure optimal anticoagulation and patient safety. The control group included patients who did not receive UFH during their ICU stay. The primary outcome was in-ICU mortality, and secondary outcomes included 28-day, 90-day, and in-hospital all-cause mortality, as well as the incidence of hemorrhage.
Statistical Analysis
Continuous variables were described using the mean (SD), whereas categorical variables were presented as counts (percentages). Statistical tests, including the t test, chi-square (χ2) test, or Wilcoxon rank-sum test, were used to compare patient characteristics between the two groups. Propensity score matching (PSM) was employed to establish baseline characteristic parity between the UFH group and the control group. A logistic regression model was utilised to compute the propensity scores using a 1:1 matching ratio, using the nearest neighbour method and a calliper width of 0.05, without replacement for both cohorts. Following PSM, standardised mean differences (SMDs) were employed to evaluate the parity of the characteristics between the two cohorts. A variable was deemed imbalanced if its SMD surpassed 0.1.
A marginal structural Cox model (MSCM) was utilised to investigate the relationship between UFH exposure and survival outcomes. The early administration of UFH in geriatric septic patients was a time-dependent variable. The impact of UFH administration on survival increases with time and was influenced by various factors, including mechanical ventilation (MV), vasopressor use, renal replacement therapy, and sequential organ failure assessment (SOFA) as well as simplified acute physiological assessment II (SAPS II) scores, which were evaluated 24 h after ICU admission. APTT was included as time-dependent confounders throughout the ICU admission period and were integrated into the MSCM. The parameters of the MSCM were predicted using inverse probability weighting (IPW) to correct for confounding biases and various types of selection biases, including informative censoring.
Subgroup analyses of the matched patients were based on the dose of UFH, sex (female vs male), age (< 80 years vs ≥ 80 years), ethnicity (white vs other), ventilation (yes vs no), vasopressor use (yes vs no), sepsis induced coagulopathy (SIC) (yes vs no), and acute kidney injury (AKI) (yes vs no). Sensitivity analyses were performed on the entire dataset to test the robustness of the findings obtained in the matched cohort. Variables with P < .05, including sex, race, age, WBC count, weight, PT, SOFA score, SAPS II score, vasopressor use, ventilation status, chronic heart disease status, chronic pulmonary disease status, diabetes status, and hypertension status, were entered into multivariable analysis for adjustment.
Results
Patient Selection
Figure 1 illustrated the process through which patients were recruited. A total of 34 678 patients with sepsis were identified, while the diagnosis of sepsis (based on Sepsis-3) was made in 33 773 patients within the first 48 h following admission to the ICU. After rigorous screening based on established inclusion and exclusion criteria, a total of 3866 patients were successfully enrolled in our analysis,1434 patients received UFH treatment within 48 h, while 2432 patients were not administered UFH during their stay in the ICU.
Flowchart of Participants Selection.
Cohort Characteristics
Table 1 showed baseline characteristics before and after matching. Across the entire cohort, patients treated with UFH were younger and exhibited fewer chronic comorbidities; however, they were administered vasoactive drugs and received mechanical ventilation in greater frequencies, had higher Sequential Organ Failure Assessment (SOFA)and Simplified Acute Physiological AssessmentII(SAPS II) scores, and had prolonged hospital stays. After PSM, 1292 patients were administered early UFH treatment, while another 1292 patients received no such therapy; the independent variables (sex, age, ethnicity, weight) between these two groups were not significantly different.
Baseline Characteristics of Septic Patients Before and After Propensity Score Matching.
Abbreviations: WBC, white blood cell; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; BUN, blood urea nitrogen; RRT, renal replacement therapy; SOFA, sequential organ failure assessment; SAPS II, simplified acute physiology score II; CCI, Charlson Comorbidity Index; APSIII, acute physiology score III; LODS, logistic organ dysfunction score; OASIS, Oxford acute severity of illness score; SIRS, systemic inflammatory response syndrome score; GCS, Glasgow Coma Scale. Values were shown as mean (SD) unless otherwise indicated.
Propensity Score Matching Analysis
PSM resulted in 1292 pairs of patients (UFH vs non-UFH). After PSM, there were no significant differences in the prevalence of preexisting chronic diseases such as hypertension, diabetes, chronic heart disease, or chronic pulmonary disease between the two groups prior to hospitalisation. Meanwhile, no statistically significant disparities were found in the duration of epinephrine and vasopressin use, SOFA score, SAPSIIscore, Charlson Comorbidity Index(CCI) score, or Glasgow Coma Scale (GCS) score during ICU treatment (P > .05) (Table 1). However,the hemoglobin (HB), platelet (PLT) count, and international normalized ratio (INR) in the UFH group were higher than those in the Non-UFH group, and the difference was statistically significant. The mechanical ventilation time in the UFH group was also significantly longer than that in the Non-UFH group. Early administration of UFH to geriatric patients with sepsis (within 48 h) significantly reduced in-ICU mortality (HR: 0.62; 95% CI 0.48-0.81; P < .001) without increasing the risk of bleeding (HR: 0.43; 95% CI 0.33 −0.56; P < .001). However, there were no statistically significant differences in terms of in-hospital mortality or mortality rates at days 28, 60, or 90 between the UFH-treated group and the non-UFH-treated group (Table 2).
