Association of prior to intensive care unit statin use with sepsis-associated delirium: a retrospective propensity score analysis

Association of prior to intensive care unit statin use with sepsis-associated delirium: a retrospective propensity score analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of prior to intensive care unit statin use with sepsis-associated delirium: a retrospective propensity score analysis Liang Hong, Jing Li, Xiao Shen, Hong Tao, Wenxiu Chen, Cui Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4588600/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background The association between statin use and sepsis-associated delirium (SAD) remains controversial. This study aimed to determine whether statin use decrease the risk of SAD. Methods This retrospective cohort study analyzed data of 6649 adult Intensive Care Unit (ICU) patients from the MIMIC-IV database who met inclusion criteria. We examined the association between prior to ICU admission (pre-ICU) statin use and the incidence of SAD by univariate and multivariable logistic regression analysis, propensity score matching (PSM), inverse probability weighting (IPW), and subgroup analysis employing propensity score matching and inverse probability weighting to adjust for potential confounders. The adjusted odds ratio (OR) with 95% CI were calculated in corresponding cohorts. Results Of the study population, 35.1% patients developed SAD. Patients with pre-ICU statin use showed a lower incidence of SAD compared to those without (27.6% vs. 38.0% in origin cohort, 27.2% vs. 33.9% in the matched cohort). Pre-ICU statin use showed a stable protective effect against SAD across different analyses: in original cohort (OR 0.562, 95% CI 0.491 ~ 0.642, P < 0.001), propensity score matched cohort (OR 0.707, 95% CI 0.630 ~ 0.794, P < 0.001) and inverse probability weighted cohort (OR 0.627, 95% CI 0.573 ~ 0.686, P < 0.001). E-value analysis suggested the robustness to unmeasured confounding. Conclusion Pre-ICU statin use is associated with a reduced incidence of SAD, particularly among elderly patients and those receiving lipophilic statins. These findings support the potential role of statins administration in the management of delirium in septic patients and underscore the importance of maintaining statin therapy during critical illness. Future prospective studies are needed to confirm these results and guide clinical practice. sepsis delirium statin critical care Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Sepsis is a life-threatening organ dysfunction caused by dysregulation of the body's response to infection[ 1 ]. Although sepsis has been well studied and researched, and that its diagnosis and treatment have become more standardized over the past few decades, it still remains a high morbidity and mortality[ 2 , 3 ]. During the acute phase of sepsis, the presence of sepsis-associated delirium (SAD) is frequently observed, exhibiting a strong correlation with elevated mortality and the potential for enduring cognitive impairments that significantly compromise the life quality of the patients and place a considerable burden on primary caregivers.[ 4 – 6 ]. Recent studies indicated that neuroinflammation, abnormal cerebral perfusion, and neurotransmitter imbalances might be the main mechanisms underlying the development of SAD[ 4 ]. Although statins possess properties including anti-inflammatory effects, enhancement of endothelial function, and anticoagulant effects, that can potentially disrupt the pathological mechanisms believed to contribute to delirium in sepsis patients, the association between statin use and SAD remains controversial. Several prospective cohort studies revealed that statins could reduce the incidence of delirium in critically ill patients[ 7 , 8 ]. However, this therapeutic effect was not replicated in other studies[ 9 ]. Furthermore, previous studies also suggested that the preventive effects of statins on delirium might be influenced by the type of statin used (hydrophilic or lipophilic) and the severity of the patients [ 10 ]. Therefore, this study intended to assess the effect of pre-ICU statin use on the occurrence of SAD during ICU stay through a retrospective cohort analysis of a large clinical database. Methods Data source This was a retrospective cohort study based on the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.2), which included 431,231 admissions for 299,712 patients admitted to Beth Israel Deaconess Medical Center between 2008 and 2019. MIMIC-IV database contained comprehensive information of all the patients during hospitalization: including demographics, diagnosis, laboratory measurements, administered medications, documented vital signs, etc. The Institutional Review Boards of the BIDMC and MIT approved the use of the MIMIC-IV database for study. Because of the retrospective nature of the study, the requirement for informed patient consent of the patients was waived. The author who signed the data use agreement and completed the Collaborative Institutional Training Initiative examination (Certification number 48772850 for author LH) had the right to access and use the database. Study populations Our study enrolled all the patients who met the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) criteria[ 11 ] and admitted to ICU for the first time in their first hospitalization from MIMIC-IV database. Patients met following criteria were excluded 1) patients with ICU stay less than 1 day, 2) patients younger than 18 years, 3) patients with comorbidity of dementia, 4) patients without CAM-ICU assessment records during ICU stay, 5) patients who were unable to receive CAM-ICU assessment, 6) patients who were admitted to ICU directly, 7) patients with delirium onset before the diagnosis of sepsis, 8) patients with delirium onset after ICU stay were excluded. Eligible patients’ demographics, comorbidities, medication prescription, disease severity assessments and treatment were extracted. Structured Query Language (SQL) was used to extract relevant information from MIMIC-IV database. Medication Exposure Statin prescription before and during hospitalization were extracted from discharge and prescription tables of MIMIC-IV database. Based on previous study[ 12 ], Statin use includes patients with record of prescription for atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. Pravastatin and rosuvastatin were considered as hydrophilic statin while atorvastatin, pitavastatin, fluvastatin, lovastatin, and simvastatin were considered as lipophilic statin. Outcomes The primary outcome was the occurrence of sepsis-associated delirium (SAD) during ICU stays. SAD was diagnosed as delirium after the onset of sepsis[ 13 ]. Sepsis was diagnosed according to Sepsis 3.0 criteria, which included suspected or confirmed infection as well as an Sequential Organ Failure Assessment (SOFA) score ≥ 2 points. Delirium was assessed using the CAM-ICU score[ 14 ], which includes the following 4 characteristics: 1) an acute onset of changes or fluctuations of mental status, 2) inattention, 3) disorganized thinking, and 4) an alerted level of consciousness. Patients who exhibited features of 1) and 2) and either 3) or 4) were diagnosed as delirium. Covariates The data for covariates were derived from previous literature findings and MIMIC-IV database characteristics, and the flowing variables were included in the analyses, demographics: age, gender, race and admission type; acute kidney injury during ICU stay; comorbidities: congestive heart failure, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), rheumatic disease, paraplegia, renal disease, diabetes, liver disease, cancer, acquired immunodeficiency syndrome (AIDS); disease severity assessment: charlson comorbidity index (CCI), simplified acute physiological score (SAPSII), logistic organ dysfunction system (LODS), sequential organ failure assessment (SOFA); treatment: statin use before ICU admission, dialysis use during ICU stay, ventilation use during ICU stay and vasopressin use during ICU stay. The labels of the covariates were given in the first column of Table 1 . Table 1. Baseline characteristics and outcomes of patients with and without delirium All No Delirium Delirium Patient characteristic N=6649 N=4314 N=2335 P Age (mean (SD)) 67.03 (14.88) 66.79 (14.60) 67.47 (15.37) 0.080 Gender (Male, %) 3952 (59.4%) 2594 (60.1%) 1358 (58.2%) 0.124 Race (%) <0.001 WHITE 4538 (68.3%) 3054 (70.8%) 1484 (63.6%) BLACK 540 (8.12%) 321 (7.44%) 219 (9.38%) OTHERS 1571 (23.6%) 939 (21.8%) 632 (27.1%) Admission Type (%) <0.001 Elective 697 (10.5%) 558 (12.9%) 139 (5.95%) Emergency 2872 (43.2%) 1694 (39.3%) 1178 (50.4%) Urgent 1155 (17.4%) 735 (17.0%) 420 (18.0%) Others 1925 (29.0%) 1327 (30.8%) 598 (25.6%) AKI (%) <0.001 I 1239 (18.6%) 928 (21.5%) 311 (13.3%) II 2376 (35.7%) 1543 (35.8%) 833 (35.7%) III 1448 (21.8%) 576 (13.4%) 872 (37.3%) Comorbidities Congestive Heart Failure (%) 1940 (29.2%) 1203 (27.9%) 737 (31.6%) 0.002 Cerebrovascular Disease (%) 711 (10.7%) 339 (7.86%) 372 (15.9%) <0.001 COPD (%) 1740 (26.2%) 1069 (24.8%) 671 (28.7%) 0.001 Rheumatic Disease (%) 277 (4.17%) 182 (4.22%) 95 (4.07%) 0.819 Paraplegia (%) 212 (3.19%) 72 (1.67%) 140 (6.00%) <0.001 Renal disease (%) 1467 (22.1%) 908 (21.0%) 559 (23.9%) 0.007 Diabetes (%) 2094 (31.5%) 1332 (30.9%) 762 (32.6%) 0.148 Liver Disease (%) 930 (14.0%) 478 (11.1%) 452 (19.4%) <0.001 Cancer (%) 1200 (18.0%) 786 (18.2%) 414 (17.7%) 0.644 AIDS (%) 51 (0.77%) 31 (0.72%) 20 (0.86%) 0.64 Disease Severity Assessment CCI (mean (SD)) 5.18 (2.92) 4.98 (2.89) 5.56 (2.94) <0.001 SAPSII Score (mean (SD)) 38.8 (13.6) 36.0 (12.4) 43.8 (14.3) <0.001 LODS Score (mean (SD)) 4.97 (2.80) 4.26 (2.43) 6.27 (2.97) <0.001 SOFA Score (mean (SD)) 5.90 (3.23) 5.19 (2.74) 7.19 (3.65) <0.001 Treatment Statin Use (%) 1831 (27.5%) 1326 (30.7%) 505 (21.6%) <0.001 Dialysis Use (%) 507 (7.63%) 178 (4.13%) 329 (14.1%) <0.001 Ventilation Use (%) 3352 (50.4%) 1655 (38.4%) 1697 (72.7%) <0.001 Vasopressin Use (%) 655 (9.85%) 197 (4.57%) 458 (19.6%) <0.001 Outcome Length of ICU Stay (Median [Q1, Q3]) 2.78 [1.61;5.20] 2.15 [1.36;3.36] 5.33 [2.97;10.1] <0.001 Length of Hospital Stay (Median [Q1, Q3]) 8.86 [5.75;15.1] 7.52 [5.24;11.8] 13.5 [7.94;22.7] <0.001 28 Days Mortality (%) 816 (12.3%) 301 (6.98%) 515 (22.1%) <0.001 1 Year Mortality (%) 1767 (26.6%) 842 (19.5%) 925 (39.6%) <0.001 AKI: acute kidney injury; COPD: chronic obstructive pulmonary disease; AIDS: acquired immunodeficiency syndrome; CCI: charlson comorbidity index; SAPS: simplified acute physiological score; LODS: logistic organ dysfunction system; SOFA: sequential organ failure assessment. Propensity score analysis In order to reduce the effect of potential confounding factors, we conducted propensity score propensity score matching (PSM) analysis to examine the association between pre-ICU statin use and SAD. Logistic regression model was used for estimating of patients’ propensity