Startseite Association between statin administration and outcome in patients with sepsis: A retrospective study
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Association between statin administration and outcome in patients with sepsis: A retrospective study

  • Jianzhu Zhou , Zeying Feng , Hui Qiu , Tong Li , Xin Huang , Ling Ye , Longjian Huang , Chengjun Guo , Chengxian Guo EMAIL logo und Li He EMAIL logo
Veröffentlicht/Copyright: 4. Februar 2025
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Open Medicine
Aus der Zeitschrift Open Medicine Band 20 Heft 1

Abstract

Background & aims

There was considerable debate regarding the effect of statins administration on the outcome of septic patients. This retrospective study aimed to assess the association between statins administration and mortality in sepsis patients and investigate whether this association differed according to the types of statins.

Methods

We performed a retrospective study based on the electronic ICU Collaborative Research Database, Medical Information Mart for Intensive Care Database, and the Amsterdam University Medical Centers Database. The participants with sepsis were divided as two groups, statins group and non-statins group. The primary endpoint was the all-cause mortality. We utilized logistic regression, propensity score matching (PSM), and sub-analysis to assess the association between statins administration and outcome in patients with sepsis.

Results

A total of 19,327 sepsis patients were enrolled. Among these, 3,721 patients were prescribed statins. Pooled analyses of three databases showed that statin users had a decreased risk of mortality in sepsis as compared with nonusers (OR 0.73, 95% CI 0.66–0.80, P < 0.001). Sub-analysis of statin showed that atorvastatin had the most distinct effectiveness in decreasing mortality (OR 0.67, 95% CI 0.59–0.76, P = 0.035), whereas pravastatin, simvastatin, and rosuvastatin were not. PSM analysis confirmed these findings for statins (OR 0.75, 95% CI 0.67–0.84, P < 0.001) and atorvastatin (OR 0.70, 95% CI 0.59–0.82, P < 0.001).

Conclusions

The use of statins could decrease the risk of mortality in patients with sepsis during the hospital period. Among different types of statins, atorvastatin showed the most significant trend to reduce the risk of mortality in patients with sepsis.

Keywords: sepsis; statin; atorvastatin; mortality; intensive care unit

1 Introduction

Sepsis, a definition of organ dysfunction caused by a dysregulated host response to infection from the guideline of 2021 Surviving Sepsis Campaign [1], is associated with high mortality of intensive patients and hospital case-fatality rate in the ICU can exceed 40% [2]. Furthermore, sepsis is costly to treat, and consumes a lot of medical resource. Consequently, sepsis has rapidly emerged as a significant global health burden. The pathogenesis of sepsis involves the excessive release of pro-inflammatory mediators in infected patients, leading to inflammation and the clinical manifestation of systemic inflammatory response syndrome (SIRS). On this basis, the compensatory anti-inflammatory response (CARS) has failed to act. This imbalance between SIRS and CARS can result in immunoparalysis, disruption of homeostasis, and potentially progress to multiorgan dysfunction [3]. Statins are inhibitors of the hydroxymethylglutaryl-CoA reductase enzyme, have a significant effect of lowering cholesterol, and widely used in hypercholesterolemia and the prevention of cardiovascular disease [4]. Recent studies have revealed potential antibacterial [5], anti-inflammatory [6], and immune modulatory effects of statins [7]. Ongoing debates persist regarding the potential of statins to enhance outcomes in patients with sepsis. Several studies have indicated that statin therapy may play a potentially beneficial role in outcomes of patients with sepsis [8–10], whereas other literature has reported no association between statin prescription and clinical outcomes in sepsis patients [11–13]. A recent review has suggested that the evidence supporting the effectiveness of statins is insufficient, and further research is required to substantiate these findings [14].

The therapeutic efficacy of statin prescribed for sepsis patients appears to vary based on the specific statin type. A prospective randomized controlled trial showed that atorvastatin administration in patients with severe sepsis significantly reduced the 28-day mortality [10]. In contrast, another randomized controlled clinical trial revealed that rosuvastatin therapy did not improve clinical outcomes in critically ill sepsis patients with acute respiratory distress syndrome (ARDS) and potentially contributed to hepatic and renal dysfunction [12]. Furthermore, a secondary analysis of patients with ARDS and sepsis indicated that simvastatin therapy seemed safe and may have reduced mortality in the low cholesterol group, whereas rosuvastatin treatment was associated with a higher risk of mortality [15]. Consistent with these findings, a cohort study suggested that simvastatin and atorvastatin exhibited greater efficacy than rosuvastatin in enhancing 30-day survival rates [16]. In experimental studies, an animal model demonstrated that pravastatin reduced pulmonary microvascular permeability, leading to improved survival in septic mice [17]. Despite numerous reports on the outcomes of sepsis after using specific statins, it remains unclear which type of statin plays a decisive role in the outcomes of patients with sepsis, and currently there is still a lack of large-scale population studies to explore this.

