Analysis of the Inflammatory Storm Response and Heparin Binding Protein Levels for the Diagnosis and Prognosis of Sepsis-Associated Encephalopathy

Analysis of the Inflammatory Storm Response and Heparin Binding Protein Levels for the Diagnosis and Prognosis of Sepsis-Associated Encephalopathy | 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 Analysis of the Inflammatory Storm Response and Heparin Binding Protein Levels for the Diagnosis and Prognosis of Sepsis-Associated Encephalopathy Dian Yu, Jun Liu, Xiaoyun Song, Yongfeng Ao, Xiaomin Li, Yi Han This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5331429/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Feb, 2025 Read the published version in European Journal of Medical Research → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Sepsis related encephalopathy(SAE) is a complication that endangers the nervous function during the development of sepsis. Its occurrence is closely related to severe systemic infection. The increase of serum Interleukin 6 and other inflammatory cytokines has certain clinical significance in the diagnosis of sepsis, However, there is no research at home or abroad indicating whether the high expression of related inflammatory cytokines (inflammatory cytokine storm，ICS) is valuable for the diagnosis and prognosis of SAE patients. Objective: The aim of this study was to analyze serum inflammatory cytokines 6 (IL-2/4/6/10, TNF-α, gamma interferon (IFN-γ)), heparin-binding protein (HBP), serum cholinesterase, and plasma fibrinogen 3 (α2-fibrin inhibitory complex, antithrombin III complex, and fibrinogen TM) levels and their clinical significance in septic patients. In this study, we defined the values of inflammatory storm (IL-6 >5000 pg/ml, IL-10 >1000 pg/ml, and HBP >300 ng/ml) in order to analyze the diagnostic value and 28-day prognostic predictive ability of inflammatory cytokine storm and the severity score in SAE patients Methods: A total of 140 patients with sepsis in the ICU and EICU of the Lianyungang First People's Hospital were included in the present study from Octobet 2021 to March 2023. Based on the Diagnostic criteria for SAE, the 140 cases were divided into 62 cases in the SAE group and 78 cases in the non-SAE group. On admission to the ICU/EICU, the patients gender, age, vital signs, and serum levels of various cytokines were recorded. The Glasgow Coma Scale (GCS), Sequential Organ Failure Scale (qSOFA), and Acute Physiological and Chronic Health Score II (APACHE-II) scores were also assessed to analyze the risk factors for the occurrence of SAE. Results: The age, Sofa score, APACHE-II score, 28-day mortality rate, serological cellular inflammatory factors (IL-2/6/10, INF-α, interferon-gamma), HBP, and antithrombin III complex were significantly higher in the SAE group than in the non-SAE group (P<0.05). In addition, the GCS score and serum cholinesterase levels in the SAE group were lower than in the non-SAE group (P5000 pg/ml), IL-10 (>1000 pg/ml), and HBP (>300 ng/ml) levels and elevated qSOFA and APACHE-II scores were risk factors for the development of SAE (P<0.05). Moreover, IL-6/10 and HBP indicators positively correlated with qSOFA and APACHE-II scores (P5000 pg/ml group compared to patients in the USAE and IL-6 <5000 pg/ml groups(P 300 ng/ml, IL-6 > 5000 pg/ml, decreased GCS score, and decreased APACHEII score were combined into a new predictive data model (risk score).In the SAE group, patients with high risk scores had a higher 28-day mortality rate compared with the low risk score group (p < 0.001) Conclusion: The occurrence of SAE is closely correlated with age, concomitant diabetes, SOFA score, APACHE II score, serum cytosolic inflammatory factor levels (IL-2/6/10, TNF-α, IFN-γ), HBP, and serum cholinesterase levels. Notably, IL-6 >5000pg/ml, IL-10 >1000pg/ml, and HBP > 300ng/ml are diagnostic indicators of SAE, with IL-6 >5000pg/ml also associated with three severe disease scores and increased 28-day mortality rate (p<0.05), suggesting that inflammatory factor storm levels may be associated with the mechanism of sepsis-associated SAEs and 28-day mortality.According to the LASSO results, when SAE patients admitted to the intensive care unit satisfy HBP > 300ng/ml, IL6 > 5000pg/ml, decreased GCS score, and increased APACHEII score, it suggests that the patient's 28-day mortality rate is higher, and it also validates that inflammatory storm can be used as a predictor of prognosis for SAE patients. inflammatory factor storm interleukin-6 sepsis-associated encephalopathy heparin-binding protein 28-day mortality Prediction model Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response mediated or caused by bacterial infections. Sepsis-associated encephalopathy (SAE) ( 1 ) , a systemic inflammatory response secondary to infection without overt central nervous system infection in vivo , is a key manifestation of sepsis. SAE is common in septic patients with acute mental-health alterations ( 2 ) . SAE is characterized by systemic metabolic, inflammatory, and hemodynamic disturbances, often manifesting as varying degrees of impaired consciousness, ranging from mild to severe drowsiness, confusion, delirium, somnolence, or coma due to diffused brain function ( 3 ) . SAE is highly positively correlated with mortality in patients with sepsis ( 4 ) . Notably, even a mild alteration in consciousness (GCS of 13–14) can indicate poor prognosis in patients suffering long-term impairments in memory, attention, verbal fluency, and executive functions after discharge. Sepsis-induced neuroinflammatory dysregulation and ischemic damage are the main causes of SAE ( 5 ) . Neuroinflammation is induced by releasing pro-inflammatory mediators from microglia and astrocytes and infiltrating peripheral inflammatory and immune cells. After an inflammatory response attack in an organism, inflammatory signals reach different brain regions through neural and humoral transmission, leading to the abnormal infiltration of the blood-brain barrier (BBB) ( 6 ) . The inflammatory damage also induces the intracranial ischemic process, which reduces cerebral perfusion crucial in developing SAE, leading to abnormal cellular metabolism and oxidative stress, which damages neuronal cells ( 7 , 8 ) . Inflammatory cytokine storm (ICS), or inflammatory storm, is a serious immune dysregulation disease manifested by the uncontrolled secretion of inflammatory cytokines and excessive release of inflammatory mediators by inflammatory cells ( 9 ) . High levels of cytokines can disrupt the brain barrier, trigger neuroinflammation and lead to dysregulation and disturbance of the neuronal environment homeostasis ( 10 ) . ICS has received a lot of attention in the pathology of the novel coronavirus disease 2019 (COVID-19) ( 11 ) and is considered to be a dysregulated pathological pattern due to the acute induction of inflammatory response and high production of inflammatory cytokines in response to an infection or trauma in an organism. The main cytokines regulating the ICS process include IL-6, IFN-γ , and IL-10. Among them, IL-6, an important pro-inflammatory cytokine with several inflammatory effects, is the most important and useful pro-inflammatory factor in the ICS process. For example, there were significantly higher serum pro-inflammatory cytokines IL-6, IL-8, and IL-10 concentrations in 91 patients associated with sepsis, acute respiratory distress syndrome, or burns than in healthy individuals ( 12 ) . SAE is a diagnosis of exclusion, with no specific serological indicators or special clinical management; thus, detecting and diagnosing SAE early is very important to improve the prognosis of sepsis patients. Although the uncontrolled release of inflammatory factors, including IL-2, IL-4, IL-6, IL-10, INF-α, IFN-γ, and Heparin-binding protein (HBP), can impair the systemic multi-organ function, SAE diagnosis based on the expression of these inflammatory factors has not been documented. Therefore, this study analyzed the correlation between serum indicators, including serum IL-6, IL-10, and HBP, with sepsis-related complications for rapid and early SAE detection.Provide new clinical evidence for the diagnosis of SAE and observe the occurrence of SAE and the impact of inflammatory factor storms on prognosis, To explore whether inflammatory Cytokine storm is valuable for the diagnosis and prognosis of SAE patients,To explore the diagnostic and prognostic value of inflammatory Cytokine storm in patients with SAE 2. Materials and Methods 2.1 Recruitment of the study subjects Based on the Helsinki Declaration,the protocols in this study were reviewed and approved by the Ethics Committee of Lianyungang First People's Hospital(approval number: KY-20221221002-01). A total of 190 patients with sepsis admitted to the ICU and EICU of Lianyungang First People's Hospital from June 2021 to December 2023 were sequentially enrolled in this study ( Fig. 1 ). Among them, 50 patients were excluded. Inclusion criteria: (1) the patients were newly admitted or untreated septic patients aged 18–80 years; (2) the septic patients met the diagnostic criteria of sepsis 3.0 ( 13 ) ; (3)patients with SAE characterized by sepsis with varying degrees of impaired consciousness (GCS score < 13) and did not meet one of the exclusion criteria; (4) patients with complete clinical information, and signed informed consent by themselves or their families. Exclusion criteria: (1) patients with sepsis combined with intracranial hemorrhage, intracranial organic lesions, central nervous system infections, and metabolic encephalopathy; (2) patients with new cerebral infarction, sequelae of previous cerebral infarctions, Alzheimer's disease and long-term mental disorders; (3) patients with sepsis combined with other diseases that can cause impaired consciousness, such as hepatic encephalopathy, pulmonary encephalopathy, and trauma; (4) patients suffering long-term psychiatric disorders, such as depression, and anxiety disorders (5) patients who used long-acting or short-acting sedatives or received special treatment before admission; (6) patients suffering serious cardiovascular and cerebrovascular emergencies, hepatic and renal insufficiency and other multiple organ failure diseases; (7) patients who died within 24 h after admission and those who refused to be examined. Finally, 140 patients with sepsis were included in the study. Septic patients were assigned to the SAE and non-SAE groups based on whether SAE occurred at the time of admission or during hospitalization (excluding sedation or tracheal intubation during hospitalization that resulted in SAE). Subjects included in the study Of the 190 patients initially clinically diagnosed with sepsis or infectious shock, 25 were directly excluded, including those who deliberately opted out due to financial pressure (n = 10), those who had undergone specific treatment such as pharmacological interventions and mechanical ventilation at an outside hospital before admission (n = 12), and those who were transferred from the hospital or died within 24 h (n = 3). The remaining 165 patients were then initially eligible for blood biomarker measurements. However, after retrospective reassessment, 25 subjects in the initial sepsis group were excluded, 12 of whom did not meet the criteria for sepsis diagnosis (no evidence of infection). Instead, the 12 subjects were diagnosed with congestive heart failure (n = 2), acute kidney injury (n = 2), hyperosmolar hyperglycemic state (n = 2), acute myocardial infarction (n = 2), and other infections (n = 4). The other 13 patients were excluded due to non-sepsis-induced impairment of consciousness, medical history of new cerebral infarction, residual impairment of consciousness due to cerebral infarction (n = 9), and central system infection-induced encephalopathy (n = 4). Out of the 190 patients enrolled in the study, only 140 were included, of which 83 were male and 57 were female aged 18–80. In addition, the 140 septic patients were divided into 62 cases in the SAE group and 78 cases in the non-SAE group ( Fig. 1 ). 