score for pre-ICU statin use. Then the patients with pre-ICU statin use were 1:1 matched with patients without pre-ICU statin use by estimated propensity score using the nearest neighbor matching algorithm with a caliper of 0.01. Using the estimated propensity scores as weights, an inverse probabilities weighting (IPW) model was used to generate a weighted cohort. A logistic regression was then performed on the weighted cohort, adjusting for the variables that remained unbalanced between the groups with and without statin use in the propensity score model, thus the term doubly robust analysis. To evaluate the effectiveness of the propensity score model in balancing the two compared groups, the imbalance of covariates for the original and the adjusted (weighted) cohorts was compared. The standardized mean differences (SMDs) between the statin and no statin groups were calculated and a value of < 0.1 is considered negligible. Correlation between pre-ICU statin use and SAD Logistic regression models, both univariate and multivariable, were used for analyzing the correlation between pre-ICU use and SAD. Initially, we calculated the crude odds ratio (OR) for the association between pre-ICU statin use and SAD. Subsequently, we conducted three multivariate analysis models to assess the association between statin use and delirium. Firstly, we adjusted for age, gender and race in the aspect of demographics (model 1). Subsequently, disease severity scores (CCI, SAPSII, LODS, SOFA) were adjusted in addition (model 2). After that, the treatments which patients received (dialysis, ventilation and vasopressin) were also included (model 3). We also calculated the odds ratio (OR) of pre-ICU statin use with the same covariates as model 3 in the propensity score matched cohort and propensity score weighted cohort. Subgroup Analysis In the subgroup analyses, we stratified the study population by statin type (lipophilic and hydrophilic statin), the continuation of statin use (discontinue to use statin or not in patients with statin use history before hospitalization), age ( > = 65 and < 65 years), and disease severity [four groups according to SAPSII score quantiles (group 1: =75th)] to analysis the correlation between pre-ICU use and SAD in corresponding subgroup. Sensitivity analyses We investigated the likelihood of unmeasured confounding factors affecting the correlation between pre-ICU statin use and SAD by calculating E-values. The E-value estimates the required magnitude of an unmeasured confounder that could nullify the observed association between pre-ICU statin use and SAD. Statistical analysis Measurement data conforming to a normal distribution were described as mean (standard deviation). Independent sample t-test was applied for inter-group comparisons. Continuous variables not conforming to normal distribution were displayed as median [lower quartile-upper quartile]. Wilcoxon rank-sum tests were performed to draw inter-group comparisons. The categorical data were presented as frequency plus percentage and compared by Pearson χ2 test (two-sided). Fisher’s exact test was applied for those expected frequencies of one or more cells less than 5. R (version 4.1.3) was applied for statistical analyses. The values were considered as statistical significance at P < 0.05. Results In the MIMIC-IV database, a total of 32,971 ICU stay records met the sepsis 3.0 criteria. After including only patients’ first hospital and ICU admissions and excluding patients with ICU stays shorter than 1 day (2,218), dementia (867), no delirium assessment (5,708), unable to assess CAM-ICU (583), direct ICU admission (5,716), delirium before sepsis (775), and delirium outside the ICU (2), 6649 patients were included for analyses (Fig. 1 ). Statin was prescribed in 27.5% of the sepsis patients before their ICU admission, and the incidence of SAD was 35.1%. Baseline characteristics and primary outcome of the patients with and without SAD The baseline clinical characteristics and short-term and long-term outcome of patients with or without SAD were presented in Table 1 . The mean age of the patients was 67.03 years, and 59.4% of them were male. Comorbidities such as congestive heart failure (31.6% vs. 27.9%, P = 0.002), cerebrovascular disease (15.9% vs. 7.86%, P < 0.001), COPD (28.7% vs. 24.8%, P = 0.001), paraplegia (6.00% vs. 1.67%, P < 0.001), renal disease (23.9% vs. 21.0%, P = 0.007), and liver disease (19.4% vs. 11.1%, P < 0.001) were more prevalent in the delirium group. Disease severity scores, including CCI, SAPSII, LODS, and SOFA, were significantly higher in patients with delirium ( P < 0.001). Patients with SAD had longer ICU stay (5.33 vs. 2.15 days, P < 0.001), prolonged hospital stay (13.5 vs. 7.52 days, P < 0.001) as well as increased mortality at 28-day (22.1% vs. 6.98%, P < 0.001) and 1-year (39.6% vs. 19.5%, P < 0.001). Propensity score analysis The characteristics of the original and matched cohort were summarized in Table 2 . The patients without pre-ICU statin use were younger (65.23 ± 15.78 years vs. 71.77 ± 10.85 years) and had fewer comorbidities, including Congestive Heart Failure 25.6 vs. 38.7, Renal Disease 26.9% vs. 43.6, Diabetes 26.9% vs. 43.6. Figure 2 illustrated the distribution of propensity scores before and after propensity score match. Figure 3 showed the balance of covariates in both groups improved after propensity score match. The balance of covariates improved between groups after matching, thereby enhancing the comparability of the two groups. Patients with pre-ICU statin use had a lower incidence of SAD in both the original cohort (27.6 vs. 38.0%) and the matched cohort (27.2 vs. 33.9%) (Table 2 ). Table 2 Comparison of the basic demographics, comorbidity conditions, disease severity, treatment and delirium between the original cohort and the matched cohort Covariate Original cohort Matched cohort No Statin Statin SMD No Statin Statin SMD n 4,818 1,831 1,612 1,612 Age (mean (SD)) 65.23 (15.78) 71.77 (10.85) 0.483 71.45 (12.90) 71.12 (10.94) 0.027 Gender (Male, %) 2716 (56.4) 1236 (67.5) 0.231 1067 (66.2) 1057 (65.6) 0.013 Race (%) 0.149 0.049 WHITE 3226 (67.0) 1312 (71.7) 1146 (71.1) 1143 (70.9) BLACK 440 (9.1) 100 (5.5) 115 (7.1) 98 (6.1) OTHERS 1152 (23.9) 419 (22.9) 351 (21.8) 371 (23.0) Admission Type (%) 0.569 0.076 Elective 375 (7.8) 322 (17.6) 250 (15.5) 258 (16.0) Emergency 2328 (48.3) 544 (29.7) 527 (32.7) 536 (33.3) Urgent 629 (13.1) 526 (28.7) 354 (22.0) 388 (24.1) Others 1486 (30.8) 439 (24.0) 481 (29.8) 430 (26.7) AKI (%) 0.294 0.029 I 794 (16.5) 445 (24.3) 385 (23.9) 367 (22.8) II 1645 (34.1) 731 (39.9) 614 (38.1) 627 (38.9) III 1116 (23.2) 332 (18.1) 309 (19.2) 306 (19.0) Comorbidities Congestive Heart Failure (%) 1232 (25.6) 708 (38.7) 0.283 602 (37.3) 594 (36.8) 0.010 Cerebrovascular Disease (%) 492 (10.2) 219 (12.0) 0.056 197 (12.2) 184 (11.4) 0.025 COPD (%) 1230 (25.5) 510 (27.9) 0.053 468 (29.0) 451 (28.0) 0.023 Rheumatic Disease (%) 206 (4.3) 71 (3.9) 0.020 68 (4.2) 60 (3.7) 0.025 Paraplegia (%) 179 (3.7) 33 (1.8) 0.117 28 (1.7) 32 (2.0) 0.018 Renal disease (%) 928 (19.3) 539 (29.4) 0.239 468 (29.0) 438 (27.2) 0.041 Diabetes (%) 1296 (26.9) 798 (43.6) 0.355 664 (41.2) 648 (40.2) 0.020 Liver Disease (%) 819 (17.0) 111 (6.1) 0.348 115 (7.1) 107 (6.6) 0.020 Cancer (%) 1003 (20.8) 197 (10.8) 0.279 187 (11.6) 187 (11.6) < 0.001 AIDS (%) 46 (1.0) 5 (0.3) 0.087 3 (0.2) 5 (0.3) 0.025 Disease Severity Assessment CCI (mean (SD)) 5.00 (2.96) 5.66 (2.75) 0.232 5.58 (2.84) 5.50 (2.72) 0.028 SAPSII Score (mean (SD)) 38.78 (13.94) 38.77 (12.60) 0.001 38.78 (12.57) 38.67 (12.93) 0.008 LODS Score (mean (SD)) 5.02 (2.85) 4.83 (2.67) 0.068 4.85 (2.63) 4.81 (2.71) 0.015 SOFA Score (mean (SD)) 5.98 (3.37) 5.67 (2.84) 0.099 5.66 (3.00) 5.62 (2.86) 0.014 Treatment Dialysis Use (%) 376 (7.8) 131 (7.2) 0.025 116 (7.2) 118 (7.3) 0.005 Ventilation Use (%) 2403 (49.9) 949 (51.8) 0.039 837 (51.9) 814 (50.5) 0.029 Vasopressin Use (%) 508 (10.5) 147 (8.0) 0.087 123 (7.6) 133 (8.3) 0.023 Delirium (%) 1830 (38.0) 505 (27.6) 0.223 547 (33.9) 438 (27.2) 0.147 AKI: acute kidney injury; COPD: chronic obstructive pulmonary disease; AIDS: acquired immunodeficiency syndrome; CCI: charlson comorbidity index; SAPS: simplified acute physiological score; LODS: logistic organ dysfunction system; SOFA: sequential organ failure assessment. Correlation between pre-ICU statin use and SAD We used four logistic regression models to investigate the correlation between pre-ICU statin use and SAD. In univariate analysis, the OR of the pre-ICU statin use was 0.622 (95%CI: 0.552–0.699, P < 0.001). The OR of pre-ICU statin use ranged from 0.562–0.621 ( P < 0.001) in all the multivariable logistic regression models (Fig. 4 ). Further multivariable regression models adjusted for all measured covariates showed identical protective effect of pre-ICU statin use against SAD in propensity score matched cohort (OR 0.707, 95% CI 0.630–0.794, P < 0.001) and weighted cohort (OR 0.6277, 95% CI 0.573–0.686, P < 0.001) (Fig. 4 ). Sensitivity Analysis We generated an E-value to assess the sensitivity to unmeasured confounding. The E-value was 0.499 for the estimate and 0.554 for the lower confidence limit, indicating that the finding was robust, unless an unmeasured confounder contributing the incidence of SAD with an OR lower than 0.499 existed. Subgroup Analysis Results of subgroup analysis were presented in Fig. 5 . Lipophilic statins exhibited a significant protective effect against SAD, whereas hydrophilic statins showed less pronounced protective effect. For patients who had taken statins prior to hospitalization, discontinuation of statin therapy on admission to hospital significantly increased the risk of developing SAD. We also made a subgroup analysis based on age given the influence of age on delirium. Results showed that the protective effects of statins were more pronounced in the elderly population ( > = 65 years) and not significant in younger patients. Taken the disease severity into consideration, the protective effect of statins against SAD was attenuated in patients with mild (group 1) or severe disease (group 4), whereas it was more pronounced in the patients with moderate severity (group 2 and group 3). Discussion This retrospective cohort study explored the association between pre-ICU statin use and the occurrence of SAD based on the MIMIC-IV database. Our findings indicated that pre-ICU statin use was associated with a reduced incidence of SAD in the sepsis patients, both in the original and matched cohorts, regardless of adjustments for other covariates, which was consistent with the hypothesis that statins may exert protective effects against SAD. In our study, we observed an incidence rate of delirium of 35.1% among sepsis patients during ICU stay, which was consistent with reported rates of SAD ranging from 30–70% in literature studies[ 15 – 17 ]. Our results support the notion that statins might mitigate some of the pathophysiological