Furthermore, a preponderance of these studies focused on Asian populations. Notably, the association between specific statin types and sepsis outcomes remained unclear. By addressing these research gaps, we can gather more robust clinical evidence on this association and to provide more targeted and effective treatment strategies, ultimately improving patient outcomes. Therefore, the primary aim of this study was to evaluate the association between statin administration and outcomes in patients with sepsis. The secondary aim was to investigate whether various types of statin make different contributions to outcomes of sepsis, with the goal of identifying the specific statin that had the most significant effectiveness. Specifically, we consolidated the clinical records and medication information for sepsis patients from three publicly accessible critical illness databases, and performed analyses using statistical methods, including logistic regression, propensity score matching (PSM), and subgroup analysis.

2 Methods

2.1 Data source

In this study, we employed three openly accessible databases for data collection and analysis. Compliance with open standards and protocols throughout the data acquisition and utilization ensured transparency and reproducibility of the obtained data. Specifically, the datasets utilized in this study originated from the Amsterdam University Medical Centers Database (AmsterdamUMCdb), the electronic ICU Collaborative Research Database (eICU), and Medical Information Mart for Intensive Care Database (MIMIC-III CareVue). AmsterdamUMCdb represents the first freely accessible intensive care database from within the European Union containing de-identified health data related to tens of thousands of European intensive care unit admissions. It contains extensive clinical data derived from 23,106 admissions involving 20,109 patients, spanning from 2003 to 2016 [18]. The eICU, a large multi-center critical care database, is made available by Philips Healthcare in collaboration with the MIT Laboratory for Computational Physiology. It contains 139,367 unique patients admitted from many intensive care units across the United States during the period of 2014–2015. Furthermore, it preserves data related to more than 200,000 hospitalized patients’ unit encounters [19]. MIMIC-III is a large, freely accessible, single-center critical care database, which integrates anonymized, comprehensive clinical data of over 40,000 patients admitted to the Beth Israel Deaconess Medical Center in Boston, Massachusetts from 2001 to 2012 [20]. The hospitals serving as the sources for the three databases constitute entirely independent datasets collected from a substantial number of hospitals situated in either the United States or the Netherlands.

2.2 Study population

2.2.1 Inclusion criteria

Patients with any of the sepsis-related diagnoses were included primarily by searching, identifying, and evaluating clinical data in databases. The diagnostic codes utilized adhere to the standards outlined in the International Classification of Diseases, Ninth Revision (ICD-9). According to the Third International Consensus on the Definition of Sepsis and Septic Shock (Sepsis-3) [21], sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.

2.2.2 Exclusion criteria

Certain special populations, including children, the elderly, pregnant women, AIDS, malignant neoplasms, etc., may contribute a potential interference or risk to the study results due to their specific physiological and pharmacokinetic characteristics. Patients with a hospital stay duration of less than 1 day may struggle to obtain abundant clinical information, thereby compromising the integrity and quality of the data. Patients with multiple hospital admissions may introduce bias in the results due to the presence of duplicated clinical data. Consequently, the exclusion criteria are formulated as follows: (1) age < 18; (2) age over the upper limit of the database, displayed as “>80” (AmsterdamUMCdb) or “>89” (eICU and MIMIC-III), where the specific number cannot be known; (3) pregnant or lactating females; (4) AIDS; (5) malignant neoplasms; (6) ICU stay < 1 day; and (7) non-first admission.

2.3 Assessment of statin use

Statins were defined according to the Anatomical Therapeutic Chemical classification system. By reviewing the database, searching for information on drugs from the prescription table to determine whether statins were administered to patients with sepsis. The seven globally prescribed statins are atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, which will be used for the subgroup analysis.

2.4 Ascertainment of outcomes

The primary endpoint was all-cause mortality in patients with sepsis, and the cause of death was determined according to the ICD-9. By reviewing databases, the information of in-hospital death could be found in the patient section.

2.5 Extraction of covariates

Three databases were reviewed to search, collect, and collate confounding factors that may impact the outcomes of septic patients. On account of the incomplete and inconsistent hospitalization information of septic patients across three databases, we used the mean to replace variables with missing values of less than 20% of the total; however, variables with more than 20% missing values were excluded. Age was an independent predictor of mortality in adult sepsis [22]. Gender, as demographic variable, was associated with risk of death among the ICU for patients with severe sepsis [23]. Appropriate insulin therapy was essential for septic patients with hyperglycemia [24]. Norepinephrine, as the first-line vasopressor, plays a significant role in outcomes of adults with septic shock [1]. Maintenance dialysis was an independent predictor of mortality in patients with severe sepsis [25]. Patients with sepsis who required mechanical ventilation were at higher risk of mortality in ICU [26]. Leukocyte kinetics was a valuable prognostic marker in sepsis, with decreasing white blood cell (WBC) counts correlating with longer survival [27]. The severity of kidney injury, assessed by creatinine levels, was associated with in-hospital mortality in sepsis [28]. Consequently, the following relevant variables were selected for analysis: (1) demographic characteristics: age and gender; (2) biochemical parameters: leukocyte count, serum creatinine, and mean blood glucose levels, recorded at the initial measurement post-admission; (3) concomitant medication use: administration of norepinephrine or insulin; and (4) therapeutic interventions: utilization of mechanical ventilation (intubated) and renal replacement therapy (dialysis) during hospitalization. Variations in collection methods were observed when extracting data from the three databases. First, the AmsterdamUMCdb database was in Dutch, requiring the translation of search terms into Dutch. Second, some pertinent variables were missing from certain databases. For example, the AmsterdamUMCdb lacked records of comorbidities within admission diagnoses. Third, retrieving the same variable may require different templates across databases. For instance, vital signs and biochemical indicators extracted from AmsterdamUMCdb and eICU were accessible within a unified section (“listitem” and “lab”), while in MIMIC-III, these were organized into two distinct sections. Additionally, MIMIC-III required an initial search for “ITEMID,” followed by the input of this “ITEMID” into the corresponding section to extract data, whereas the other two databases simply required the input of keywords. Finally, the units used for the same variable may have differed across databases, necessitating unit conversion.