2.2 Personal and clinical data collection The medical records and clinical data of the included patients were independently reviewed to determine the severity of sepsis. Basic information, such as name, gender, age, and past medical history, was also recorded. Subsequently, admission criteria were analyzed, and the source of infection was determined according to the patients' clinical manifestations and various infection indicators and imaging localization. In addition, the GCS ( 14 ) , qSOFA ( 15 ) , and APACHE-II ( 16 ) scores were strictly completed on the day of admission according to the scoring rules. 1.2.2 Serological index tests 5ml blood was drawn on the day the patient was transferred to the ICU, and serum was separated by centrifuge for examination (all blood samples were obtained within 6 hours of the clinical diagnosis of sepsis or septic shock). Serum cytokine levels (IL-2/4/6/10, INF-α, interferon gamma), heparin-binding protein, serum cholinesterase, and other cytokines were quantitatively determined by solid-phase sandwich assay using a cytokine 6-item kit (Raisecare) in the NAVIO flow cytometer (Beckman Coulter), and the absorbance was measured by the steps in the manual. The absorbance was measured and the concentration in serum was calculated. 1.2.3 Statistical analysis Data analysis was performed using SPSS 25 software. Serological indicators of this study were analyzed by t-test or Mann-Whitney U test based on the data distribution, and the results were expressed as mean ± standard error of the mean (x s). Qualitative variables were analyzed using a 2 × 2 column table and chi-square test. All count data were expressed as [n (%)]. The correlation between changes in the test indexes and the three severe disease scores was analyzed by bivariate correlation analysis. Subsequently, the subject operator characteristics (ROC) curve was plotted, and the accuracy of serological indexes in differentiating between patients with sepsis and septic encephalopathy was assessed by calculating the area under the curve (AUC). In addition,the Kaplan Meier curve is mainly used to describe the survival status of patients in each group. Kaplan-Meier curves were plotted to compare 28-day mortality between SAE and non-SAE groups and between IL-6 (> 5000 pg/mL) and IL-6 (< 5000 pg/mL) groups. The lasso algorithm (last absolute shrinkage and selection operator, LASSO) was used for variable screening, and its moderating parameters were validated using 10-fold crossover. Variables that were not zero were included in a multifactor logistic regression model, and risk factors were screened stepwise to construct a risk prediction model. 3. Results 3.1 Univariate analysis of general information in the SAE and non-SAE groups The incidence of SAE was 44.29% in 62 of the 140 sepsis patients, while the non-SAE group had 78 sepsis patients ( Fig. 1 ). Among the 140 sepsis patients, the most common sources of infection were pulmonary infection in 57 cases (40.71%), urinary tract infection in 43 cases (30.71%), gastrointestinal infection in 34 cases (24.29%), skin and soft tissue in 12 cases (8.57%), and 1 case (0.71%) of ductal infection. Overall, in SAE and non-SAE groups, pulmonary, urinary tract, and gastrointestinal infections were the main causes of sepsis and SAE, and the source of infection in the two groups was not no statistically different based on univariate analysis. However, the age of patients with diabetes mellitus in the SAE group was statistically different relative to the non-SAE group. In addition, the SOFA score of the SAE group was statistically different from the non-SAE group (P < 0.001). The GCS score of the SAE group was also significantly lower than that of the non-SAE group (P < 0.001). In contrast, the 28-day mortality rate in the SAE group was significantly higher than that of the non-SAE group (P < 0.001). Moreover, the gender and underlying disease other than diabetes of patients in the SAE group were statistically different from those in the non-SAE group. Table 1 Univariate analysis of general information of SAE and non-SAE groups (x̄±s) Variables SAE group (n = 62) Non-SAE group (n = 78) X 2 /t P Gender Male[n(%)] 34(54.84) 49(62.82) 0.912 0.340 Female[n(%)] 28(45.16) 29(37.17) Age 68.60 ± 10.86 59.88 ± 14.69 4.032 P < 0.001 Type of underlying disease High blood pressure 21(33.87) 18(23.08) 2.003 0.157 Diabetes 28(45.16) 18(23.08) 7.637 0.006 History of cancer/oncology 8(12.90) 5(6.41) 1.729 0.189 Coronary heart disease 10(16.13) 11(14.10) 0.111 0.739 Rheumatoid 1(1.61) 4(5.19) 1.239 0.266 Urinary stones 14(22.58) 16(20.51) 0.088 0.767 Source of infection Lung infection 23(37.10) 34(43.59) 0.603 0.437 Urinary tract infections 17(27.42) 25(32.05) 0.353 0.552 Digestive tract infections 16(25.81) 16(20.51) 0.549 0.459 Soft tissue skin infections 8(12.90) 4(5.13) 2.665 0.103 Catheter-based infections 0(0) 1(1.28) 0.000 1.000 Critical illness score GCS 6.66 ± 2.77 14.78 ± 0.66 -22.588 P < 0.001 SOFA 12.56 ± 3.04 6.73 ± 3.99 9.824 P < 0.001 APACHEII 26.45 ± 8.52 14.92 ± 7.22 8.663 P < 0.001 28-day mortality rate Survival[n(%)] 20(32.26) 63(80.77) 33.678 P < 0.001 Death[n(%)] 42(67.74) 15(19.23) Survival days 4.48 ± 3.98 9.94 ± 8.42 -3.364 0.001 3.2 Univariate analysis of serological indicators in the SAE and non-SAE groups 3.2.1 Comparison of growth stimulating expressed gene 2, thrombomodulin III, and serum cholinesterase levels between SAE and non-SAE groups The serum growth-stimulating expressed gene 2 protein, antithrombin III complex, and HBP were significantly higher in the SAE group than in the non-SAE group (P < 0.05). In contrast, the serum cholinesterase level was significantly lower in the SAE group than in the non-SAE group (P 0.05) (Attachment Table 1 ). 3.2.2 IL-6, IL-10, and HBP levels in SAE and non-SAE groups The serological cellular inflammatory factors IL-2, IL-6, IL-10, INF-α, and IFN-γ expression levels were significantly higher in the SAE group than in the non-SAE group (P < 0.05)( Table 2 ). Among them, IL-6 and IL-10 levels were statistically significantly different in the SAE group (P 0.05 ). When IL-6 levels were > 5000 pg/ml, IL-10 levels > 1000 pg/ml, and HBP levels > 300 ng/ml (P < 0.001), suggesting a more likely predisposition to SAE when IL-6/10 and HBP are expressed at ultra-high levels ( Table 2 ). Table 2 IL-6, IL-10, and HBP expression levels in SAE and non-SAE groups Variables SAE group (n = 62) Non-SAE group (n = 78) X 2 /t P Inflammatory cytokines IL-6(>5000pg/ml) 36(58.06%) 12(15.38%) 27.928 P 10000pg/ml) 28(46.77%) 3(3.85%) 34.201 P 20000pg/ml) 20(32.26%) 0(0%) 29.355 P 5000pg/ml) 6(9.68%) 1(1.28%) 3.511 0.061 IL-10(>2000pg/ml) 23(37.10%) 4(5.13%) 22.679 P 1000pg/ml) 28(45.16%) 7(8.97%) 24.125 P < 0.001 HBP 247.30 ± 86.18 144.72 ± 100.30 5.857 P 300ng/ml 39(65.30%) 11(14.10%) 35.831 P 5000 pg/ml), IL-10 (> 1000 pg/ml), elevated HBP (> 300 ng/ml), elevated SOFA score, elevated APACHE-II score, and low cholinesterase levels in the serum were positively correlated with the occurrence of SAE (P < 0.05); thus, they were considered as risk factors for the occurrence of SAE ( Table 3 ). Table 3: Multifactorial logistic regression between SAE occurrence and risk factors Variables β SE Wald X 2 P OR 95%CI Age 1.385 0.614 5.090 0.024 3.996 1.199-13.312 Diabetes 0.968 0.770 1.583 0.208 2.633 0.583-11.898 Hypertension 0.226 0.511 0.196 0.658 1.254 0.461-3.411 IL-2 1.272 0.939 1.835 0.176 3.567 0.567-22.456 IL-6 (>5000pg/ml) 1.067 0.503 4.506 0.034 2.906 1.085-7.782 IL-10 (>1000pg/ml) 2.068 0.658 9.875 0.002 7.911 2.178-28.742 INF-α 0.200 1.136 0.031 0.860 1.221 0.132-11.316 Interferon-gamma 0.208 0.827 0.064 0.801 0.812 0.161-4.106 Heparin binding protein 2.343 0.622 14.165 P300ng/ml 2.161 0.453 22.716 P<0.001 8.681 3.570-21.113 Decreased serum cholinesterase 1.528 0.719 4.839 0.015 4.863 1.188-19.907 Elevated SOFA score 2.798 0.825 11.516 P<0.001 16.415 3.558-50.558 Elevated APACHEII score 1.378 0.672 14.705 0.040 3.966 1.062-14.803 3.4 Bivariate correlation analysis between IL-6, IL-10, and HBP levels and the three critical illness scores Correlation analysis between inflammatory cytokines IL-6, IL-10, and HBP levels and the three critical illness scores revealed that IL-6 and HBP levels were positively correlated with qSOFA and APACHE-II scores (r-value positive, P < 0.05) and negatively correlated with the GCS score (r-value negative, P < 0.05) ( Table 3 ). In contrast, IL- 10 levels were positively correlated with SOFA scores (P 5000 pg/ml), IL-10 (> 1000 pg/ml), and HBP (> 300 ng/ml) levels were positively correlated with, SOFA, and APACHE-II scores, and negative correlation with GCS score (P < 0.05) 3.5 ROC curve analysis The ROC curve analysis of serum IL-6, IL-10, and HBP levels, and qSOFA and APACHE-II scores for the diagnosis of SAE are shown in Table 4 , and the ROC curves are presented in Fig. 2 . It can be seen that the area under the curves of HBP (> 300ng/ml), IL-6 (> 5000pg/ml), IL-10 (> 1000pg/ml), SOFA score, and APACHEII score are all greater than 0.7, indicating a positive correlation between inflammatory factor storm, SOFA score, and APACHEII in the diagnosis of SAE in sepsis patients (P < 0.001). Table 4 ROC curve for predicting the SAE risk factors Variables AUC(95%CI) Cross-sectional values Asymptotic Significance 95% CI Lower limit Upper limit HBP .746 .048 .000 .651 .841 IL-6 .863 .035 .000 .795 .931 IL-10 .833 .039 .000 .757 .910 HBP(>300ng/ml) .740 .056 .000 .680 .850 IL-6(>5000pg/ml) .727 .059 .000 .612 .847 IL-10(>1000pg/ml) .732 .059 .000 .617 .801 SOFA .864 .039 .000 .787 .942 APACHE-II .833 .044 .000 .747 .919 3.6 Inflammatory storms influence 28-day mortality in septic patients Table 5 Cox regression analysis of risk factors in patients who died at 28 days (x¯±s) Variables 28-day death group (n = 57) 28-day survival group (n = 83) X 2 /t P Type of disease SAE group 42(78.95%) 20(24.10%) 33.678 P 5000pg/ml) 33(57.89%) 15(18.07%) 35.028 P 1000pg/ml) 19(45.16%) 16(19.28%) 3.561 0.059 HBP > 300ng/ml 25(43.86%) 25(30.12%) 2.778 0.096 GCS score 8.19 ± 4.98 12.96 ± 3.39 -5.552 P < 0.001 SOFA score 11.09 ± 4.35 8.37 ± 4.53 3.160 0.002 APACHEII score 25.26 ± 10.77 11.09 ± 7.80 4.483 P 5000 pg/ml) in patients who died at 28 days was significantly higher relative to the surviving patients at 28 days (P < 0.001)( Table 5 ), suggesting that when IL-6 was expressed at ultra-high levels, it was more likely to elevate the 28-day mortality rate. In addition, the SOFA and APACHE-II scores in patients who died at 28 days were significantly higher than those of surviving patients, but the GCS scores were significantly lower (P = 0.002/P 5000 pg/Ml and < 5000 pg/mL in the SAE group were significantly different (p 5000 pg/mL) groups, with a worse prognosis. 3.7 28-Day Mortality Analysis and Prognostic Risk Column Line Modeling for SAE Patients The data of 62 patients in SAE group were selected and divided into death group and survival group according to whether they survived for 28 days or not, and the lasso algorithm (last absolute shrinkage and selection operator (LASSO)) was used to screen the relevant variables to judge the prognosis of SAE patients, and the 10-fold crossover was utilized to verify the regulation parameters, and the result was specifically shown in Fig. 4 A/B. It can be concluded that the parameter min value is 4, and the screening results are HBP > 300ng/ml, IL-6 > 5000pg/ml, decreased GCS score, and decreased APACHEII score (coefficients are 0.539146362, 0.13861381, -0.158770187, and 0.001551349, respectively). 3.8 KM curves, column plots of Risk-Score, a prognostic risk model for SAE patients Using R software, Nomogram plots were drawn based on the results of the multifactorial logistic regression model, and the four predictive items, HBP > 300 ng/ml, IL-6 > 5000 pg/ml, declining GCS score, and declining APACHEII score, were synthesized into a new predictive data model (Risk-Score). As shown in Fig. 5 A /B, SAE patients with a high Risk-Score score tended to have a higher 28-day mortality rate than those with a low score. 