processes leading to delirium in sepsis patients, possibly due to their anti-inflammatory and neuroprotective properties[ 18 ]. Statin may counteract the inflammation-induced action of proinflammatory phenotype microglial activation during sepsis[ 19 ]. In animal experiments, investigators observed that statin exerted a neuroprotective role by upregulation of the Bcl-2 and cytokines reduction, which may prevent the cognitive deficit observed in sepsis survivor animals[ 20 ]. It is noteworthy that animal and human studies have also shown that abrupt discontinuation of statin use could lead to an acute rebound inflammation and worsening of clinical outcomes, which was in compliance with our results. The role of neuroinflammation in the pathophysiology of SAD has been fully established[ 21 , 22 ]. Data from animal and human studies had suggested that neuroinflammation to sepsis is systemic inflammation relaying to the innate immunity in the central nervous system(CNS) via various routes[ 13 , 23 ]. Circulating cytokines and chemokines also plays an important role in SAD pathogenesis[ 24 ]. This neuroinflammation may cause cognitive deficits through activation of microglia, edema and apoptosis[ 25 ]. The differential impact of lipophilic versus hydrophilic statins on SAD suggested the potential role of statin solubility and blood-brain barrier penetrance in mediating their protective effects[ 26 , 27 ]. Lipophilic statins, which could more readily cross the blood-brain barrier, showed a stronger association with reduced SAD compared to hydrophilic statins. This finding underscores the importance of considering statin properties in clinical decision-making processes, especially in populations at high risk for delirium. Additionally, result from our subgroup analysis highlighted the significance of continuity in statin therapy. Discontinuation of statins upon hospital admission was linked with an increased risk of developing SAD, emphasizing the potential risks of interrupting statin therapy during critical illness. This risk may stem from a rebound in inflammatory responses upon discontinuation of statins[ 28 , 29 ], which potentially drives this increased risk. The pronounced protective effects in elderly patients further align with existing literature suggesting that older adults may particularly benefit from the neuroprotective effects of statins. While our analysis benefits from a large sample size and the robustness of findings across multiple analyses, there are inherent limitations associated with retrospective analyses, including potential biases from unmeasured confounders. However, the calculated E-values suggest that a confounder would need to be exceptionally strong to invalidate our findings, reinforcing the potential causality of the observed associations. This study also has several other limitations, as only the effect of statin use exposure was explored, without considering the dosage and duration. Future prospective studies should aim to delineate the optimal types and timing of statin therapy in sepsis and explore mechanistic pathways through which statins may reduce the risk of SAD. Additionally, only short-term outcomes were examined, the long-term cognitive impacts of statin use on sepsis survivors could yield further insights into the broader implications of our findings for patient care following ICU discharge. Future prospective studies should aim to delineate the optimal types and timing of statin therapy in sepsis and explore mechanistic pathways through which statins may reduce the risk of SAD. Furthermore, exploring the long-term cognitive outcomes of statin use in sepsis survivors could provide deeper insights into the broader implications of our findings for patient care post-ICU discharge. Conclusion This study revealed an association between statin use prior to ICU admission and decreased risk of SAD. Our findings advocate for a careful consideration of statin therapy in sepsis patients, especially among those at elevated risk for cognitive complications. Declarations Ethics approval and consent to participate The establishment of this database was approved by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA), and consent was obtained for the original data collection. Therefore, the ethical approval statement and the need for informed consent were waived for this manuscript. Consent for publication No applicable. Availability of data and materials The datasets presented in the current study are available in the MIMIC-IV database (https://physionet.org/content/mimiciv/2.2/). Competing interests The authors declare that they have no competing interests. Funding This study was funded by National Natural Science Foundation of China (82372217). The study sponsors had no involvement in the study design, the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the paper for publication. Author’s contributions HL and LJ contributed to all aspects of this manuscript, including study conception and design; acquisition, analysis, and interpretation of data; and drafting the article. SX, TH, CWX helped write and review the manuscript. YM and ZC led the project and designed the study. All authors have read and approved the manuscript. References Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10. Fleischmann-Struzek C, Mellhammar L, Rose N, Cassini A, Rudd KE, Schlattmann P, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med. 2020;46:1552–62. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–11. Tsuruta R, Oda Y. A clinical perspective of sepsis-associated delirium. J Intensive Care. 2016;4:18. Mostel Z, Perl A, Marck M, Mehdi SF, Lowell B, Bathija S, et al. Post-sepsis syndrome – an evolving entity that afflicts survivors of sepsis. Mol Med. 2020;26:6. Chung H-Y, Wickel J, Brunkhorst FM, Geis C. Sepsis-Associated Encephalopathy: From Delirium to Dementia? J Clin Med. 2020;9:703. Page VJ, Davis D, Zhao XB, Norton S, Casarin A, Brown T, et al. Statin Use and Risk of Delirium in the Critically Ill. Am J Respir Crit Care Med. 2014;189:666–73. Morandi A, Hughes CG, Thompson JL, Pandharipande PP, Shintani AK, Vasilevskis EE, et al. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med. 2014;42:1899–909. Needham DM, Colantuoni E, Dinglas VD, Hough CL, Wozniak AW, Jackson JC, et al. Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir Med. 2016;4:203–12. An JY, Park JY, Cho J, Kim HE, Park J, Oh J. The Relationship between Delirium and Statin Use According to Disease Severity in Patients in the Intensive Care Unit. Clin Psychopharmacol Neurosci. 2023;21:179–87. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45:486–552. Kunutsor SK, Laukkanen JA. Heart Failure Risk Reduction: Hydrophilic or Lipophilic Statins? Cardiology. 2020;145:384–6. Tsuruta R, Oda Y. A clinical perspective of sepsis-associated delirium. J Intensive Care. 2016;4:18. Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, et al. Evaluation of delirium in critically ill patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29:1370. Sonneville R, De Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. 2017;43:1075–84. Tauber SC, Djukic M, Gossner J, Eiffert H, Brück W, Nau R. Sepsis-associated encephalopathy and septic encephalitis: an update. Expert Rev Anti Infect Ther. 2021;19:215–31. Danielski LG, Giustina AD, Gava FF, Barichello T, Petronilho F. The Many Faces of Astrocytes in the Septic Brain. Mol Neurobiol. 2022;59:7229–35. Bu D, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;22:165–70. Morandi A, Hughes CG, Girard TD, McAuley DF, Ely EW, Pandharipande PP. Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest. 2011;140:580–5. Catalão CHR, Santos-Junior NN, da Costa LHA, Souza AO, Cárnio EC, Sebollela A, et al. Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration. Neurotox Res. 2020;38:871–86. Tokuda R, Nakamura K, Takatani Y, Tanaka C, Kondo Y, Ohbe H, et al. Sepsis-Associated Delirium: A Narrative Review. J Clin Med. 2023;12:1273. Manabe T, Heneka MT. Cerebral dysfunctions caused by sepsis during ageing. Nat Rev Immunol. 2022;22:444–58. Ji M-H, Gao Y-Z, Shi C-N, Wu X-M, Yang J-J. Acute and long-term cognitive impairment following sepsis: mechanism and prevention. Expert Rev Neurother. 2023;23:931–43. Brummel NE, Hughes CG, McNeil JB, Pandharipande PP, Thompson JL, Orun OM, et al. Systemic inflammation and delirium during critical illness. Intensive Care Med. 2024;50:687–96. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet Lond Engl. 2010;375:773–5. Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as Neuroprotectants: A Comparative In Vitro Study of Lipophilicity, Blood-Brain-Barrier Penetration, Lowering of Brain Cholesterol, and Decrease of Neuron Cell Death. J Alzheimers Dis. 2011;23:307–18. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3–11. Li J-J, Li Y-S, Chu J-M, Zhang C-Y, Wang Y, Huang Y, et al. Changes of plasma inflammatory markers after withdrawal of statin therapy in patients with hyperlipidemia. Clin Chim Acta. 2006;366:269–73. Sposito AC, Carvalho LSF, Cintra RMR, Araújo ALR, Ono AH, Andrade JM, et al. Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis. 2009;207:191–4. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 18 Jun, 2024 Submission checks completed at journal 18 Jun, 2024 First submitted to journal 16 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4588600","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":315846723,"identity":"7b9d50ac-ffdb-486b-a386-15ca05b09b1a","order_by":0,"name":"Liang Hong","email":"","orcid":"","institution":"The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Hong","suffix":""},{"id":315846724,"identity":"a57d85f3-a941-43e3-bb40-d6ef2699fbd3","order_by":1,"name":"Jing Li","email":"","orcid":"","institution":"Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Li","suffix":""},{"id":315846725,"identity":"df71bf87-9872-48e0-898a-5e313af65225","order_by":2,"name":"Xiao Shen","email":"","orcid":"","institution":"Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Shen","suffix":""},{"id":315846726,"identity":"f116724c-28d2-4655-9d75-56929961e3eb","order_by":3,"name":"Hong Tao","email":"","orcid":"","institution":"Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Tao","suffix":""},{"id":315846727,"identity":"f0438235-38f2-4003-bed8-66a073e33826","order_by":4,"name":"Wenxiu Chen","email":"","orcid":"","institution":"Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenxiu","middleName":"","lastName":"Chen","suffix":""},{"id":315846728,"identity":"d67ef3df-3a72-417a-8c8a-b37d33137148","order_by":5,"name":"Cui Zhang","email":"","orcid":"","institution":"Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cui","middleName":"","lastName":"Zhang","suffix":""},{"id":315846729,"identity":"eb8a6575-fec7-45e4-8862-e42bd7df2750","order_by":6,"name":"Min Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYNACAwY5Bgkwi5l4LcakamFgSGwgWovB8bOHX90ouJPeP7s7TYKhwjqxgf3sAfxazuSlWecYPMudcefsNgmGM+mJDTx5Cfi1HMgxM84xOJzbcCN3mwRj22GgC3kM8Gs5/wasJV0erOUfMVpu5Bg/BmpJMABraSBCi+SNN2bMQC2GG2/kbrZIOJZu3MaTg18L3/kc4885fw7Ly93I3XjjQ421bD/7GfxaFA4wsEnAeQlAzIZXPRDINzAwfyCkaBSMglEwCkY4AABB70mDxUtvaQAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":true,"prefix":"","firstName":"Min","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-06-16 