2.6 Statistical analysis

We conducted a normality test (D’Agostino test), followed by a descriptive analysis of the data. Continuous variables were reported as mean (standard deviation), and compared using independent samples t-test for each dataset. Categorical variables were presented as frequencies (percentages) and compared using the Chi-square test. Two statistical analysis models were established. The first model, termed the “crude model,” was a simple regression model considering only statin use and mortality. The second model, referred to as the “multivariable adjusted model,” was constructed using covariates common to the three databases and potentially influencing the outcome. Specifically, the independent variables included in this multivariable adjusted model were age, gender, insulin use, norepinephrine administration, dialysis, intubation, WBC count, creatinine levels, and mean blood glucose levels. Multivariable binary logistic regression was conducted to assess the association between in-hospital therapeutic outcomes and statin use among septic patients during hospitalization. For each of the three databases, 95% confidence interval (CI) and odds ratio (OR) were calculated. Pooled the three databases and performed the regression analysis again, obtaining overall 95% CI and OR. Subgroup analyses for different types of statins were conducted using the aforementioned method. PSM was utilized to enhance the robustness of our research findings. In this study, the PSM model utilized a one-to-one nearest neighbor matching algorithm with a caliper width of 0.02. We evaluated matching efficiency by comparing the post-PSM differences (P-values) between the two groups using chi-square or t-tests. The P-values for all baseline characteristics in both groups exceeded 0.05, suggesting that the baseline characteristics were well matched between the groups. In the PSM cohort, we conducted subgroup analyses to not only examine the correlation between statin type and mortality but also to ascertain whether the association between statin administration and in-hospital mortality is modulated by factors including gender, age, norepinephrine administration, insulin usage, dialysis necessity, and tracheal intubation status. Statistical significance was defined as P-values <0.05 (two-tailed). Statistical analyses were conducted using IBM SPSS Statistics version 22 and R version 4.4.0.

3 Results

3.1 Baseline characteristics of included patients with sepsis

This study encompassed 205,996 critically ill patients from AmsterdamUMCdb (N = 20,109), eICU (N = 139,367), and MIMIC-III (N = 46,520). According to the “Sepsis-3” diagnostic criteria and the inclusion criteria of this study, a total of 19,327 patients with sepsis were deemed eligible for analysis, distributed across AmsterdamUMCdb (N = 4,776), eICU (N = 12,395), and MIMIC-III (N = 2,156). Among these, 3,721 statin users were identified in AmsterdamUMCdb (N = 1,659), eICU (N = 1,416), and MIMIC-III (N = 646) (Figure 1 for the study flowchart). The baseline characteristics of patients with sepsis are presented in Table 1. Compared to non-statin users (N = 15,606), statin users across all three databases (N = 3,721) exhibited significant differences in older age, greater proportion of insulin users, and higher average blood glucose levels. The pooled analysis results revealed significant differences between the two groups in all characteristics except for dialysis, with statin users having a lower proportion of males, a higher proportion of insulin and norepinephrine users, a greater proportion of patients undergoing mechanical ventilation, lower levels of WBCs and blood creatinine, and higher mean blood glucose levels.

Figure 1 Flowchart of participant selection.
Figure 1

Flowchart of participant selection.