4. Discussion Notably, sepsis patients with diabetes mellitus at an advanced age are more likely to develop SAE.It has been widely reported that diabetic patients are a susceptible population to sepsis, with a significantly increased risk of infection in diabetic patients compared to age-matched non-diabetic patients ( 17 , 18 ) . In addition Solange de Souza Stork has shown that diabetic Wistar rats have a significantly increased inflammatory process and increased IL-6 production compared to the non-diabetic group 24 hours after the sepsis model was constructed ( 19 ) . Serum cholinesterase is a performance indicator of liver function ( 20 ) , with a decreased cholinesterase indicating impaired liver function and reduced activity associated with the development of severe complications and mortality in septic patients ( 21 ) . In the present study, decreased cholinesterase levels in the SAE group were accompanied by increased inflammatory markers, IL-6, IL-10, and HBP, suggesting that sepsis may contribute to the development of SAE by affecting cholinesterase activity and the affected cholinergic pathways may induce delirium in critically ill patients. The hemodynamics, organ function, intraorganic environment, and tissue perfusion oxygenation function in SAE patients are significantly dysregulated ( 22 ) . The acute and chronic impairment of consciousness in SAE patients is reflected by reduced GCS scores, which significantly increase the SOFA and APACHE-II scores. Therefore, the more severe the inflammatory response in an organism is, the higher the risk of SAE in septic patients ( 23 ) . Cytokines play important roles in many fundamental life and disease processes. This study focused on the role of cytokines in inflammation leading to disease progression. Severe systemic inflammatory responses promote the release of local inflammatory factors in the brain ( 24 ) . However, large amounts of pro-inflammatory factors can damage cerebral nerves ( 25 ) , adversely affecting neuronal function, clinically manifested as acute and chronic impairment of consciousness or cognitive impairment such as memory and attention loss during the sleep-wake cycle ( 26 ) . Cytokine storms have been associated with the worsening of many infectious diseases, including severe acute respiratory syndrome ( 27 ) and the severity of COVID-19 ( 28 , 29 ) . In this study, SAE occurrence may be related to ICS in septic patients. ICS is a clinical manifestation of SAE, leading to death in critically ill septic patients. Among the associated cytokines, IL-6 is an important inflammatory cytokine ( 30 ) whose high expression level has neurotoxic effects, which damage nerves. IL-6 produced systemically during sepsis can also activate brain microglia through its receptor (sIL-6R/IL-6 protein forming complex), releasing inflammatory mediators, which lead to abnormal neuronal function and the development of SAE ( 31 ) . IL-10 is a cytokine with anti-inflammatory properties that plays a central role in limiting the immune response to pathogens during infection, thereby preventing damage to the host ( 32 ) . In this study, the serum IL-6 and IL-10 levels in the SAE group were higher than in the non-SAE group. Therefore, if the levels of IL-6 (> 5000pg/ml) and IL-10 (> 1000pg/ml) were artificially defined as inflammatory factor storms, the chance of inflammatory factor storms in the SAE group was significantly higher than that in the non-SAE group. Moreover, the inflammatory storm was associated with the changes in GCS, qSOFA, and APACHE-II scores, with IL-6 > 5000 pg/ml and IL-10 > 1000 pg/ml having some diagnostic value for SAE patients. At the same time, ultra-high levels of IL-6 (> 5000 pg/ml) more likely favored elevated 28-day mortality, resulting in significantly different survival curves between patients in the SAE group and IL-6 (> 5000 pg/mL). Generally, patients with SAE have a significantly higher 28-day mortality rate than those with common sepsis. IL-6 (> 5000 pg/mL) predicted 28-day mortality, suggesting a worse patient prognosis. HBP is a biological protein rapidly and abundantly secreted by neutrophils upon activation ( 33 ) . Once released, HBP exhibits a strong pro-inflammatory activity; thus, it is a valuable diagnostic marker during sepsis progression and a relevant determinant of sepsis severity ( 34 ) . For example, HBP quantification in suspected meningitis samples from 145 patients ( 35 ) classified 41 samples as acute bacterial meningitis. Patients with acute bacterial meningitis have significantly higher HBP concentrations than those without central nervous system inflammation. Therefore, elevated HBP levels early in the response to an infection is highly biologically plausible and predictive of organ failure ( 36 ) . In addition, the high HBP expression is positively correlated with sepsis complicating circulatory failure ( 37 , 38 ) , Acute respiratory distress syndrome ( 39 , 40 ) , and acute kidney injury ( 41 ) . In the present study, plasma HBP was significantly increased during sepsis and its level positively correlated with the development of cerebral organ dysfunction. Notably, the HBP levels were significantly higher in the SAE group than in the non-SAE group, with HBP > 300 ng/ml being a key diagnostic marker for SAE, suggesting that the detection of HBP concentration after admission could help in the early SAE diagnosis and the prediction of sepsis progression. However, there was no significant relationship between the high HBP levels and the septic patient's 28-day mortality rate.Subsequently, we used LASSO analysis to obtain a risk prediction model for the prognosis of SAE patients based on the risk factor results of SAE, and the risk indicators incorporated a representative indicator of inflammatory factor storm, HBP > 300 ng/ml and IL6 > 5000 pg/ml, as well as the GCS and APACHEII scores, and fused the four indicators into a Risk-Score as a new prognostic prediction model. Based on the results of the column line graph and survival curve, it is seen that when SAE patients admitted to ICU fulfill HBP > 300ng/ml, IL6 > 5000pg/ml, decreased GCS score and increased APACHEII score, it means that the patients have a higher 28-day mortality rate.At the same time, this study had the limitation of only testing the serological level on the day the patient was admitted to the intensive care unit. Suppose serum IL-6, IL-10, and HBP levels are continuously monitored during hospitalization. In that case, the dynamic changes of various indicators during the development of sepsis and SAE can be observed, which can be the focus of subsequent studies on this topic. Conclusion Serum IL-6, IL-10, and HBP levels are SAE risk factors. In addition, the inflammatory storm is related to the SAE mechanism, with the high expression levels of inflammatory cytokines IL-6, IL-10, and HBP in sepsis patients contributing to the early diagnosis of SAE. Additionally, the ultra-high level expression of IL-6 predicts the 28-day mortality rate in patients, suggesting a worse prognosis. Declarations Ethical Approval -Agree to this research proposal and paper submission: This study was reviewed by the Ethics Committee of the First People's Hospital of Lianyungang City (School of Clinical Medicine, Nanjing Medical University). The duties, composition and workflow of this Ethics Committee followed the ICH GCP, Chinese GCP, and conformed to the principles of the Helsinki and complied with the laws of the People's Republic of China. Funding Acknowledgement Funding for this study was provided by the Innovation Program of Jiangsu Provincial Department of Science and Technology as well as the Provincial Subject Funding of Jiangsu Province, which is funded by the following programs, as shown in the attached documents:Jiangsu Provincial Postgraduate Practice Innovation Project (SJCX22-0679); Jiangsu Provincial Science and Technology Department Social Development Program (BE2020670); Jiangsu Provincial Health Care Commission Program (H2019109) . Author Contribution Yu and Liu mainly conducted data collection, experimental design, and paper writing for the thesisSong and Ao mainly signed patients' informed consent, applied for ethics, conducted the experiment, and recorded general informationProf. Han was responsible for writing, reviewing, and revising the paper, as well as applying for the grant program.All authors reviewed the manuscript. References Maddux AB, Hiller TD, Overdier KH, Pyle LL, Douglas IS. Innate Immune Function and Organ Failure Recovery in Adults With Sepsis. J Intensive Care Med. 2019;34(6):486–94. 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(2):215–31. Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012;8(10):557–66. Manabe T, Heneka MT. Cerebral dysfunctions caused by sepsis during ageing. Nat Rev Immunol. 2022;22(7):444–58. Ren C, Yao RQ, Zhang H, Feng YW, Yao YM. Sepsis-associated encephalopathy: a vicious cycle of immunosuppression. J Neuroinflammation. 2020;17(1):14. Catarina AV, Branchini G, Bettoni L, De Oliveira JR, Nunes FB. Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies. Mol Neurobiol. 2021;58(6):2770–9. Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045. Peng X, Luo Z, He S, Zhang L, Li Y. Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy. Front Cell Infect Microbiol. 2021;11:768108. Prescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. Jama. 2018;319(1):62–75. Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127–48. Fara A, Mitrev Z, Rosalia RA, Assas BM. Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines. Open Biol. 2020;10(9):200160. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020;117(36):22351–6. 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(8):801–10. Enriquez CM, Chisholm KH, Madden LK, Larsen AD, de Longpré T, Stannard D. Glasgow Coma Scale: Generating Clinical Standards. J Neurosci Nurs. 2019;51(3):142–6. Usman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. Am J Emerg Med. 2019;37(8):1490–7. Rojek-Jarmuła A, Hombach R, Krzych Ł J. APACHE II score cannot predict successful weaning from prolonged mechanical ventilation. Chron Respir Dis. 2017;14(3):270–5. Costantini E, Carlin M, Porta M, Brizzi MF. Type 2 diabetes mellitus and sepsis: state of the art, certainties and missing evidence. Acta Diabetol. 2021;58(9):1139–51. Lu Z, Tao G, Sun X, Zhang Y, Jiang M, Liu Y, et al. Association of Blood Glucose Level and Glycemic Variability With Mortality in Sepsis Patients During ICU Hospitalization. Front Public Health. 2022;10:857368. de Souza Stork S, Hübner M, Biehl E, Danielski LG, Bonfante S, Joaquim L, et al. Diabetes Exacerbates Sepsis-Induced Neuroinflammation and Brain Mitochondrial Dysfunction. Inflammation. 2022;45(6):2352–67. Arbel Y, Shenhar-Tsarfaty S, Waiskopf N, Finkelstein A, Halkin A, Revivo M, et al. Decline in serum cholinesterase activities predicts 2-year major adverse cardiac events. Mol Med. 2014;20(1):38–45. Bahloul M, Baccouch N, Chtara K, Turki M, Turki O, Hamida CB, et al. Value of Serum Cholinesterase Activity in the Diagnosis of Septic Shock Due to Bacterial Infections. J Intensive Care Med. 2017;32(5):346–52. Atterton B, Paulino MC, Povoa P, Martin-Loeches I. Sepsis Associated Delirium. Medicina (Kaunas). 2020;56(5). Song J, Park DW, Moon S, Cho HJ, Park JH, Seok H, et al. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: a prospective controlled study according to the Sepsis-3 definitions. BMC Infect Dis. 2019;19(1):968. Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Exp Mol Med. 2021;53(7):1116–23. Zhao L, Gao Y, Guo S, Lu X, Yu S, Ge ZZ, et al. Sepsis-Associated Encephalopathy: Insight into Injury and Pathogenesis. CNS Neurol Disord Drug Targets. 2021;20(2):112–24. Shulyatnikova T, Verkhratsky A. Astroglia in Sepsis Associated Encephalopathy. Neurochem Res. 2020;45(1):83–99. Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185–94. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93(1):250–6. Koçak Tufan Z, Kayaaslan B, Mer M. COVID-19 and Sepsis. Turk J Med Sci. 2021;51(Si-1):3301–11. Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021;184(1):149 – 68.e17. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010;375(9716):773–5. Saxton RA, Tsutsumi N, Su LL, Abhiraman GC, Mohan K, Henneberg LT, et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science. 2021;371(6535). Honore PM, De Bels D, Barreto Gutierrez L, Redant S, Spapen HD. Heparin-binding protein in sepsis: player! predictor! positioning? Ann Intensive Care. 2019;9(1):71. Zhou Y, Liu Z, Huang J, Li G, Li F, Cheng Y, et al. Usefulness of the heparin-binding protein level to diagnose sepsis and septic shock according to Sepsis-3 compared with procalcitonin and C reactive protein: a prospective cohort study in China. BMJ Open. 2019;9(4):e026527. Linder A, Akesson P, Brink M, Studahl M, Björck L, Christensson B. Heparin-binding protein: a diagnostic marker of acute bacterial meningitis. Crit Care Med. 2011;39(4):812–7. Tydén J, Herwald H, Sjöberg F, Johansson J. Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure. PLoS One. 2016;11(3):e0152035. Sjöbeck M, Sternby H, Herwald H, Thorlacius H, Regnér S. Heparin-binding protein is significantly increased in acute pancreatitis. BMC Gastroenterol. 2021;21(1):337. Liu Z, Chen M, Sun Y, Li X, Cao L, Ma X. Transforming growth factor-β receptor type 2 is required for heparin-binding protein-induced acute lung injury and vascular leakage for transforming growth factor-β/Smad/Rho signaling pathway activation. Faseb j. 2022;36(11):e22580. Huang C, Zhang C, Zhang J, Zhang L, Mo Y, Mo L. Heparin-Binding Protein in Critically Ill Children With Severe Community-Acquired Pneumonia. Front Pediatr. 2021;9:759535. Paulsson M, Thelaus L, Riesbeck K, Qvarfordt I, Smith ME, Lindén A, et al. Heparin-binding protein in lower airway samples as a biomarker for pneumonia. Respir Res. 2021;22(1):174. Fisher J, Russell JA, Bentzer P, Parsons D, Secchia S, Mörgelin M, et al. Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury. Shock. 2017;48(3):313–20. Annex Table 1: Comparison of growth-expressed gene 2 and plasma thrombus III and serum cholinesterase levels in SAE and non-SAE groups (x¯±s) pg/ml Additional Declarations No competing interests reported. Supplementary Files AnnexTables.docx Cite Share Download PDF Status: Published Journal Publication published 18 Feb, 2025 Read the published version in European Journal of Medical Research → Version 1 posted Editorial decision: Revision requested 01 Nov, 2024 Editor assigned by journal 29 Oct, 2024 Submission checks completed at journal 29 Oct, 2024 First submitted to journal 25 Oct, 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-5331429","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":372910183,"identity":"7aa6433e-d59c-4d11-b314-7823c0ea3a37","order_by":0,"name":"Dian Yu","email":"data:image/png;base64,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","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":true,"prefix":"","firstName":"Dian","middleName":"","lastName":"Yu","suffix":""},{"id":372910184,"identity":"35377b58-0ff3-4341-bb25-53a5156cbd6e","order_by":1,"name":"Jun Liu","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Liu","suffix":""},{"id":372910185,"identity":"a13195f7-8ad6-4097-a7c3-9eed9b3b5f46","order_by":2,"name":"Xiaoyun Song","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyun","middleName":"","lastName":"Song","suffix":""},{"id":372910186,"identity":"0950cabe-c6a7-43f8-895e-4b697c0a72de","order_by":3,"name":"Yongfeng Ao","email":"","orcid":"","institution":"The First People’s Hospital of Lianyungang","correspondingAuthor":false,"prefix":"","firstName":"Yongfeng","middleName":"","lastName":"Ao","suffix":""},{"id":372910187,"identity":"7d11c5ec-fee0-4aa2-9f5d-1713ef0ff9c1","order_by":4,"name":"Xiaomin Li","email":"","orcid":"","institution":"The First People’s Hospital of Lianyungang","correspondingAuthor":false,"prefix":"","firstName":"Xiaomin","middleName":"","lastName":"Li","suffix":""},{"id":372910189,"identity":"b2816748-d467-4df6-b1fc-090cfd89687b","order_by":5,"name":"Yi Han","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Han","suffix":""}],"badges":[],"createdAt":"2024-10-25 09:53:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5331429/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5331429/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-025-02369-x","type":"published","date":"2025-02-18T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69435406,"identity":"90a483e3-27ae-4bed-ba09-a9566409d702","added_by":"auto","created_at":"2024-11-20 10:29:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":68647,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe inclusion and exclusion flow chart of septic patients into the SAE and non-SAE groups\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/1a8d2815a8f9853675002ae4.jpg"},{"id":69436191,"identity":"860a078e-8520-4128-9425-a6ff1272673c","added_by":"auto","created_at":"2024-11-20 10:37:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45173,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIL-6, IL-10, and HBP levels and qSOFA and APACHE-II scores for predicting SAE\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/27757991e43c9ad4fa67666c.jpg"},{"id":69437237,"identity":"91addc26-5045-42ee-987d-90f018dd1795","added_by":"auto","created_at":"2024-11-20 10:45:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":51398,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/3fd57d7a61bd271a0f810de1.png"},{"id":69435411,"identity":"0b8c2d90-8edd-4e4a-8dd3-feac7165725e","added_by":"auto","created_at":"2024-11-20 10:29:31","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51230,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLASSO regression feature downscaling for SAE patients who died at 28 days. (A) Penalty plot of coefficients of LASSO regression variables (values); (B) Ten-fold cross-validation and minimization criteria to identify the optimal penalty coefficients of the LASSO regression model (values).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/b0d45c9db74c47516720bfbc.jpg"},{"id":69435407,"identity":"544d8cf0-f9d6-480f-88cd-8aa7e7ee79ea","added_by":"auto","created_at":"2024-11-20 10:29:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":108927,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of risk prediction model for 28-day prognosis of SAE patients (A) KM curve of Risk-score of prognostic risk prediction model. (B) Risk model prediction column line graph for 28-day prognosis of SAE patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/cfe9b0a50994c507a7cc21e7.png"},{"id":77053814,"identity":"22b77295-0ac7-44b9-9749-c279ae046316","added_by":"auto","created_at":"2025-02-24 16:30:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10146984,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/d39dd9da-3f59-4220-a286-75427aa196e5.pdf"},{"id":69436193,"identity":"ff389009-dd17-44d3-bffe-8d19d5c3a16f","added_by":"auto","created_at":"2024-11-20 10:37:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18150,"visible":true,"origin":"","legend":"","description":"","filename":"AnnexTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5331429/v1/9a08e7359fe59ae0dc518d17.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of the Inflammatory Storm Response and Heparin Binding Protein Levels for the Diagnosis and Prognosis of Sepsis-Associated Encephalopathy","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003e \u003cb\u003eSepsis is a complex clinical syndrome characterized by a systemic inflammatory response mediated or caused by bacterial infections. Sepsis-associated encephalopathy (SAE)\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e, \u003cb\u003ea systemic inflammatory response secondary to infection without overt central nervous system infection\u003c/b\u003e \u003cb\u003ein vivo\u003c/b\u003e, \u003cb\u003eis a key manifestation of sepsis. SAE is common in septic patients with acute mental-health alterations\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSAE is characterized by systemic metabolic, inflammatory, and hemodynamic disturbances, often manifesting as varying degrees of impaired consciousness, ranging from mild to severe drowsiness, confusion, delirium, somnolence, or coma due to diffused brain function\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eSAE is highly positively correlated with mortality in patients with sepsis\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e. \u003cb\u003eNotably, even a mild alteration in consciousness (GCS of 13\u0026ndash;14) can indicate poor prognosis in patients suffering long-term impairments in memory, attention, verbal fluency, and executive functions after discharge.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eSepsis-induced neuroinflammatory dysregulation and ischemic damage are the main causes of SAE\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eNeuroinflammation is induced by releasing pro-inflammatory mediators from microglia and astrocytes and infiltrating peripheral inflammatory and immune cells. After an inflammatory response attack in an organism, inflammatory signals reach different brain regions through neural and humoral transmission, leading to the abnormal infiltration of the blood-brain barrier (BBB)\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e. \u003cb\u003eThe inflammatory damage also induces the intracranial ischemic process, which reduces cerebral perfusion crucial in developing SAE, leading to abnormal cellular metabolism and oxidative stress, which damages neuronal cells\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInflammatory cytokine storm (ICS), or inflammatory storm, is a serious immune dysregulation disease manifested by the uncontrolled secretion of inflammatory cytokines and excessive release of inflammatory mediators by inflammatory cells\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eHigh levels of cytokines can disrupt the brain barrier, trigger neuroinflammation and lead to dysregulation and disturbance of the neuronal environment homeostasis\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e. \u003cb\u003eICS has received a lot of attention in the pathology of the novel coronavirus disease 2019 (COVID-19)\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eand is considered to be a dysregulated pathological pattern due to the acute induction of inflammatory response and high production of inflammatory cytokines in response to an infection or trauma in an organism. The main cytokines regulating the ICS process include IL-6, IFN-γ\u003c/b\u003e, \u003cb\u003eand IL-10. Among them, IL-6, an important pro-inflammatory cytokine with several inflammatory effects, is the most important and useful pro-inflammatory factor in the ICS process. For example, there were significantly higher serum pro-inflammatory cytokines IL-6, IL-8, and IL-10 concentrations in 91 patients associated with sepsis, acute respiratory distress syndrome, or burns than in healthy individuals\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSAE is a diagnosis of exclusion, with no specific serological indicators or special clinical management; thus, detecting and diagnosing SAE early is very important to improve the prognosis of sepsis patients. Although the uncontrolled release of inflammatory factors, including IL-2, IL-4, IL-6, IL-10, INF-α, IFN-γ, and Heparin-binding protein (HBP), can impair the systemic multi-organ function, SAE diagnosis based on the expression of these inflammatory factors has not been documented. Therefore, this study analyzed the correlation between serum indicators, including serum IL-6, IL-10, and HBP, with sepsis-related complications for rapid and early SAE detection.Provide new clinical evidence for the diagnosis of SAE and observe the occurrence of SAE and the impact of inflammatory factor storms on prognosis, To explore whether inflammatory Cytokine storm is valuable for the diagnosis and prognosis of SAE patients,To explore the diagnostic and prognostic value of inflammatory Cytokine storm in patients with SAE\u003c/b\u003e \u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Recruitment of the study subjects\u003c/h2\u003e \u003cp\u003e\u003cb\u003e Based on the Helsinki Declaration,the protocols in this study were reviewed and approved by the Ethics Committee of Lianyungang First People's Hospital(approval number: KY-20221221002-01). A total of 190 patients with sepsis admitted to the ICU and EICU of Lianyungang First People's Hospital from June 2021 to December 2023 were sequentially enrolled in this study (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e). Among them, 50 patients were excluded. Inclusion criteria: (1) the patients were newly admitted or untreated septic patients aged 18\u0026ndash;80 years; (2) the septic patients met the diagnostic criteria of sepsis 3.0\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e;\u003cb\u003e(3)patients with SAE characterized by sepsis with varying degrees of impaired consciousness (GCS score\u0026thinsp;\u0026lt;\u0026thinsp;13) and did not meet one of the exclusion criteria; (4) patients with complete clinical information, and signed informed consent by themselves or their families. Exclusion criteria: (1) patients with sepsis combined with intracranial hemorrhage, intracranial organic lesions, central nervous system infections, and metabolic encephalopathy; (2) patients with new cerebral infarction, sequelae of previous cerebral infarctions, Alzheimer's disease and long-term mental disorders; (3) patients with sepsis combined with other diseases that can cause impaired consciousness, such as hepatic encephalopathy, pulmonary encephalopathy, and trauma; (4) patients suffering long-term psychiatric disorders, such as depression, and anxiety disorders (5) patients who used long-acting or short-acting sedatives or received special treatment before admission; (6) patients suffering serious cardiovascular and cerebrovascular emergencies, hepatic and renal insufficiency and other multiple organ failure diseases; (7) patients who died within 24 h after admission and those who refused to be examined. Finally, 140 patients with sepsis were included in the study. Septic patients were assigned to the SAE and non-SAE groups based on whether SAE occurred at the time of admission or during hospitalization (excluding sedation or tracheal intubation during hospitalization that resulted in SAE).