06:08:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4588600/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4588600/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60443308,"identity":"81998d19-5060-4e03-98a8-7a68de4494d5","added_by":"auto","created_at":"2024-07-16 20:20:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55144,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the study population\u003c/p\u003e","description":"","filename":"floatimage121.png","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/b2649bf4a12dc247f4f27718.png"},{"id":60443313,"identity":"2fa9e74c-25bb-4f1d-b479-79cc9f017980","added_by":"auto","created_at":"2024-07-16 20:20:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53093,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of propensity score before and after matching. Red color represents “No Statin” group and blue color represents “Statin”\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/d19ae3a15e7805720ab59090.png"},{"id":60443310,"identity":"9a865fcf-bdae-4858-8255-659ac4c4f3be","added_by":"auto","created_at":"2024-07-16 20:20:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40442,"visible":true,"origin":"","legend":"\u003cp\u003eBalance of covariates before and after propensity score matching. Red squares represent before adjustment and blue circles represent after matching.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/4d041bef53e1aeba6e82f07a.png"},{"id":60443309,"identity":"80a42e60-99ee-44b6-aff1-0d024ee908e2","added_by":"auto","created_at":"2024-07-16 20:20:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":82006,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between Preadmission Statin Use and Sepsis Induced Delirium in the Crude Analysis, Multivariable Analysis, and Propensity-Score Analyses.\u003c/p\u003e\n\u003cp\u003eModel 1 = Preadmission Statin Use adjusted for Age + Gender + Race\u003c/p\u003e\n\u003cp\u003eModel 2 = Model 1 + (CCI, SAPSII Score, LODS Score, SOFA Score)\u003c/p\u003e\n\u003cp\u003eModel 3 = Model 2 + (Dialysis Use, Ventilation Use, Vasopressin Use)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/130be295026929bfe7a4bd62.png"},{"id":60443311,"identity":"9ae8b69c-b4d2-4192-ad14-6bb5c662b007","added_by":"auto","created_at":"2024-07-16 20:20:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":110855,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses\u003c/p\u003e\n\u003cp\u003eThe patients' SAPSII groups were determined based on the quantile values of their SAPSII scores.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/7b91b30ea890db3b793a8377.png"},{"id":60444300,"identity":"1a4e3be2-583e-4b46-8466-4e8282fec245","added_by":"auto","created_at":"2024-07-16 20:28:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":994724,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4588600/v1/084092d2-aa5e-469f-a1e4-c51bb3478f60.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of prior to intensive care unit statin use with sepsis-associated delirium: a retrospective propensity score analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis is a life-threatening organ dysfunction caused by dysregulation of the body's response to infection[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although sepsis has been well studied and researched, and that its diagnosis and treatment have become more standardized over the past few decades, it still remains a high morbidity and mortality[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. During the acute phase of sepsis, the presence of sepsis-associated delirium (SAD) is frequently observed, exhibiting a strong correlation with elevated mortality and the potential for enduring cognitive impairments that significantly compromise the life quality of the patients and place a considerable burden on primary caregivers.[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies indicated that neuroinflammation, abnormal cerebral perfusion, and neurotransmitter imbalances might be the main mechanisms underlying the development of SAD[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although statins possess properties including anti-inflammatory effects, enhancement of endothelial function, and anticoagulant effects, that can potentially disrupt the pathological mechanisms believed to contribute to delirium in sepsis patients, the association between statin use and SAD remains controversial. Several prospective cohort studies revealed that statins could reduce the incidence of delirium in critically ill patients[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, this therapeutic effect was not replicated in other studies[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, previous studies also suggested that the preventive effects of statins on delirium might be influenced by the type of statin used (hydrophilic or lipophilic) and the severity of the patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, this study intended to assess the effect of pre-ICU statin use on the occurrence of SAD during ICU stay through a retrospective cohort analysis of a large clinical database.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003e This was a retrospective cohort study based on the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.2), which included 431,231 admissions for 299,712 patients admitted to Beth Israel Deaconess Medical Center between 2008 and 2019. MIMIC-IV database contained comprehensive information of all the patients during hospitalization: including demographics, diagnosis, laboratory measurements, administered medications, documented vital signs, etc. The Institutional Review Boards of the BIDMC and MIT approved the use of the MIMIC-IV database for study. Because of the retrospective nature of the study, the requirement for informed patient consent of the patients was waived. The author who signed the data use agreement and completed the Collaborative Institutional Training Initiative examination (Certification number 48772850 for author LH) had the right to access and use the database.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy populations\u003c/h2\u003e \u003cp\u003eOur study enrolled all the patients who met the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) criteria[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and admitted to ICU for the first time in their first hospitalization from MIMIC-IV database. Patients met following criteria were excluded 1) patients with ICU stay less than 1 day, 2) patients younger than 18 years, 3) patients with comorbidity of dementia, 4) patients without CAM-ICU assessment records during ICU stay, 5) patients who were unable to receive CAM-ICU assessment, 6) patients who were admitted to ICU directly, 7) patients with delirium onset before the diagnosis of sepsis, 8) patients with delirium onset after ICU stay were excluded. Eligible patients\u0026rsquo; demographics, comorbidities, medication prescription, disease severity assessments and treatment were extracted. Structured Query Language (SQL) was used to extract relevant information from MIMIC-IV database.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMedication Exposure\u003c/h2\u003e \u003cp\u003eStatin prescription before and during hospitalization were extracted from discharge and prescription tables of MIMIC-IV database. Based on previous study[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], Statin use includes patients with record of prescription for atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. Pravastatin and rosuvastatin were considered as hydrophilic statin while atorvastatin, pitavastatin, fluvastatin, lovastatin, and simvastatin were considered as lipophilic statin.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was the occurrence of sepsis-associated delirium (SAD) during ICU stays. SAD was diagnosed as delirium after the onset of sepsis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Sepsis was diagnosed according to Sepsis 3.0 criteria, which included suspected or confirmed infection as well as an Sequential Organ Failure Assessment (SOFA) score\u0026thinsp;\u0026ge;\u0026thinsp;2 points. Delirium was assessed using the CAM-ICU score[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], which includes the following 4 characteristics: 1) an acute onset of changes or fluctuations of mental status, 2) inattention, 3) disorganized thinking, and 4) an alerted level of consciousness. Patients who exhibited features of 1) and 2) and either 3) or 4) were diagnosed as delirium.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCovariates\u003c/h2\u003e \u003cp\u003eThe data for covariates were derived from previous literature findings and MIMIC-IV database characteristics, and the flowing variables were included in the analyses, demographics: age, gender, race and admission type; acute kidney injury during ICU stay; comorbidities: congestive heart failure, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), rheumatic disease, paraplegia, renal disease, diabetes, liver disease, cancer, acquired immunodeficiency syndrome (AIDS); disease severity assessment: charlson comorbidity index (CCI), simplified acute physiological score (SAPSII), logistic organ dysfunction system (LODS), sequential organ failure assessment (SOFA); treatment: statin use before ICU admission, dialysis use during ICU stay, ventilation use during ICU stay and vasopressin use during ICU stay. The labels of the covariates were given in the first column of Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eTable 1. Baseline characteristics and outcomes of patients with and without delirium\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003eNo Delirium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003eDelirium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003ePatient characteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003eN=6649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003eN=4314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003eN=2335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eAge (mean (SD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\" valign=\"top\"\u003e\n \u003cp\u003e67.03 (14.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\" valign=\"top\"\u003e\n \u003cp\u003e66.79 (14.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\" valign=\"top\"\u003e\n \u003cp\u003e67.47 (15.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\" valign=\"top\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eGender (Male, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\" valign=\"top\"\u003e\n \u003cp\u003e3952 (59.