Table 1

Baseline characteristics by the use of statins in patients with sepsis

Characteristics AmsterdamUMC (N = 4,776) P-value eICU (N = 12,395) P-value MIMICIII (N = 2,156) P-value Pool (N = 19,327) P-value
Non-statins group (N = 3,117) Statins group (N = 1,659) Non-statins group (N = 10,979) Statins group (N = 1,416) Non-statins group (N = 1,510) Statins group (N = 646) Non-statins group (N = 15,606) Statins group (N = 3,721)
Mean (SD) age, years 56.2 (16.1) 66.1 (9.5) <0.001 63.9 (15.8) 69.4 (12.1) <0.001 61.5 (17.0) 71.1 (11.8) <0.001 62.2 (16.2) 68.2 (11.1) <0.001
Gender <0.001 0.129 0.523 <0.001
Male, % 62.8 73.5 49.2 47.1 55.1 56.6 48.4 41.7
Any use of insulin, % 56.2 75.1 <0.001 31.9 65.6 <0.001 69.4 80.1 <0.001 40.4 72.4 <0.001
Any use of norepinephrine, % 52.1 51.6 0.754 21.1 23.3 0.059 44.4 42.5 0.423 29.5 39.2 <0.001
Dialysis, % 1.1 0.6 0.076 5.5 7.2 0.007 11.7 13.9 0.167 5.2 5.4 0.589
Intubated, % 70.4 85.1 <0.001 18.8 15.6 0.003 28 29.4 0.510 30 49 <0.001
Mean (SD) WBC, 109/L 11.8 (9.2) 10.9 (5.1) <0.001 15.7 (10.1) 15.7 (9.0) 0.852 13.9 (8.7) 14.0 (7.6) 0.958 14.7 (9.9) 13.3 (7.6) <0.001
Mean (SD) creatinine, mg/dL 1.2 (1.5) 1.1 (0.9) 0.281 2.0 (1.8) 2.2 (2.0) <0.001 1.8 (1.5) 2.1 (1.8) <0.001 1.8 (1.7) 1.7 (1.6) 0.030
Mean (SD) mean blood glucose, mg/dL 142.1 (27.4) 154.2 (26.8) <0.001 140.8 (50.1) 152.3 (56.4) <0.001 129.9 (37.0) 139.2 (34.3) <0.001 140.0 (45.4) 150.9 (42.0) <0.001

Data are presented as mean ± standard deviation or count (percentage). WBC: white blood cell. P-values less than 0.05 are in bold.

3.2 Association between statins and mortality in patients with sepsis

The univariate analysis of the AmsterdamUMC database indicated that, compared to the non-statin group, the statin group had a reduced risk of in-hospital mortality (OR 0.88, 95% CI 0.77–1.02), although this difference was not statistically significant. After adjusting for covariates, a significant association between statin use and mortality in patients with sepsis was observed. The analysis revealed that patients with sepsis who received statins, had improved outcomes, with reduced in-hospital mortality (OR 0.71, 95% CI 0.60–0.83, P < 0.001).

The univariate analysis found that, compared to the other two databases, the statin group in eICU demonstrated the greatest risk reduction in hospital mortality (OR 0.69, 95% CI 0.58–0.82), and the difference was statistically significant (P < 0.001). The multivariable analysis confirmed a similar trend. This association was intensified somewhat, and remained significant after multivariable adjustment as well (OR 0.61, 95% CI 0.50–0.73, P < 0.001).

The univariate analysis of MIMIC-III revealed that the mortality risk in the statin group was comparable to that in the AmsterdamUMCdb (OR 0.87, 95% CI 0.71–1.07), with no statistically significant difference. The multivariate adjusted analysis demonstrated a statistically significant reduced mortality risk in the statin group (OR 0.62, 95% CI 0.49–0.78, P < 0.001).

When the three databases were pooled for analysis, the univariate analysis unexpectedly revealed that the reduced mortality risk trend in the statin group observed in the individual databases was no longer present, with a non-significant trend toward increased mortality risk (OR 1.06, 95% CI 0.97–1.16). Notably, the multivariate adjusted analysis confirmed a significant trend toward reduced mortality risk in the statin group (OR 0.73, 95% CI 0.66–0.80, P < 0.001) (Table 2).

Table 2

Association between statin and mortality in sepsis patients

Crude model Multivariable adjusted model
Cases/participants OR (95% CI) P-value OR (95% CI) P-value
AmsterdamUMCdb
Non-statins 809/3,117 1.00 (Reference) Reference 1.00 (Reference) Reference
Statins 394/1,659 0.88 (0.77–1.02) 0.095 0.71 (0.60–0.83) <0.001
eICU
Non-statins 1,616/10,979 1.00 (Reference) Reference 1.00 (Reference) Reference
Statins 151/1,416 0.69 (0.58–0.82) <0.001 0.61 (0.50–0.73) <0.001
MIMIC-III
Non-statins 465/1,510 1.00 (Reference) Reference 1.00 (Reference) Reference
Statins 181/646 0.87 (0.71–1.07) 0.198 0.62 (0.49–0.78) <0.001
Pool
Non-statins 2,890/15,606 1.00 (Reference) Reference 1.00 (Reference) Reference
Statins 726/3,721 1.06 (0.97–1.16) 0.163 0.73 (0.66–0.80) <0.001

Multivariable adjusted model included age, gender, insulin, norepinephrine, dialysis, intubation, WBC (white blood cell) count, creatinine levels, and mean blood glucose levels. OR: odds ratio; CI: confidence interval. P-values less than 0.05 are in bold.

3.3 Subgroup analysis of statins used in patients with sepsis

The univariate analysis of the AmsterdamUMC database indicated that, compared to the non-statin group, patients who used atorvastatin or rosuvastatin exhibited a reduced risk of mortality, whereas those prescribed pravastatin or simvastatin showed a potential increase in mortality. However, these differences did not reach statistical significance. After adjusting for covariates, significant associations were observed between various statin types and mortality in patients with sepsis. A trend toward decreased mortality risk was observed for all statin types, including atorvastatin, rosuvastatin, pravastatin, and simvastatin. Notably, statistically significant differences were observed in the atorvastatin group (OR 0.73, 95% CI 0.59–0.91, P = 0.005) and the rosuvastatin group (OR 0.51, 95% CI 0.26–0.98, P = 0.045).