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSubjects included in the study\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eOf the 190 patients initially clinically diagnosed with sepsis or infectious shock, 25 were directly excluded, including those who deliberately opted out due to financial pressure (n\u0026thinsp;=\u0026thinsp;10), those who had undergone specific treatment such as pharmacological interventions and mechanical ventilation at an outside hospital before admission (n\u0026thinsp;=\u0026thinsp;12), and those who were transferred from the hospital or died within 24 h (n\u0026thinsp;=\u0026thinsp;3). The remaining 165 patients were then initially eligible for blood biomarker measurements. However, after retrospective reassessment, 25 subjects in the initial sepsis group were excluded, 12 of whom did not meet the criteria for sepsis diagnosis (no evidence of infection). Instead, the 12 subjects were diagnosed with congestive heart failure (n\u0026thinsp;=\u0026thinsp;2), acute kidney injury (n\u0026thinsp;=\u0026thinsp;2), hyperosmolar hyperglycemic state (n\u0026thinsp;=\u0026thinsp;2), acute myocardial infarction (n\u0026thinsp;=\u0026thinsp;2), and other infections (n\u0026thinsp;=\u0026thinsp;4). The other 13 patients were excluded due to non-sepsis-induced impairment of consciousness, medical history of new cerebral infarction, residual impairment of consciousness due to cerebral infarction (n\u0026thinsp;=\u0026thinsp;9), and central system infection-induced encephalopathy (n\u0026thinsp;=\u0026thinsp;4). Out of the 190 patients enrolled in the study, only 140 were included, of which 83 were male and 57 were female aged 18\u0026ndash;80. In addition, the 140 septic patients were divided into 62 cases in the SAE group and 78 cases in the non-SAE group (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Personal and clinical data collection\u003c/h2\u003e \u003cp\u003e \u003cb\u003eThe medical records and clinical data of the included patients were independently reviewed to determine the severity of sepsis. Basic information, such as name, gender, age, and past medical history, was also recorded. Subsequently, admission criteria were analyzed, and the source of infection was determined according to the patients' clinical manifestations and various infection indicators and imaging localization. In addition, the GCS\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e, \u003cb\u003eqSOFA\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003eand APACHE-II\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e \u003cb\u003escores were strictly completed on the day of admission according to the scoring rules.\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e1.2.2 Serological index tests\u003c/h2\u003e \u003cp\u003e \u003cb\u003e5ml blood was drawn on the day the patient was transferred to the ICU, and serum was separated by centrifuge for examination (all blood samples were obtained within 6 hours of the clinical diagnosis of sepsis or septic shock). Serum cytokine levels (IL-2/4/6/10, INF-α, interferon gamma), heparin-binding protein, serum cholinesterase, and other cytokines were quantitatively determined by solid-phase sandwich assay using a cytokine 6-item kit (Raisecare) in the NAVIO flow cytometer (Beckman Coulter), and the absorbance was measured by the steps in the manual. The absorbance was measured and the concentration in serum was calculated.\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e1.2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003e \u003cb\u003eData analysis was performed using SPSS 25 software. Serological indicators of this study were analyzed by t-test or Mann-Whitney U test based on the data distribution, and the results were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean (x s). Qualitative variables were analyzed using a 2 \u0026times; 2 column table and chi-square test. All count data were expressed as [n (%)]. The correlation between changes in the test indexes and the three severe disease scores was analyzed by bivariate correlation analysis. Subsequently, the subject operator characteristics (ROC) curve was plotted, and the accuracy of serological indexes in differentiating between patients with sepsis and septic encephalopathy was assessed by calculating the area under the curve (AUC). In addition,the Kaplan Meier curve is mainly used to describe the survival status of patients in each group. Kaplan-Meier curves were plotted to compare 28-day mortality between SAE and non-SAE groups and between IL-6 (\u0026gt;\u0026thinsp;5000 pg/mL) and IL-6 (\u0026lt;\u0026thinsp;5000 pg/mL) groups. The lasso algorithm (last absolute shrinkage and selection operator, LASSO) was used for variable screening, and its moderating parameters were validated using 10-fold crossover. Variables that were not zero were included in a multifactor logistic regression model, and risk factors were screened stepwise to construct a risk prediction model.\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Univariate analysis of general information in the SAE and non-SAE groups\u003c/h2\u003e \u003cp\u003e \u003cb\u003eThe incidence of SAE was 44.29% in 62 of the 140 sepsis patients, while the non-SAE group had 78 sepsis patients (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e). Among the 140 sepsis patients, the most common sources of infection were pulmonary infection in 57 cases (40.71%), urinary tract infection in 43 cases (30.71%), gastrointestinal infection in 34 cases (24.29%), skin and soft tissue in 12 cases (8.57%), and 1 case (0.71%) of ductal infection. Overall, in SAE and non-SAE groups, pulmonary, urinary tract, and gastrointestinal infections were the main causes of sepsis and SAE, and the source of infection in the two groups was not no statistically different based on univariate analysis. However, the age of patients with diabetes mellitus in the SAE group was statistically different relative to the non-SAE group. In addition, the SOFA score of the SAE group was statistically different from the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The GCS score of the SAE group was also significantly lower than that of the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, the 28-day mortality rate in the SAE group was significantly higher than that of the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Moreover, the gender and underlying disease other than diabetes of patients in the SAE group were statistically different from those in the non-SAE group.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of general information of SAE and non-SAE groups (x̄\u0026plusmn;s)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSAE group (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-SAE group (n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e /t\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale[n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34(54.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49(62.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale[n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(45.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29(37.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.60\u0026thinsp;\u0026plusmn;\u0026thinsp;10.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59.88\u0026thinsp;\u0026plusmn;\u0026thinsp;14.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of underlying disease\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh blood pressure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(33.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(23.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.157\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\u003e28(45.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(23.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of cancer/oncology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(12.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5(6.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.729\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.189\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronary heart disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(16.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11(14.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.739\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(5.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary stones\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(22.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(20.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.767\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of infection\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(37.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34(43.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(27.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25(32.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDigestive tract infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(25.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(20.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.549\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoft tissue skin infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(12.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(5.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCatheter-based infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCritical illness score\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.66\u0026thinsp;\u0026plusmn;\u0026thinsp;2.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-22.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHEII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.45\u0026thinsp;\u0026plusmn;\u0026thinsp;8.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.92\u0026thinsp;\u0026plusmn;\u0026thinsp;7.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28-day mortality rate\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival[n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(32.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63(80.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33.678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath[n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42(67.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15(19.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvival days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.48\u0026thinsp;\u0026plusmn;\u0026thinsp;3.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.94\u0026thinsp;\u0026plusmn;\u0026thinsp;8.