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\" valign=\"top\"\u003e\n \u003cp\u003e2594 (60.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\" valign=\"top\"\u003e\n \u003cp\u003e1358 (58.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.82113821138211%\"\u003e\n \u003cp\u003eRace (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.82113821138211%\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.357723577235772%\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;WHITE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e4538 (68.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e3054 (70.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e1484 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;BLACK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e540 (8.12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e321 (7.44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e219 (9.38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;OTHERS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1571 (23.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e939 (21.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e632 (27.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.82113821138211%\"\u003e\n \u003cp\u003eAdmission Type (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.82113821138211%\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.357723577235772%\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Elective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e697 (10.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e558 (12.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e139 (5.95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Emergency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e2872 (43.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1694 (39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e1178 (50.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Urgent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1155 (17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e735 (17.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e420 (18.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1925 (29.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1327 (30.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e598 (25.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.82113821138211%\"\u003e\n \u003cp\u003eAKI (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.82113821138211%\" colspan=\"3\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.357723577235772%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1239 (18.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e928 (21.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e311 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e2376 (35.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1543 (35.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e833 (35.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1448 (21.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e576 (13.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e872 (37.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"66.12377850162866%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Congestive Heart Failure (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1940 (29.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1203 (27.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e737 (31.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Cerebrovascular Disease (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e711 (10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e339 (7.86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e372 (15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;COPD (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1740 (26.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1069 (24.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e671 (28.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Rheumatic Disease (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e277 (4.17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e182 (4.22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e95 (4.07%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.819\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Paraplegia (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e212 (3.19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e72 (1.67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e140 (6.00%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eRenal disease (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1467 (22.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e908 (21.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e559 (23.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp;Diabetes (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e2094 (31.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1332 (30.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e762 (32.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp;Liver Disease (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e930 (14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e478 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e452 (19.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp;Cancer (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1200 (18.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e786 (18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e414 (17.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.644\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; AIDS (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e51 (0.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e31 (0.72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e20 (0.86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eDisease Severity Assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"66.12377850162866%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CCI (mean (SD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e5.18 (2.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e4.98 (2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e5.56 (2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;SAPSII Score (mean (SD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e38.8 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e36.0 (12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e43.8 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;LODS Score (mean (SD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e4.97 (2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e4.26 (2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e6.27 (2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;SOFA Score (mean (SD))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e5.90 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e5.19 (2.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e7.19 (3.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"66.12377850162866%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Statin Use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1831 (27.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1326 (30.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e505 (21.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eDialysis Use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e507 (7.63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e178 (4.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e329 (14.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Ventilation Use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e3352 (50.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e1655 (38.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e1697 (72.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Vasopressin Use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e655 (9.85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e197 (4.57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e458 (19.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"66.12377850162866%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Length of ICU Stay (Median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e2.78 [1.61;5.20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e2.15 [1.36;3.36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e5.33 [2.97;10.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Length of Hospital Stay (Median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e8.86 [5.75;15.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e7.52 [5.24;11.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e13.5 [7.94;22.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;28 Days Mortality (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e816 (12.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e301 (6.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e515 (22.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.876221498371336%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 Year Mortality (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.03257328990228%\"\u003e\n \u003cp\u003e1767 (26.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.403908794788272%\"\u003e\n \u003cp\u003e842 (19.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.309446254071661%\"\u003e\n \u003cp\u003e925 (39.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.37785016286645%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAKI: acute kidney injury; COPD: chronic obstructive pulmonary disease; AIDS: acquired immunodeficiency syndrome; CCI: charlson comorbidity index; SAPS: simplified acute physiological score; LODS: logistic organ dysfunction system; SOFA: sequential organ failure assessment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePropensity score analysis\u003c/h2\u003e \u003cp\u003eIn order to reduce the effect of potential confounding factors, we conducted propensity score propensity score matching (PSM) analysis to examine the association between pre-ICU statin use and SAD. Logistic regression model was used for estimating of patients\u0026rsquo; propensity score for pre-ICU statin use. Then the patients with pre-ICU statin use were 1:1 matched with patients without pre-ICU statin use by estimated propensity score using the nearest neighbor matching algorithm with a caliper of 0.01. Using the estimated propensity scores as weights, an inverse probabilities weighting (IPW) model was used to generate a weighted cohort. A logistic regression was then performed on the weighted cohort, adjusting for the variables that remained unbalanced between the groups with and without statin use in the propensity score model, thus the term doubly robust analysis. To evaluate the effectiveness of the propensity score model in balancing the two compared groups, the imbalance of covariates for the original and the adjusted (weighted) cohorts was compared. The standardized mean differences (SMDs) between the statin and no statin groups were calculated and a value of \u0026lt;\u0026thinsp;0.1 is considered negligible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between pre-ICU statin use and SAD\u003c/h2\u003e \u003cp\u003eLogistic regression models, both univariate and multivariable, were used for analyzing the correlation between pre-ICU use and SAD. Initially, we calculated the crude odds ratio (OR) for the association between pre-ICU statin use and SAD. Subsequently, we conducted three multivariate analysis models to assess the association between statin use and delirium. Firstly, we adjusted for age, gender and race in the aspect of demographics (model 1). Subsequently, disease severity scores (CCI, SAPSII, LODS, SOFA) were adjusted in addition (model 2). After that, the treatments which patients received (dialysis, ventilation and vasopressin) were also included (model 3). We also calculated the odds ratio (OR) of pre-ICU statin use with the same covariates as model 3 in the propensity score matched cohort and propensity score weighted cohort.