Association Between Heparin use and Clinic Outcomes in Septic Patient.
adjusted for: age, SOFA score, OASIS score, SAPS II score, bun, platelet, WBC, urine output, RRT, vasopressor use, hypertension, congestive heart disease.
adjusted for: age, SOFA score, ethnicity, weight, APTT, platelet, WBC, urine output, RRT, ventilation, vasopressor use, congestive heart disease, hypertension.
adjusted for: ethnicity, vasopressor use, SOFA score. Abbreviations: HR, hazard ratio; ICU, intensive care unit.
Marginal Structural Cox Model and Subgroup Analysis
The analysis of the MSCM revealed that early administration of UFH conferred overall benefits in geriatric patients with sepsis. As demonstrated by the MSCM, in general, treatment with UFH significantly decreased in-ICU mortality (HR, 0.58; 95% CI, 0.44-0.75; P < .001). Based on stratification analysis, UFH administration significantly decreased in-ICU mortality among patients with AKI and those who received mechanical ventilation, with HRs of 0.59 and 0.55, respectively (P < .05). Furthermore, subgroup analysis showed that early administration of UFH had no marked effect on sex, age, ethnicity, SIC or those requiring treatment with vasopressors (Figure 2).
Results of lCU Mortality in Overall Population with MSCM and Stratification Analysis.
UFH Treatment Regimen
Thirty-seven percent of patients in the cohort were treated with UFH (1434/3866). The UFH dose across the UFH treatment cohort ranged from 5000 to 15 000 U, with 258 patients (18%) receiving a dose of 5000 U, 298 patients (21%) receiving a dose between 5000 and 10 000 U, 345 patients (24%) receiving a dose of at least 10 000 U, and 381 patients (27%) receiving a dose between 10 000 and 15 000 U. Additionally, 152 patients (8%) were treated with a dose of ≥15 000 U (Table 3). Correlation analysis revealed that only patients receiving a daily dose of UFH exceeding 5000 U experienced a beneficial impact on in-ICU mortality (Table 3).
Dose-Response Relationship Between Heparin and ICU Mortality.
*The number of patients with prophylactic heparin administration.
Sensitivity Analysis
Multivariate Cox regression analysis conducted after PSM revealed that several factors, including the number of WBCs (HR, 1.03; 95% CI, 1.02-1.05), prothrombin time (HR, 1.02; 95% CI, 1.01-1.03), SOFA score (HR, 1.32; 95% CI, 1.27-1.37), SAPS II (HR, 1.08; 95% CI, 1.06-1.09), utilisation of vasopressors (HR, 1.81; 95% CI, 1.27-2.59), requirement for mechanical ventilation (HR, 2.26; 95% CI, 1.58-3.23), and presence of complicated hypertension (HR, 0.63; 95% CI, 0.46-0.86), significantly influenced the in-ICU mortality (Table 4).
Multivariable cox Regression Model After Propensity Score Matching in Elderly Critically ill Patients with Sepsis.
Abbreviations: PT, prothrombin time; AKI, acute kidney injury; RRT, renal replacement therapy; SOFA, sequential organ failure assessment; SAPS II, simplified acute physiology score II.
The E value was used to evaluate the influence of unmeasured confounders on the in-in-ICU mortality (https://www.evalue-calculator. com/evalue/). The E-value was greater than 2 (The calculated value of this cohort was 2.61), suggesting that the research results exhibit high robustness against unmeasured confounding factors. Therefore, it could be inferred that unknown unmeasured confounders did not exert a statistically significant impact on the in-ICU mortality compared to known risk factors.
Discussion
This retrospective analysis suggests that the administration of subcutaneous UFH within 48 h of admission to the ICU in elderly patients with sepsis is associated with a significant reduction in-ICU mortality, without an increased risk of bleeding complications. However, it shows no correlation with in-hospital mortality rates or the 28-day, 60-day, and 90-day mortality. Additionally, we observed that hemoglobin (Hb), platelet count (PLT), and international normalized ratio (INR) exhibited significant improvements in the UFH group compared to the Non-UFH group.These three indicators were within the normal range in the Non-UFH group, hence they were not reasons to restrict the use of UFH,The bias resulting from these factors does not affect the research results. After UFH treatment, Hb and PLT increased, and INR decreased, which might imply that the use of UFH inhibited the inflammatory response, protected the endothelium, and impeded the activation of coagulation, ultimately leading to reduced bleeding, decreased platelet consumption, and stabilized coagulation function.