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Univariate analysis of serological indicators in the SAE and non-SAE groups\u003c/h2\u003e \u003cp\u003e \u003cb\u003e3.2.1 Comparison of growth stimulating expressed gene 2, thrombomodulin III, and serum cholinesterase levels between SAE and non-SAE groups\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe serum growth-stimulating expressed gene 2 protein, antithrombin III complex, and HBP were significantly higher in the SAE group than in the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In contrast, the serum cholinesterase level was significantly lower in the SAE group than in the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, the α2-fibrinolytic enzyme-inhibitor complex and thrombomodulin TM levels were not statistically different between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Attachment\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2 IL-6, IL-10, and HBP levels in SAE and non-SAE groups\u003c/h2\u003e \u003cp\u003e \u003cb\u003eThe serological cellular inflammatory factors IL-2, IL-6, IL-10, INF-α, and IFN-γ expression levels were significantly higher in the SAE group than in the non-SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05)(\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e). Among them, IL-6 and IL-10 levels were statistically significantly different in the SAE group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but not with IL-4 levels (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 ). When IL-6 levels were \u0026gt;\u0026thinsp;5000 pg/ml, IL-10 levels\u0026thinsp;\u0026gt;\u0026thinsp;1000 pg/ml, and HBP levels\u0026thinsp;\u0026gt;\u0026thinsp;300 ng/ml (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting a more likely predisposition to SAE when IL-6/10 and HBP are expressed at ultra-high levels (\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\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\u003eIL-6, IL-10, and HBP expression levels in SAE and non-SAE groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSAE group (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-SAE group (n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e /t\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInflammatory cytokines\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6(\u0026gt;5000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36(58.06%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(15.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.928\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6(\u0026gt;10000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(46.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(3.85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6(\u0026gt;20000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20(32.26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10(\u0026gt;5000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(9.68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1.28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10(\u0026gt;2000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(37.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(5.13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.679\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10(\u0026gt;1000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(45.16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(8.97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e247.30\u0026thinsp;\u0026plusmn;\u0026thinsp;86.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e144.72\u0026thinsp;\u0026plusmn;\u0026thinsp;100.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.857\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBP\u0026thinsp;\u0026gt;\u0026thinsp;300ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39(65.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(14.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35.831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk factor analysis for the occurrence of SAE\u003c/h2\u003e \u003cp\u003e \u003cb\u003eMultifactorial logistic regression analysis revealed that advanced age, elevated IL-6 (\u0026gt;\u0026thinsp;5000 pg/ml), IL-10 (\u0026gt;\u0026thinsp;1000 pg/ml), elevated HBP (\u0026gt;\u0026thinsp;300 ng/ml), elevated SOFA score, elevated APACHE-II score, and low cholinesterase levels in the serum were positively correlated with the occurrence of SAE (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05); thus, they were considered as risk factors for the occurrence of SAE (\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 3: Multifactorial logistic regression between SAE occurrence and risk factors\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;border: none;width: 567px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105.75pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eVariables\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.05pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e\u0026beta;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eSE\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eWald X\u003csup\u003e2\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.65pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eOR\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border-top: 1.5pt solid windowtext;border-left: none;border-bottom: 1pt solid windowtext;border-right: none;padding: 0in 5.4pt;height: 17.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e95%CI\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105.75pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.05pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.385\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.614\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e5.090\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003e0.024\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.65pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.996\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.199-13.312\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105.75pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eDiabetes\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.05pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.968\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.770\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.583\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.208\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.65pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.633\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.583-11.898\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105.75pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eHypertension\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.05pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.226\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.511\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.196\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.658\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.65pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.254\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.461-3.411\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105.75pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eIL-2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.05pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.272\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.939\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.835\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.176\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46.65pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.567\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.567-22.456\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eIL-6 (\u0026gt;5000pg/ml)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.067\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.503\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e4.506\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003e0.034\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.906\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.085-7.782\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eIL-10 (\u0026gt;1000pg/ml)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.068\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.658\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e9.875\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003e0.002\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e7.911\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.178-28.742\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eINF-\u0026alpha;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.200\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.136\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.031\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.860\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.221\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.132-11.316\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eInterferon-gamma\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.208\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.827\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.064\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.801\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.812\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.161-4.106\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eHeparin binding protein\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.343\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.622\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e14.165\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003eP\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e10.408\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.073-35.251\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eHBP\u0026gt;300ng/ml\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.161\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.453\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e22.716\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003eP\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e8.681\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.570-21.113\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eDecreased serum cholinesterase\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.528\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.719\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e4.839\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003e0.015\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e4.863\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.188-19.907\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eElevated SOFA score\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e2.798\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.825\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e11.516\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003eP\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e16.415\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.558-50.558\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003eElevated APACHEII score\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.378\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e0.672\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56.3pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e14.705\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;color:red;\"\u003e0.040\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e3.966\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1.5pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-family:SimSun;\"\u003e1.062-14.803\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Bivariate correlation analysis between IL-6, IL-10, and HBP levels and the three critical illness scores\u003c/h2\u003e \u003cp\u003e \u003cb\u003eCorrelation analysis between inflammatory cytokines IL-6, IL-10, and HBP levels and the three critical illness scores revealed that IL-6 and HBP levels were positively correlated with qSOFA and APACHE-II scores (r-value positive, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and negatively correlated with the GCS score (r-value negative, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e). In contrast, IL- 10 levels were positively correlated with SOFA scores (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) but not with GCS and PACHE-II scores. Extraction of IL-6, IL-10, and HBP levels in patients defined as inflammatory factor storm revealed that elevated