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup Analysis\u003c/h2\u003e \u003cp\u003eIn the subgroup analyses, we stratified the study population by statin type (lipophilic and hydrophilic statin), the continuation of statin use (discontinue to use statin or not in patients with statin use history before hospitalization), age (\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;65 and \u0026lt;\u0026thinsp;65 years), and disease severity [four groups according to SAPSII score quantiles (group 1: \u0026lt;25th; group 2: 25-49th; group 3:50-74th; group 4:\u0026gt;=75th)] to analysis the correlation between pre-ICU use and SAD in corresponding subgroup.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eWe investigated the likelihood of unmeasured confounding factors affecting the correlation between pre-ICU statin use and SAD by calculating E-values. The E-value estimates the required magnitude of an unmeasured confounder that could nullify the observed association between pre-ICU statin use and SAD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMeasurement data conforming to a normal distribution were described as mean (standard deviation). Independent sample t-test was applied for inter-group comparisons. Continuous variables not conforming to normal distribution were displayed as median [lower quartile-upper quartile]. Wilcoxon rank-sum tests were performed to draw inter-group comparisons. The categorical data were presented as frequency plus percentage and compared by Pearson χ2 test (two-sided). Fisher\u0026rsquo;s exact test was applied for those expected frequencies of one or more cells less than 5. R (version 4.1.3) was applied for statistical analyses. The values were considered as statistical significance at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn the MIMIC-IV database, a total of 32,971 ICU stay records met the sepsis 3.0 criteria. After including only patients\u0026rsquo; first hospital and ICU admissions and excluding patients with ICU stays shorter than 1 day (2,218), dementia (867), no delirium assessment (5,708), unable to assess CAM-ICU (583), direct ICU admission (5,716), delirium before sepsis (775), and delirium outside the ICU (2), 6649 patients were included for analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Statin was prescribed in 27.5% of the sepsis patients before their ICU admission, and the incidence of SAD was 35.1%.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics and primary outcome of the patients with and without SAD\u003c/h2\u003e \u003cp\u003eThe baseline clinical characteristics and short-term and long-term outcome of patients with or without SAD were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of the patients was 67.03 years, and 59.4% of them were male. Comorbidities such as congestive heart failure (31.6% vs. 27.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), cerebrovascular disease (15.9% vs. 7.86%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), COPD (28.7% vs. 24.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), paraplegia (6.00% vs. 1.67%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), renal disease (23.9% vs. 21.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), and liver disease (19.4% vs. 11.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were more prevalent in the delirium group. Disease severity scores, including CCI, SAPSII, LODS, and SOFA, were significantly higher in patients with delirium (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with SAD had longer ICU stay (5.33 vs. 2.15 days, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), prolonged hospital stay (13.5 vs. 7.52 days, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) as well as increased mortality at 28-day (22.1% vs. 6.98%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 1-year (39.6% vs. 19.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePropensity score analysis\u003c/h2\u003e \u003cp\u003eThe characteristics of the original and matched cohort were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The patients without pre-ICU statin use were younger (65.23\u0026thinsp;\u0026plusmn;\u0026thinsp;15.78 years vs. 71.77\u0026thinsp;\u0026plusmn;\u0026thinsp;10.85 years) and had fewer comorbidities, including Congestive Heart Failure 25.6 vs. 38.7, Renal Disease 26.9% vs. 43.6, Diabetes 26.9% vs. 43.6. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrated the distribution of propensity scores before and after propensity score match. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e showed the balance of covariates in both groups improved after propensity score match. The balance of covariates improved between groups after matching, thereby enhancing the comparability of the two groups. Patients with pre-ICU statin use had a lower incidence of SAD in both the original cohort (27.6 vs. 38.0%) and the matched cohort (27.2 vs. 33.9%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the basic demographics, comorbidity conditions, disease severity, treatment and delirium between the original cohort and the matched cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCovariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eOriginal cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMatched cohort\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo Statin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStatin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo Statin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eStatin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1,612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.23 (15.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.77 (10.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71.45 (12.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71.12 (10.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (Male, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2716 (56.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1236 (67.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1067 (66.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1057 (65.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHITE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3226 (67.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1312 (71.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1146 (71.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1143 (70.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBLACK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e440 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e115 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e98 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOTHERS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1152 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e419 (22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e351 (21.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e371 (23.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmission Type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e375 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e322 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e250 (15.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e258 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2328 (48.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e544 (29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e527 (32.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e536 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrgent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e629 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e526 (28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e354 (22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e388 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1486 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e439 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e481 (29.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e430 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAKI (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e794 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e445 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e385 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e367 (22.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1645 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e731 (39.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e614 (38.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e627 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1116 (23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e332 (18.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e309 (19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e306 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongestive Heart Failure (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1232 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e708 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e602 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e594 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebrovascular Disease (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e492 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e219 (12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e197 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e184 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1230 (25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e510 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e468 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e451 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatic Disease (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e206 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaplegia (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal disease (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e928 (19.