The univariate analysis in eICU revealed that, compared to the non-statin group, the atorvastatin, pravastatin, and simvastatin groups all exhibited trends toward reduced mortality risk in sepsis patients, with the atorvastatin group showing statistical significance (OR 0.68, 95% CI 0.56–0.82, P < 0.001). The multivariate adjusted analysis confirmed a slight intensification of the trend toward decreased mortality among various statins, with the atorvastatin group maintaining statistical significance (OR 0.61, 95% CI 0.50–0.75, P < 0.001).

The univariate analysis of MIMIC-III revealed that the pravastatin and simvastatin groups exhibited a reduced risk of mortality, while the atorvastatin and rosuvastatin groups showed an increased risk. However, only the pravastatin group demonstrated statistical significance (OR 0.33, 95% CI 0.14–0.79, P = 0.013). The lovastatin group had too few cases (N = 3) for meaningful analysis. The multivariate adjusted analysis demonstrated a decreased risk of mortality for the atorvastatin (OR 0.74, 95% CI 0.57–0.98, P = 0.035), pravastatin (OR 0.24, 95% CI 0.10–0.61, P = 0.003), and simvastatin (OR 0.70, 95% CI 0.50–0.97, P = 0.035) groups, with all three groups showing statistical significance. Despite a reduced trend in increasing mortality risk in the rosuvastatin group, this trend was not statistically significant.

We pooled and analyzed data from the three databases. The univariate analysis demonstrated that the atorvastatin group reduced the mortality risk and the difference was statistically significant (OR 0.88, 95% CI 0.78–0.99, P = 0.043). Conversely, the simvastatin group demonstrated a statistically significant trend toward increased mortality risk (OR 1.40, 95% CI 1.23–1.60, P < 0.001). However, no statistically significant increase in mortality risk was observed for the pravastatin and rosuvastatin groups. After adjusting for covariates, the analysis revealed that different types of statins reduced the risk of mortality, albeit only the atorvastatin group reached statistical significance (OR 0.67, 95% CI 0.59–0.76, P = 0.035). Notably, after multivariable adjustment, simvastatin shifted from an elevated to reduced mortality risk, albeit this change was not statistically significant (Table 3).

Table 3

Subgroup analysis of statin types in sepsis patients

Crude model Multivariable adjusted model
Cases/participants OR (95% CI) P-value OR (95% CI) P-value
AmsterdamUMCdb
Statins 394/1,659
Atorvastatin 136/618 0.81 (0.66–1.00) 0.051 0.73 (0.59–0.91) 0.005
Pravastatin 31/111 1.15 (0.75–1.75) 0.501 0.99 (0.63–1.56) 0.997
Simvastatin 226/879 1.03 (0.87–1.22) 0.693 0.85 (0.71–1.02) 0.093
Rosuvastatin 12/74 0.57 (0.30–1.06) 0.077 0.51 (0.26–0.98) 0.045
eICU
Statins 151/1,416
Atorvastatin 123/1,175 0.68 (0.56–0.82) <0.001 0.61 (0.50–0.75) <0.001
Pravastatin 4/58 0.44 (0.16–1.22) 0.118 0.35 (0.12–1.00) 0.051
Simvastatin 26/201 0.89 (0.58–1.35) 0.590 0.78 (0.51–1.20) 0.264
MIMIC-III
Statins 181/646
Atorvastatin 109/358 1.02 (0.80–1.31) 0.827 0.74 (0.57–0.98) 0.035
Pravastatin 6/47 0.33 (0.14–0.79) 0.013 0.24 (0.10–0.61) 0.003
Simvastatin 66/247 0.83 (0.62–1.12) 0.238 0.70 (0.50–0.97) 0.035
Rosuvastatin 7/18 1.49 (0.57–3.86) 0.410 1.23 (0.45–3.38) 0.677
Lovastatin 0/3 NA NA NA NA
Pool
Statins 726/3,721
Atorvastatin 368/2,151 0.88 (0.78–0.99) 0.043 0.67 (0.59–0.76) 0.035
Pravastatin 41/216 1.01 (0.72–1.43) 0.918 0.70 (0.49–1.00) 0.053
Simvastatin 318/1,327 1.40 (1.23–1.60) <0.001 0.96 (0.84–1.11) 0.632
Rosuvastatin 19/92 1.13 (0.68–1.87) 0.632 0.76 (0.45–1.29) 0.323
Lovastatin 0/3 NA NA NA NA

Multivariable adjusted model included age, gender, insulin, norepinephrine, dialysis, intubation, WBC (white blood cell) count, creatinine levels, and mean blood glucose levels. OR: odds ratio; CI: confidence interval. NA: not applicable. P-values less than 0.05 are in bold.