IL-6 (\u0026gt;\u0026thinsp;5000 pg/ml), IL-10 (\u0026gt;\u0026thinsp;1000 pg/ml), and HBP (\u0026gt;\u0026thinsp;300 ng/ml) levels were positively correlated with, SOFA, and APACHE-II scores, and negative correlation with GCS score (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.5 ROC curve analysis\u003c/h2\u003e \u003cp\u003e \u003cb\u003eThe ROC curve analysis of serum IL-6, IL-10, and HBP levels, and qSOFA and APACHE-II scores for the diagnosis of SAE are shown in\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cb\u003eand the ROC curves are presented in\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. \u003cb\u003eIt can be seen that the area under the curves of HBP (\u0026gt;\u0026thinsp;300ng/ml), IL-6 (\u0026gt;\u0026thinsp;5000pg/ml), IL-10 (\u0026gt;\u0026thinsp;1000pg/ml), SOFA score, and APACHEII score are all greater than 0.7, indicating a positive correlation between inflammatory factor storm, SOFA score, and APACHEII in the diagnosis of SAE in sepsis patients (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eROC curve for predicting the SAE risk factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAUC(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCross-sectional values\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAsymptotic Significance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLower limit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUpper limit\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.651\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.841\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.931\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBP(\u0026gt;300ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.850\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6(\u0026gt;5000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.727\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.847\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10(\u0026gt;1000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.732\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.617\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.801\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.864\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.787\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.942\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.747\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Inflammatory storms influence 28-day mortality in septic patients\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox regression analysis of risk factors in patients who died at 28 days (x\u0026macr;\u0026plusmn;s)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28-day death group (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28-day survival group (n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e /t\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of disease\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAE group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42(78.95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20(24.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33.678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-SAE group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(26.32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63(75.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (\u0026gt;\u0026thinsp;5000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33(57.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15(18.07%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10 (\u0026gt;\u0026thinsp;1000pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(45.16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(19.28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBP\u0026thinsp;\u0026gt;\u0026thinsp;300ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(43.86%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25(30.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.778\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCS score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.19\u0026thinsp;\u0026plusmn;\u0026thinsp;4.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.96\u0026thinsp;\u0026plusmn;\u0026thinsp;3.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-5.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.09\u0026thinsp;\u0026plusmn;\u0026thinsp;4.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHEII score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25.26\u0026thinsp;\u0026plusmn;\u0026thinsp;10.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.09\u0026thinsp;\u0026plusmn;\u0026thinsp;7.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe serological cytosolic inflammatory IL-6 (\u0026gt;\u0026thinsp;5000 pg/ml) in patients who died at 28 days was significantly higher relative to the surviving patients at 28 days (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)(\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e), suggesting that when IL-6 was expressed at ultra-high levels, it was more likely to elevate the 28-day mortality rate. In addition, the SOFA and APACHE-II scores in patients who died at 28 days were significantly higher than those of surviving patients, but the GCS scores were significantly lower (P\u0026thinsp;=\u0026thinsp;0.002/P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe Kaplan-Meier survival curves of patients with IL-6 levels at \u0026gt;\u0026thinsp;5000 pg/Ml and \u0026lt;\u0026thinsp;5000 pg/mL in the SAE group were significantly different (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e). This implies that the 28-day mortality rate was significantly higher in the SAE and IL-6 (\u0026gt;\u0026thinsp;5000 pg/mL) groups, with a worse prognosis.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.7 28-Day Mortality Analysis and Prognostic Risk Column Line Modeling for SAE Patients\u003c/h2\u003e \u003cp\u003eThe data of 62 patients in SAE group were selected and divided into death group and survival group according to whether they survived for 28 days or not, and the lasso algorithm (last absolute shrinkage and selection operator (LASSO)) was used to screen the relevant variables to judge the prognosis of SAE patients, and the 10-fold crossover was utilized to verify the regulation parameters, and the result was specifically shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA/B. It can be concluded that the parameter min value is 4, and the screening results are HBP\u0026thinsp;\u0026gt;\u0026thinsp;300ng/ml, IL-6\u0026thinsp;\u0026gt;\u0026thinsp;5000pg/ml, decreased GCS score, and decreased APACHEII score (coefficients are 0.539146362, 0.13861381, -0.158770187, and 0.001551349, respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.8 KM curves, column plots of Risk-Score, a prognostic risk model for SAE patients\u003c/h2\u003e \u003cp\u003e \u003cb\u003eUsing R software, Nomogram plots were drawn based on the results of the multifactorial logistic regression model, and the four predictive items, HBP\u0026thinsp;\u0026gt;\u0026thinsp;300 ng/ml, IL-6\u0026thinsp;\u0026gt;\u0026thinsp;5000 pg/ml, declining GCS score, and declining APACHEII score, were synthesized into a new predictive data model (Risk-Score). As shown in\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA\u003cb\u003e/B, SAE patients with a high Risk-Score score tended to have a higher 28-day mortality rate than those with a low score.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cb\u003eNotably, sepsis patients with diabetes mellitus at an advanced age are more likely to develop SAE.It has been widely reported that diabetic patients are a susceptible population to sepsis, with a significantly increased risk of infection in diabetic patients compared to age-matched non-diabetic patients\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eIn addition Solange de Souza Stork has shown that diabetic Wistar rats have a significantly increased inflammatory process and increased IL-6 production compared to the non-diabetic group 24 hours after the sepsis model was constructed\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003cb\u003eSerum cholinesterase is a performance indicator of liver function\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003ewith a decreased cholinesterase indicating impaired liver function and reduced activity associated with the development of severe complications and mortality in septic patients\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003cb\u003eIn the present study, decreased cholinesterase levels in the SAE group were accompanied by increased inflammatory markers, IL-6, IL-10, and HBP, suggesting that sepsis may contribute to the development of SAE by affecting cholinesterase activity and the affected cholinergic pathways may induce delirium in critically ill patients.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe hemodynamics, organ function, intraorganic environment, and tissue perfusion oxygenation function in SAE patients are significantly dysregulated\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eThe acute and chronic impairment of consciousness in SAE patients is reflected by reduced GCS scores, which significantly increase the SOFA and APACHE-II scores. Therefore, the more severe the inflammatory response in an organism is, the higher the risk of SAE in septic patients\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCytokines play important roles in many fundamental life and disease processes. This study focused on the role of cytokines in inflammation leading to disease progression. Severe systemic inflammatory responses promote the release of local inflammatory factors in the brain\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eHowever, large amounts of pro-inflammatory factors can damage cerebral nerves\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/b\u003e,\u003c/sup\u003e \u003cb\u003eadversely affecting neuronal function, clinically manifested as acute and chronic impairment of consciousness or cognitive impairment such as memory and attention loss during the sleep-wake cycle\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e. \u003cb\u003eCytokine storms have been associated with the worsening of many infectious diseases, including severe acute respiratory syndrome\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eand the severity of COVID-19\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003cb\u003eIn this study, SAE occurrence may be related to ICS in septic patients. ICS is a clinical manifestation of SAE, leading to death in critically ill septic patients. Among the associated cytokines, IL-6 is an important inflammatory cytokine\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e \u003cb\u003ewhose high expression level has neurotoxic effects, which damage nerves. IL-6 produced systemically during sepsis can also activate brain microglia through its receptor (sIL-6R/IL-6 protein forming complex), releasing inflammatory mediators, which lead to abnormal neuronal function and the development of SAE\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIL-10 is a cytokine with anti-inflammatory properties that plays a central role in limiting the immune response to pathogens during infection, thereby preventing damage to the host\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e.\u003cb\u003eIn this study, the serum IL-6 and IL-10 levels in the SAE group were higher than in the non-SAE group. Therefore, if the levels of IL-6 (\u0026gt; 5000pg/ml) and IL-10 (\u0026gt; 1000pg/ml) were artificially defined as inflammatory factor storms, the chance of inflammatory factor storms in the SAE group was significantly higher than that in the non-SAE group. Moreover, the inflammatory storm was associated with the changes in GCS, qSOFA, and APACHE-II scores, with IL-6 \u0026gt; 5000 pg/ml and IL-10 \u0026gt; 1000 pg/ml having some diagnostic value for SAE patients. At the same time, ultra-high levels of IL-6 (\u0026gt; 5000 pg/ml) more likely favored elevated 28-day mortality, resulting in significantly different survival curves between patients in the SAE group and IL-6 (\u0026gt; 5000 pg/mL). Generally, patients with SAE have a significantly higher 28-day mortality rate than those with common sepsis. IL-6 (\u0026gt; 5000 pg/mL) predicted 28-day mortality, suggesting a worse patient prognosis.