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e539 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e468 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e438 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1296 (26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e798 (43.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e664 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e648 (40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver Disease (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e819 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e115 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e107 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1003 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e197 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e187 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e187 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAIDS (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Severity Assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCI (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.00 (2.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.66 (2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.58 (2.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.50 (2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAPSII Score (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.78 (13.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.77 (12.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.78 (12.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.67 (12.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLODS Score (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.02 (2.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.83 (2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.85 (2.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.81 (2.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA Score (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.98 (3.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.67 (2.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.66 (3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.62 (2.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis Use (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e376 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e131 (7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e116 (7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e118 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVentilation Use (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2403 (49.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e949 (51.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e837 (51.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e814 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasopressin Use (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e508 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e123 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e133 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelirium (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1830 (38.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e505 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e547 (33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e438 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.147\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAKI: acute kidney injury; COPD: chronic obstructive pulmonary disease; AIDS: acquired immunodeficiency syndrome; CCI: charlson comorbidity index; SAPS: simplified acute physiological score; LODS: logistic organ dysfunction system; SOFA: sequential organ failure assessment.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between pre-ICU statin use and SAD\u003c/h2\u003e \u003cp\u003eWe used four logistic regression models to investigate the correlation between pre-ICU statin use and SAD. In univariate analysis, the OR of the pre-ICU statin use was 0.622 (95%CI: 0.552\u0026ndash;0.699, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The OR of pre-ICU statin use ranged from 0.562\u0026ndash;0.621 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in all the multivariable logistic regression models (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Further multivariable regression models adjusted for all measured covariates showed identical protective effect of pre-ICU statin use against SAD in propensity score matched cohort (OR 0.707, 95% CI 0.630\u0026ndash;0.794, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and weighted cohort (OR 0.6277, 95% CI 0.573\u0026ndash;0.686, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity Analysis\u003c/h2\u003e \u003cp\u003eWe generated an E-value to assess the sensitivity to unmeasured confounding. The E-value was 0.499 for the estimate and 0.554 for the lower confidence limit, indicating that the finding was robust, unless an unmeasured confounder contributing the incidence of SAD with an OR lower than 0.499 existed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup Analysis\u003c/h2\u003e \u003cp\u003eResults of subgroup analysis were presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Lipophilic statins exhibited a significant protective effect against SAD, whereas hydrophilic statins showed less pronounced protective effect. For patients who had taken statins prior to hospitalization, discontinuation of statin therapy on admission to hospital significantly increased the risk of developing SAD. We also made a subgroup analysis based on age given the influence of age on delirium. Results showed that the protective effects of statins were more pronounced in the elderly population (\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;65 years) and not significant in younger patients. Taken the disease severity into consideration, the protective effect of statins against SAD was attenuated in patients with mild (group 1) or severe disease (group 4), whereas it was more pronounced in the patients with moderate severity (group 2 and group 3).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective cohort study explored the association between pre-ICU statin use and the occurrence of SAD based on the MIMIC-IV database. Our findings indicated that pre-ICU statin use was associated with a reduced incidence of SAD in the sepsis patients, both in the original and matched cohorts, regardless of adjustments for other covariates, which was consistent with the hypothesis that statins may exert protective effects against SAD. In our study, we observed an incidence rate of delirium of 35.1% among sepsis patients during ICU stay, which was consistent with reported rates of SAD ranging from 30\u0026ndash;70% in literature studies[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur results support the notion that statins might mitigate some of the pathophysiological processes leading to delirium in sepsis patients, possibly due to their anti-inflammatory and neuroprotective properties[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Statin may counteract the inflammation-induced action of proinflammatory phenotype microglial activation during sepsis[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In animal experiments, investigators observed that statin exerted a neuroprotective role by upregulation of the Bcl-2 and cytokines reduction, which may prevent the cognitive deficit observed in sepsis survivor animals[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It is noteworthy that animal and human studies have also shown that abrupt discontinuation of statin use could lead to an acute rebound inflammation and worsening of clinical outcomes, which was in compliance with our results. The role of neuroinflammation in the pathophysiology of SAD has been fully established[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Data from animal and human studies had suggested that neuroinflammation to sepsis is systemic inflammation relaying to the innate immunity in the central nervous system(CNS) via various routes[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Circulating cytokines and chemokines also plays an important role in SAD pathogenesis[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This neuroinflammation may cause cognitive deficits through activation of microglia, edema and apoptosis[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe differential impact of lipophilic versus hydrophilic statins on SAD suggested the potential role of statin solubility and blood-brain barrier penetrance in mediating their protective effects[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Lipophilic statins, which could more readily cross the blood-brain barrier, showed a stronger association with reduced SAD compared to hydrophilic statins. This finding underscores the importance of considering statin properties in clinical decision-making processes, especially in populations at high risk for delirium.\u003c/p\u003e \u003cp\u003eAdditionally, result from our subgroup analysis highlighted the significance of continuity in statin therapy. Discontinuation of statins upon hospital admission was linked with an increased risk of developing SAD, emphasizing the potential risks of interrupting statin therapy during critical illness. This risk may stem from a rebound in inflammatory responses upon discontinuation of statins[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], which potentially drives this increased risk. The pronounced protective effects in elderly patients further align with existing literature suggesting that older adults may particularly benefit from the neuroprotective effects of statins.\u003c/p\u003e \u003cp\u003eWhile our analysis benefits from a large sample size and the robustness of findings across multiple analyses, there are inherent limitations associated with retrospective analyses, including potential biases from unmeasured confounders. However, the calculated E-values suggest that a confounder would need to be exceptionally strong to invalidate our findings, reinforcing the potential causality of the observed associations.\u003c/p\u003e \u003cp\u003eThis study also has several other limitations, as only the effect of statin use exposure was explored, without considering the dosage and duration. Future prospective studies should aim to delineate the optimal types and timing of statin therapy in sepsis and explore mechanistic pathways through which statins may reduce the risk of SAD. Additionally, only short-term outcomes were examined, the long-term cognitive impacts of statin use on sepsis survivors could yield further insights into the broader implications of our findings for patient care following ICU discharge. Future prospective studies should aim to delineate the optimal types and timing of statin therapy in sepsis and explore mechanistic pathways through which statins may reduce the risk of SAD. Furthermore, exploring the long-term cognitive outcomes of statin use in sepsis survivors could provide deeper insights into the broader implications of our findings for patient care post-ICU discharge.