Older adults exhibit age-related immune dysfunction and haematological changes, resulting in distinct pathophysiological alterations in senile sepsis, characterised by a weakened inflammatory response, sustained endothelial activation, and a heightened procoagulant state (predisposing patients to disseminated intravascular coagulation [DIC]).6,18–20 A leukocyte transcriptome analysis conducted by Michels et al showed that septic patients aged >70 years exhibited enhanced expression of endothelial and coagulation-activating genes compared to those aged < 50 years. 18 The interplay among these factors serves as a crucial determinant of organ dysfunction and is a significant contributor to the high mortality rates observed. Aging is associated with increased production of circulating inflammatory cytokines and acute phase reactive proteins, both of which are robust predictors of mortality.18,21 Chronic inflammatory stimulation leads to elevated levels of coagulation factors, including VII, VIII, fibrinogen (Fib), and plasminogen activator inhibitor-1 (PAI-1) in the geriatric population, thereby promoting thrombosis.22–25 Several clinical and animal studies have consistently indicated that geriatric patients with sepsis in the ICU exhibit a significantly more pronounced hypercoagulable state, which is strongly correlated with an unfavourable prognosis. Clinical trials investigating activated protein C (an endogenous anticoagulant molecule) in severe septic patients demonstrated that its efficacy was most pronounced among geriatric patients, suggesting an augmented prothrombotic state associated with advanced age. 26 To sum up, the pathophysiological process of sepsis encompasses various biological pathways, and the multi-target effect of UFH might be the cause for the intriguing research findings presented in this study.
Numerous clinical studies and animal model investigations also suggest that the administration of UFH may enhance outcomes in sepsis. A meta-analysis encompassing 15 RCTs with 2617 patients suggested that UFH could decrease 28-day mortality and enhance clinical effectiveness in septic patients without causing bleeding complications. 27 A systematic review of 9 clinical trials with 2637 patients revealed a potential association between UFH use and reduced mortality in patients with sepsis, septic shock, and infection-associated DIC. 28 Another study on 6666 patients from the MIMIC-IV database suggested a potential link between early UFH prescriptions and a lower risk-adjusted in-hospital mortality rate as well as a reduction in the 60-day mortality rate among septic patients 29 Results from animal studies showed that the administration of UFH significantly improved survival rates among septic mice challenged with E. coli. 30 An in vitro experiment confirmed that UFH attenuated LPS-induced IL-8 secretion by modulating the PI3 K/Akt/NF-κB signalling pathway in human endothelial cells. 31 The findings of our study were consistent with those of the previously mentioned prospective RCTs, indicating that UFH may offer potential benefits for patients with sepsis. We have also discovered a correlation between the dose of UFH and the mortality rate in the ICU. It is suggested that a daily dose exceeding 5000 U might be beneficial without augmenting the risk of bleeding.
To minimise confounding bias and to ensure reliability, we utilised PSM which minimises disparities between the UFH and non-UFH groups, ensuring scientifically valid outcomes. 32 The unique characteristics of UFH require adjustments in its effectiveness and dosing schedule over time, subsequently influencing the study outcomes,to address the influence of time-varying confounding factors, we established a MSCM.33,34 Simultaneously, we performed sensitivity analysis and subgroup analysis to further validate the reliability of the research results. Subgroup analyses demonstrated that early UFH administration has a protective effect on patients with AKI, SIC, mechanical ventilation, and vasopressor requirements. These discoveries might imply that patients in the UFH group had graver conditions, with multiple organ dysfunctions existing in the early stage of the illness, which could also be the cause for the early application of heparin treatment.
Study Limitations
The current study has the following limitations. First, despite the use of PSM and multifactor regression analysis and the establishment of a marginal structure causality (MSC) prediction model with subgroup analysis, this retrospective study may still be influenced by confounding factors due to its extended time frame. Second, certain patient-related variables were not retrieved from the database, leading to potential confusion or bias. We employed E-value sensitivity analysis to assess the potential impact of unretrieved confounders and determined that they are unlikely to significantly influence the overall treatment effect. Third, significant variations exist in the standardisation of sepsis management, which might impact the study outcomes. Last, variations in clinical status may occur alongside disease severity, subsequently influencing outcomes.
Conclusions
Administration of UFH to geriatric patients in the early stages of sepsis is associated with a reduction in-ICU mortality without an increased risk of bleeding. Further prospective studies are necessary to validate these findings.
Footnotes
Ethics Approval and Consent to Participate
This study was approved by the Research Ethics Committee of Shenzhen Second People's Hospital (2025-381-01PJ). The need for informed consent from individual patients was waived because of the retrospective and observational nature of the study.
Author Contributions
JJH and MW conceived of and designed the study. JJH contributed to data management. JJH contributed to data analyses. ZJY, DZL, YHC, and YHG were responsible for literature retrieval. ZFR and MW interpreted the data and drafted the manuscript. ZFL and MW supervised the project and critically reviewed the final version of the manuscript. All authors have read and approved the final manuscript and were fully accountable for ensuring integrity and accuracy.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.