3.4 PSM and subgroup analysis

After PSM, 3,716 statin users and 3,716 non-statin users were included in the final analysis. The baseline characteristics were well balanced between the two groups, with all P-values exceeding 0.05 (Table 4). Univariate logistic regression within the PSM cohort demonstrated a significant reduction in mortality among sepsis patients associated with statin use (OR 0.75, 95% CI 0.67–0.84, P < 0.001) (Figure 2). In the PSM cohort, different types of statins exerted varying effects on patient mortality. Atorvastatin and pravastatin were associated with a reduced risk of mortality, whereas simvastatin and rosuvastatin were associated with an increased risk of mortality. However, only atorvastatin (OR 0.70, 95% CI 0.59–0.82, P < 0.001) and simvastatin (OR 1.54, 95% CI 1.30–1.82, P < 0.001) demonstrated statistically significant differences (Figure 3). Furthermore, subgroup analyses were conducted on the PSM cohort. Across different subgroups, a consistent trend was observed: statin use was associated with a reduced in-hospital mortality rate among sepsis patients. Moreover, this association was statistically significant (P < 0.05) in all subgroups except for those receiving norepinephrine and without intubation (Figure 4).

Table 4

Baseline characteristics of sepsis patients after PSM

Post-matched characteristics Non-statins N = 3,716 Statins N = 3,716 P-value
Mean (SD) age, years 68.4 (12.8) 68.2 (11.2) 0.596
Gender 0.260
Male, % 56.9 58.2
Any use of insulin, % 72.6 72.3 0.815
Any use of norepinephrine, % 40.7 39.3 0.193
Dialysis, % 5.8 5.4 0.513
Intubated, % 48.8 48.9 0.945
Mean (SD) WBC, 109/L 13.4 (8.4) 13.3 (7.6) 0.506
Mean (SD) creatinine, mg/dL 1.8 (1.6) 1.8 (1.7) 0.638
Mean (SD) mean blood glucose, mg/dL 150.3 (49.0) 150.9 (42.1) 0.603

Data are presented as mean ± standard deviation or count (percentage). WBC: white blood cell.

Figure 2 Association between statin use and mortality of sepsis patients before and after PSM. OR: odds ratio; CI: confidence interval; crude model: without adjustment; multivariable adjusted model: adjusted for age, gender, insulin, norepinephrine, dialysis, intubation, WBC (white blood cell) count, creatinine levels, and mean blood glucose levels. PSM: propensity score matching.
Figure 2

Association between statin use and mortality of sepsis patients before and after PSM. OR: odds ratio; CI: confidence interval; crude model: without adjustment; multivariable adjusted model: adjusted for age, gender, insulin, norepinephrine, dialysis, intubation, WBC (white blood cell) count, creatinine levels, and mean blood glucose levels. PSM: propensity score matching.

Figure 3 Subgroup analysis of statin types in sepsis patients after PSM. OR: odds ratio; CI: confidence interval; PSM: propensity score matching.
Figure 3

Subgroup analysis of statin types in sepsis patients after PSM. OR: odds ratio; CI: confidence interval; PSM: propensity score matching.

Figure 4 Association between statin use and mortality of sepsis patients in subgroup after PSM. OR: odds ratio; CI: confidence interval; PSM: propensity score matching.
Figure 4

Association between statin use and mortality of sepsis patients in subgroup after PSM. OR: odds ratio; CI: confidence interval; PSM: propensity score matching.

4 Discussion

A pooled analysis of three population-based databases revealed that statin treatment during hospitalization was associated with a 27% reduction in the risk of mortality in patients with sepsis compared to those who did not receive statin therapy. Further analysis of different statin types showed that atorvastatin treatment was associated with a 33% reduction in mortality risk. After conducting PSM analysis, the beneficial effect of statins on improving outcomes remained evident. Additionally, subgroup analyses confirmed that this trend of reduced mortality remained consistent across various subgroups.

Although statins have been widely investigated, their therapeutic efficacy in sepsis remains a contentious issue. Pertzov et al. [29] and Deshpande et al. [30], each published a meta-analysis, respectively, pointing out that statins did not reduce 30-day all-cause mortality in a subgroup of patients with severe sepsis. Goodin et al. [31] also reported no beneficial effect of statin use on hospital mortality among patients admitted with sepsis. However, these studies had limited sample sizes, and the meta-analysis encompassed patients who developed sepsis during their hospital stay. It might encompass non-sepsis patients, potentially biasing the true effect of statins on patients. Therefore, these limitations may have underestimated the true impact of statins on sepsis patients. Conversely, an increasing number of studies supported the notion that statins may improve survival in patients with sepsis. Ghayda et al. [32] identified a protective effect of statins on bacteremia/sepsis-related mortality, albeit with a weak level of evidence. Lee et al. [33] revealed that preadmission statin therapy was associated with a 12% reduction in mortality in a cohort study of sepsis development. The results of this retrospective study were consistent with these findings, demonstrating a significant trend toward reduced hospital mortality risk in patients with sepsis following multivariate adjustment. Ou et al. [34] utilized PSM to analyze a population-based cohort study, where high-potency statins, defined as rosuvastatin ≥10 mg, atorvastatin ≥20 mg, and simvastatin ≥40 mg, were more effective in improving sepsis outcomes than low-potency statins (all other dose of statin treatments). Lee et al. [16] investigated the drug-specific effects of statins and their correlation with lipid-lowering potency. Their results suggested that, compared with non-users, atorvastatin and simvastatin were associated with improved 30-day survival, whereas rosuvastatin was not. Ouellette et al. [35] demonstrated that patients who had received atorvastatin prior to hospitalization had a significantly lower mortality rate than those who received simvastatin. Furthermore, atorvastatin treatment prior to sepsis was associated with improved in-hospital outcomes in this study. Liang et al. [36] also reported that atorvastatin was associated with better 30-day outcomes than simvastatin in patients with sepsis. These findings seemed to indicate that the effect of statins on patients with sepsis may vary among different statin types. Most studies with positive findings were based on large-scale cohort studies, many of which specifically focused on Asian populations. Yang et al. [37] suggested that to achieve statistical significance in studies examining sepsis mortality, a sample size exceeding 6,000–7,000 patients was necessary. In this study, the sepsis sample size from Europe and the United States exceeded 19,000 patients, which may allow the results to more accurately reflect the true impact of statins in these regions. Our subgroup analysis results, pooled from the data of this study, were consistent with previous reports, indicating that atorvastatin, a highly potent statin, significantly reduced the risk of mortality in sepsis patients. In our PSM cohort, it is also apparent that atorvastatin significantly improves in-hospital outcomes compared to other statin types. We observed that not only rosuvastatin in AmsterdamUMCdb, but also pravastatin and simvastatin in MIMIC-III demonstrated a statistical significance in reducing risk of mortality. However, due to the limited sample size, the results were not very reliable. In the pooled analysis, these statin types did not exhibit a statistically significant effect in improving patient outcomes.