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study revealed an association between statin use prior to ICU admission and decreased risk of SAD. Our findings advocate for a careful consideration of statin therapy in sepsis patients, especially among those at elevated risk for cognitive complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe establishment of this database was approved by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA), and consent was obtained for the original data collection. Therefore, the ethical approval statement and the need for informed consent were waived for this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets presented in the current study are available in the MIMIC-IV database (https://physionet.org/content/mimiciv/2.2/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by National Natural Science Foundation of China (82372217). The study sponsors had no involvement in the study design, the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the paper for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHL and LJ contributed to all aspects of this manuscript, including study conception and design; acquisition, analysis, and interpretation of data; and drafting the article. SX, TH, CWX helped write and review the manuscript. YM and ZC led the project and designed the study. All authors have read and approved the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSinger M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischmann-Struzek C, Mellhammar L, Rose N, Cassini A, Rudd KE, Schlattmann P, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med. 2020;46:1552\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990\u0026ndash;2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuruta R, Oda Y. A clinical perspective of sepsis-associated delirium. J Intensive Care. 2016;4:18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMostel Z, Perl A, Marck M, Mehdi SF, Lowell B, Bathija S, et al. Post-sepsis syndrome \u0026ndash; an evolving entity that afflicts survivors of sepsis. Mol Med. 2020;26:6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung H-Y, Wickel J, Brunkhorst FM, Geis C. Sepsis-Associated Encephalopathy: From Delirium to Dementia? J Clin Med. 2020;9:703.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage VJ, Davis D, Zhao XB, Norton S, Casarin A, Brown T, et al. Statin Use and Risk of Delirium in the Critically Ill. Am J Respir Crit Care Med. 2014;189:666\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorandi A, Hughes CG, Thompson JL, Pandharipande PP, Shintani AK, Vasilevskis EE, et al. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med. 2014;42:1899\u0026ndash;909.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeedham DM, Colantuoni E, Dinglas VD, Hough CL, Wozniak AW, Jackson JC, et al. Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir Med. 2016;4:203\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAn JY, Park JY, Cho J, Kim HE, Park J, Oh J. The Relationship between Delirium and Statin Use According to Disease Severity in Patients in the Intensive Care Unit. Clin Psychopharmacol Neurosci. 2023;21:179\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45:486\u0026ndash;552.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKunutsor SK, Laukkanen JA. Heart Failure Risk Reduction: Hydrophilic or Lipophilic Statins? Cardiology. 2020;145:384\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuruta R, Oda Y. A clinical perspective of sepsis-associated delirium. J Intensive Care. 2016;4:18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEly EW, Margolin R, Francis J, May L, Truman B, Dittus R, et al. Evaluation of delirium in critically ill patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29:1370.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSonneville R, De Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. 2017;43:1075\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTauber SC, Djukic M, Gossner J, Eiffert H, Br\u0026uuml;ck W, Nau R. Sepsis-associated encephalopathy and septic encephalitis: an update. Expert Rev Anti Infect Ther. 2021;19:215\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanielski LG, Giustina AD, Gava FF, Barichello T, Petronilho F. The Many Faces of Astrocytes in the Septic Brain. Mol Neurobiol. 2022;59:7229\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBu D, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;22:165\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorandi A, Hughes CG, Girard TD, McAuley DF, Ely EW, Pandharipande PP. Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest. 2011;140:580\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCatal\u0026atilde;o CHR, Santos-Junior NN, da Costa LHA, Souza AO, C\u0026aacute;rnio EC, Sebollela A, et al. Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration. Neurotox Res. 2020;38:871\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTokuda R, Nakamura K, Takatani Y, Tanaka C, Kondo Y, Ohbe H, et al. Sepsis-Associated Delirium: A Narrative Review. J Clin Med. 2023;12:1273.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManabe T, Heneka MT. Cerebral dysfunctions caused by sepsis during ageing. Nat Rev Immunol. 2022;22:444\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi M-H, Gao Y-Z, Shi C-N, Wu X-M, Yang J-J. Acute and long-term cognitive impairment following sepsis: mechanism and prevention. Expert Rev Neurother. 2023;23:931\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrummel NE, Hughes CG, McNeil JB, Pandharipande PP, Thompson JL, Orun OM, et al. Systemic inflammation and delirium during critical illness. Intensive Care Med. 2024;50:687\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet Lond Engl. 2010;375:773\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSierra S, Ramos MC, Molina P, Esteo C, V\u0026aacute;zquez JA, Burgos JS. Statins as Neuroprotectants: A Comparative In Vitro Study of Lipophilicity, Blood-Brain-Barrier Penetration, Lowering of Brain Cholesterol, and Decrease of Neuron Cell Death. J Alzheimers Dis. 2011;23:307\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J-J, Li Y-S, Chu J-M, Zhang C-Y, Wang Y, Huang Y, et al. Changes of plasma inflammatory markers after withdrawal of statin therapy in patients with hyperlipidemia. Clin Chim Acta. 2006;366:269\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSposito AC, Carvalho LSF, Cintra RMR, Ara\u0026uacute;jo ALR, Ono AH, Andrade JM, et al. Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis. 2009;207:191\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-informatics-and-decision-making","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"midm","sideBox":"Learn more about [BMC Medical Informatics and Decision Making](http://bmcmedinformdecismak.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/midm/default.aspx","title":"BMC Medical Informatics and Decision Making","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sepsis, delirium, statin, critical care","lastPublishedDoi":"10.21203/rs.3.rs-4588600/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4588600/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe association between statin use and sepsis-associated delirium (SAD) remains controversial. This study aimed to determine whether statin use decrease the risk of SAD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study analyzed data of 6649 adult Intensive Care Unit (ICU) patients from the MIMIC-IV database who met inclusion criteria. We examined the association between prior to ICU admission (pre-ICU) statin use and the incidence of SAD by univariate and multivariable logistic regression analysis, propensity score matching (PSM), inverse probability weighting (IPW), and subgroup analysis employing propensity score matching and inverse probability weighting to adjust for potential confounders. The adjusted odds ratio (OR) with 95% CI were calculated in corresponding cohorts.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the study population, 35.1% patients developed SAD. Patients with pre-ICU statin use showed a lower incidence of SAD compared to those without (27.6% vs. 38.0% in origin cohort, 27.2% vs. 33.9% in the matched cohort). Pre-ICU statin use showed a stable protective effect against SAD across different analyses: in original cohort (OR 0.562, 95% CI 0.491\u0026thinsp;~\u0026thinsp;0.642, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), propensity score matched cohort (OR 0.707, 95% CI 0.630\u0026thinsp;~\u0026thinsp;0.794, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and inverse probability weighted cohort (OR 0.627, 95% CI 0.573\u0026thinsp;~\u0026thinsp;0.686, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). E-value analysis suggested the robustness to unmeasured confounding.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePre-ICU statin use is associated with a reduced incidence of SAD, particularly among elderly patients and those receiving lipophilic statins. These findings support the potential role of statins administration in the management of delirium in septic patients and underscore the importance of maintaining statin therapy during critical illness. Future prospective studies are needed to confirm these results and guide clinical practice.\u003c/p\u003e","manuscriptTitle":"Association of prior to intensive care unit statin use with sepsis-associated delirium: a retrospective propensity score analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 20:20:50","doi":"10.21203/rs.3.rs-4588600/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-06-18T10:18:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-18T10:17:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Informatics and Decision Making","date":"2024-06-16T06:07:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-informatics-and-decision-making","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"midm","sideBox":"Learn more about [BMC Medical Informatics and Decision Making](http://bmcmedinformdecismak.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/midm/default.aspx","title":"BMC Medical Informatics and Decision Making","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"521876ad-ab17-49f0-bc35-773d1baf66e2","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-16T20:20:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-16 20:20:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4588600","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4588600","identity":"rs-4588600","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}