The reduction in sepsis-related mortality associated with statin use during hospitalization was likely attributable to their pleiotropic effects. The mechanisms underlying these pleiotropic effects of statins encompassed enhancements in endothelial function and vascular tone, plaque stabilization, anti-inflammation actions, anti-thrombosis properties, and reduction of oxidative stress [38]. On the one hand, statins executed anti-inflammatory effects by modulating upstream intracellular signaling pathways [39], on the other hand, cytokines such as TNF, IL-1β, and IL-6, were pivotal in the manifestation of SIRS and might serve as prognostic biomarkers in sepsis [40]. Atorvastatin significantly decreased the levels of IL-1β, TNF-α, and IL-6 [41], while simvastatin reduced the expression of IL-6 and IL-8 in peripheral blood mononuclear cells [42]. Statins also possessed potential anti-infective properties [4] by influencing the biosynthesis of cholesterol, isoprenoid, and lipid compounds biosynthesis, which were crucial for the cellular signaling and structure of pathogens. However, the precise mechanisms underlying the differences in antimicrobial activity among different statin types remained elusive, and the chemical structures and properties of the various statins may influence their antibacterial targeting. Existing literature suggested that the antimicrobial activity of statins was associated with specific chemical functional groups, for instance, the presence of structures such as hydrophobic moieties, lactone ring, or dihydroxy acid within the ring system was closely correlated with anti-Staphylococcus aureus activity [43]. The lipophilic nature of simvastatin or atorvastatin may facilitate better binding to bacterial cell walls compared to the hydrophilic rosuvastatin. Gram-negative bacteria were predominant among septic pathogenic pathogens, followed by Gram-positive bacteria [44]. The most common pathogenic bacteria in bloodstream infections included Escherichia coli, Klebsiella pneumoniae, S. aureus, and Streptococcus pyogenes [45]. Atorvastatin and simvastatin demonstrated greater antibacterial effects against Gram-positive bacteria, including methicillin-sensitive S. aureus and methicillin-resistant S. aureus. Additionally, atorvastatin exhibited higher antibacterial activity against Gram-negative bacteria, such as E. coli, Proteus mirabilis, and Enterobacter cloacae [46]. Sepsis pathophysiology indicated that the homeostatic imbalance between SIRS and CARS contributed to the clinical progression of multiple organ dysfunction. The pleiotropic effects of statins, including antimicrobial, anti-inflammatory, and immunomodulatory properties, might underlie their potential mechanism of action in sepsis. Atorvastatin, characterized by high efficiency, lipophilicity, and a broad antimicrobial spectrum, might distinguish itself from other statin types and exhibit a trend toward significantly reducing mortality risk in sepsis patients.

This study reported on the association between statin use and in-hospital mortality risk among sepsis patients, drawing data from three intensive care databases. We observed consistent associations across three independent critical illness databases from the United States and the Netherlands, indicating that statins improve outcomes for sepsis patients. Specifically, atorvastatin demonstrated a significant trend toward reducing the risk of in-hospital mortality. The findings of this study provided a potential basis for considering statins in the treatment of sepsis patients. When the indications for statin therapy are met, clinicians may consider prescribing statins to sepsis patients, as this may potentially improve patient prognosis. When selecting a statin, atorvastatin should be prioritized due to its significant mortality-reducing effect, which is likely to exert greater beneficial effects in sepsis patients. However, caution should be exercised when choosing simvastatin.

There were several limitations in this study. First, the retrospective design limited causality inference. Additionally, the study excluded children, pregnant women, and other special populations, necessitating further research to validate statin use and its impact on sepsis prognosis in these groups. Second, subjectivity might have influenced data collection, and earlier datasets might not account for the impact of COVID-19. Moreover, the absence of data from Asia, Africa, or other regions, limited the broad representativeness and generalizability of the results. Inconsistencies among the three databases could result in omitted information regarding certain sepsis patients. Third, the retrospective nature of the study may have introduced confounding factors, such as the comorbidities and selection bias which may affect the results. Furthermore, potential confounders, including microbial sources, inflammatory cytokine levels, genetic variations affecting statin efficacy, and infection sites, were not accounted for in the analysis, introducing uncertainties. Lastly, statin types varied across databases, and we observed that some statin types had small sample sizes, potentially leading to sampling errors. Based on current evidence, further randomized controlled trials, prospective studies are warranted to confirm whether the use of statins in sepsis can benefit patients through pleiotropic effects during hospitalization.

5 Conclusion

The use of statins had the potential to decrease the risk of mortality in patients with sepsis during hospitalization. Among the various types of statins, atorvastatin demonstrated the most prominent trend in reducing the risk of mortality among patients with sepsis.

# Contributed equally.

Acknowledgements

Not applicable.

  1. Funding information: This work was supported by the National Natural Science Foundation of China (81974511), Natural Science Foundation of Hunan Province (2021JJ30424 and 2023JJ30822), Natural Science Foundation of Guangdong Province (20181015528), Scientific and Technological Project of Changsha (kq2004147), and the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (YX202110).

  2. Author contributions: Chengxian Guo and Li He designed the study; Jianzhu Zhou, Zeying Feng, and Hui Qiu extracted and analyzed the data; Jianzhu Zhou and Zeying Feng drafted the manuscript; Xin Huang, Ling Ye, Tong Li, and Chengxian Guo interpreted the results and revised the first draft of the manuscript; Longjian Huang, Chengjun Guo, and Li He organized the study as an overall supervisor. All the authors approved the final version of the manuscript and agreed to submit.

  3. Conflict of interest: The authors declare no competing interests.

  4. Data availability statement: The datasets supporting the conclusions of this article are available in the following repositories: eICU Collaborative Research Database (https://eicu-crd.mit.edu/), AmsterdamUMCdb (https://amsterdammedicaldatascience.nl/database/), and Medical Information Mart for Intensive Care (https://mimic.mit.edu/).

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Received: 2024-03-21
Revised: 2024-11-12
Accepted: 2024-11-18
Published Online: 2025-02-04

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Review Articles
  128. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  129. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  130. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  131. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  132. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  133. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  134. The application of augmented reality in robotic general surgery: A mini-review
  135. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  136. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  137. Plant polyphenols, terpenes, and terpenoids in oral health
  138. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  139. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  140. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  141. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  142. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  143. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  144. Giant borderline ovarian tumours – review of the literature
  145. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  146. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  147. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  148. Supplement strategies for infertility in overweight women: Evidence and legal insights
  149. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  150. Case Reports
  151. Delayed graft function after renal transplantation
  152. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  153. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  154. Giant right atrial hemangioma presenting with ascites: A case report
  155. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  156. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  157. Rapid Communication
  158. Biological properties of valve materials using RGD and EC
  159. Letter to the Editor
  160. Role of enhanced external counterpulsation in long COVID
  161. Expression of Concern
  162. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  163. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  164. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  165. Corrigendum
  166. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  167. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  168. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  169. Retraction
  170. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  171. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  172. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  173. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  174. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  175. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  176. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  177. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  178. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  179. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  180. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  181. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  182. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  183. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  184. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  185. Special Issue Diabetes
  186. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  187. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  188. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  189. A review of brain research on T2DM-related cognitive dysfunction
  190. Special Issue Biomarker Discovery and Precision Medicine
  191. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2024-1112
Schlagwörter für diesen Artikel
sepsis; statin; atorvastatin; mortality; intensive care unit
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Review Articles
  128. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  129. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  130. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  131. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  132. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  133. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  134. The application of augmented reality in robotic general surgery: A mini-review
  135. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  136. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  137. Plant polyphenols, terpenes, and terpenoids in oral health
  138. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  139. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  140. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  141. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  142. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  143. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  144. Giant borderline ovarian tumours – review of the literature
  145. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  146. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  147. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  148. Supplement strategies for infertility in overweight women: Evidence and legal insights
  149. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  150. Case Reports
  151. Delayed graft function after renal transplantation
  152. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  153. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  154. Giant right atrial hemangioma presenting with ascites: A case report
  155. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  156. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  157. Rapid Communication
  158. Biological properties of valve materials using RGD and EC
  159. Letter to the Editor
  160. Role of enhanced external counterpulsation in long COVID
  161. Expression of Concern
  162. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  163. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  164. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  165. Corrigendum
  166. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  167. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  168. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  169. Retraction
  170. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  171. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  172. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  173. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  174. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  175. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  176. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  177. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  178. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  179. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  180. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  181. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  182. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  183. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  184. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  185. Special Issue Diabetes
  186. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  187. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  188. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  189. A review of brain research on T2DM-related cognitive dysfunction
  190. Special Issue Biomarker Discovery and Precision Medicine
  191. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
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