\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eHBP is a biological protein rapidly and abundantly secreted by neutrophils upon activation\u003c/b\u003e \u003csup\u003e \u003cb\u003e(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)\u003c/b\u003e \u003c/sup\u003e. \u003cb\u003eOnce released, HBP exhibits a strong pro-inflammatory activity; thus, it is a valuable diagnostic marker during sepsis progression and a relevant determinant of sepsis severity\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e. \u003cb\u003eFor example, HBP quantification in suspected meningitis samples from 145 patients\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e \u003cb\u003eclassified 41 samples as acute bacterial meningitis. Patients with acute bacterial meningitis have significantly higher HBP concentrations than those without central nervous system inflammation. Therefore, elevated HBP levels early in the response to an infection is highly biologically plausible and predictive of organ failure\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003cb\u003eIn addition, the high HBP expression is positively correlated with sepsis complicating circulatory failure\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003eAcute respiratory distress syndrome\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003eand acute kidney injury\u003c/b\u003e\u003csup\u003e\u003cb\u003e(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)\u003c/b\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn the present study, plasma HBP was significantly increased during sepsis and its level positively correlated with the development of cerebral organ dysfunction. Notably, the HBP levels were significantly higher in the SAE group than in the non-SAE group, with HBP \u0026gt; 300 ng/ml being a key diagnostic marker for SAE, suggesting that the detection of HBP concentration after admission could help in the early SAE diagnosis and the prediction of sepsis progression. However, there was no significant relationship between the high HBP levels and the septic patient's 28-day mortality rate.Subsequently, we used LASSO analysis to obtain a risk prediction model for the prognosis of SAE patients based on the risk factor results of SAE, and the risk indicators incorporated a representative indicator of inflammatory factor storm, HBP \u0026gt; 300 ng/ml and IL6 \u0026gt; 5000 pg/ml, as well as the GCS and APACHEII scores, and fused the four indicators into a Risk-Score as a new prognostic prediction model. Based on the results of the column line graph and survival curve, it is seen that when SAE patients admitted to ICU fulfill HBP \u0026gt; 300ng/ml, IL6 \u0026gt; 5000pg/ml, decreased GCS score and increased APACHEII score, it means that the patients have a higher 28-day mortality rate.At the same time, this study had the limitation of only testing the serological level on the day the patient was admitted to the intensive care unit. Suppose serum IL-6, IL-10, and HBP levels are continuously monitored during hospitalization. In that case, the dynamic changes of various indicators during the development of sepsis and SAE can be observed, which can be the focus of subsequent studies on this topic.\u003c/b\u003e \u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003e \u003cb\u003eSerum IL-6, IL-10, and HBP levels are SAE risk factors. In addition, the inflammatory storm is related to the SAE mechanism, with the high expression levels of inflammatory cytokines IL-6, IL-10, and HBP in sepsis patients contributing to the early diagnosis of SAE. Additionally, the ultra-high level expression of IL-6 predicts the 28-day mortality rate in patients, suggesting a worse prognosis.\u003c/b\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical Approval -Agree to this research proposal and paper submission:\u003c/p\u003e\n\u003cp\u003eThis study was reviewed by the Ethics Committee of the First People\u0026apos;s Hospital of Lianyungang City (School of Clinical Medicine, Nanjing Medical University). The duties, composition and workflow of this Ethics Committee followed the ICH GCP, Chinese GCP, and conformed to the principles of the Helsinki and complied with the laws of the People\u0026apos;s Republic of China.\u003c/p\u003e\n\u003cp\u003eFunding Acknowledgement\u003c/p\u003e\n\u003cp\u003eFunding for this study was provided by the Innovation Program of Jiangsu Provincial Department of Science and Technology as well as the Provincial Subject Funding of Jiangsu Province, which is funded by the following programs, as shown in the attached documents:Jiangsu Provincial Postgraduate Practice Innovation Project (SJCX22-0679); Jiangsu Provincial Science and Technology Department Social Development Program (BE2020670); Jiangsu Provincial Health Care Commission Program (H2019109) .\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYu and Liu mainly conducted data collection, experimental design, and paper writing for the thesisSong and Ao mainly signed patients' informed consent, applied for ethics, conducted the experiment, and recorded general informationProf. Han was responsible for writing, reviewing, and revising the paper, as well as applying for the grant program.All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMaddux AB, Hiller TD, Overdier KH, Pyle LL, Douglas IS. Innate Immune Function and Organ Failure Recovery in Adults With Sepsis. J Intensive Care Med. 2019;34(6):486\u0026ndash;94.\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(2):215\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012;8(10):557\u0026ndash;66.\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(7):444\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRen C, Yao RQ, Zhang H, Feng YW, Yao YM. Sepsis-associated encephalopathy: a vicious cycle of immunosuppression. J Neuroinflammation. 2020;17(1):14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCatarina AV, Branchini G, Bettoni L, De Oliveira JR, Nunes FB. Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies. Mol Neurobiol. 2021;58(6):2770\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng X, Luo Z, He S, Zhang L, Li Y. Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy. Front Cell Infect Microbiol. 2021;11:768108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. Jama. 2018;319(1):62\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFara A, Mitrev Z, Rosalia RA, Assas BM. Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines. Open Biol. 2020;10(9):200160.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020;117(36):22351\u0026ndash;6.\u003c/span\u003e\u003c/li\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(8):801\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnriquez CM, Chisholm KH, Madden LK, Larsen AD, de Longpr\u0026eacute; T, Stannard D. Glasgow Coma Scale: Generating Clinical Standards. J Neurosci Nurs. 2019;51(3):142\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUsman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. Am J Emerg Med. 2019;37(8):1490\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRojek-Jarmuła A, Hombach R, Krzych Ł J. APACHE II score cannot predict successful weaning from prolonged mechanical ventilation. Chron Respir Dis. 2017;14(3):270\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCostantini E, Carlin M, Porta M, Brizzi MF. Type 2 diabetes mellitus and sepsis: state of the art, certainties and missing evidence. Acta Diabetol. 2021;58(9):1139\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu Z, Tao G, Sun X, Zhang Y, Jiang M, Liu Y, et al. Association of Blood Glucose Level and Glycemic Variability With Mortality in Sepsis Patients During ICU Hospitalization. Front Public Health. 2022;10:857368.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Souza Stork S, H\u0026uuml;bner M, Biehl E, Danielski LG, Bonfante S, Joaquim L, et al. Diabetes Exacerbates Sepsis-Induced Neuroinflammation and Brain Mitochondrial Dysfunction. Inflammation. 2022;45(6):2352\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArbel Y, Shenhar-Tsarfaty S, Waiskopf N, Finkelstein A, Halkin A, Revivo M, et al. Decline in serum cholinesterase activities predicts 2-year major adverse cardiac events. Mol Med. 2014;20(1):38\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBahloul M, Baccouch N, Chtara K, Turki M, Turki O, Hamida CB, et al. Value of Serum Cholinesterase Activity in the Diagnosis of Septic Shock Due to Bacterial Infections. J Intensive Care Med. 2017;32(5):346\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtterton B, Paulino MC, Povoa P, Martin-Loeches I. Sepsis Associated Delirium. Medicina (Kaunas). 2020;56(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong J, Park DW, Moon S, Cho HJ, Park JH, Seok H, et al. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: a prospective controlled study according to the Sepsis-3 definitions. BMC Infect Dis. 2019;19(1):968.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Exp Mol Med. 2021;53(7):1116\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao L, Gao Y, Guo S, Lu X, Yu S, Ge ZZ, et al. Sepsis-Associated Encephalopathy: Insight into Injury and Pathogenesis. CNS Neurol Disord Drug Targets. 2021;20(2):112\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShulyatnikova T, Verkhratsky A. Astroglia in Sepsis Associated Encephalopathy. Neurochem Res. 2020;45(1):83\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93(1):250\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKo\u0026ccedil;ak Tufan Z, Kayaaslan B, Mer M. COVID-19 and Sepsis. Turk J Med Sci. 2021;51(Si-1):3301\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021;184(1):149\u0026thinsp;\u0026ndash;\u0026thinsp;68.e17.\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. 2010;375(9716):773\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaxton RA, Tsutsumi N, Su LL, Abhiraman GC, Mohan K, Henneberg LT, et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science. 2021;371(6535).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHonore PM, De Bels D, Barreto Gutierrez L, Redant S, Spapen HD. Heparin-binding protein in sepsis: player! predictor! positioning? Ann Intensive Care. 2019;9(1):71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Liu Z, Huang J, Li G, Li F, Cheng Y, et al. Usefulness of the heparin-binding protein level to diagnose sepsis and septic shock according to Sepsis-3 compared with procalcitonin and C reactive protein: a prospective cohort study in China. BMJ Open. 2019;9(4):e026527.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinder A, Akesson P, Brink M, Studahl M, Bj\u0026ouml;rck L, Christensson B. Heparin-binding protein: a diagnostic marker of acute bacterial meningitis. Crit Care Med. 2011;39(4):812\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTyd\u0026eacute;n J, Herwald H, Sj\u0026ouml;berg F, Johansson J. Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure. PLoS One. 2016;11(3):e0152035.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSj\u0026ouml;beck M, Sternby H, Herwald H, Thorlacius H, Regn\u0026eacute;r S. Heparin-binding protein is significantly increased in acute pancreatitis. BMC Gastroenterol. 2021;21(1):337.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Z, Chen M, Sun Y, Li X, Cao L, Ma X. Transforming growth factor-β receptor type 2 is required for heparin-binding protein-induced acute lung injury and vascular leakage for transforming growth factor-β/Smad/Rho signaling pathway activation. Faseb j. 2022;36(11):e22580.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang C, Zhang C, Zhang J, Zhang L, Mo Y, Mo L. Heparin-Binding Protein in Critically Ill Children With Severe Community-Acquired Pneumonia. Front Pediatr. 2021;9:759535.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaulsson M, Thelaus L, Riesbeck K, Qvarfordt I, Smith ME, Lind\u0026eacute;n A, et al. Heparin-binding protein in lower airway samples as a biomarker for pneumonia. Respir Res. 2021;22(1):174.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFisher J, Russell JA, Bentzer P, Parsons D, Secchia S, M\u0026ouml;rgelin M, et al. Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury. Shock. 2017;48(3):313\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnnex Table 1: Comparison of growth-expressed gene 2 and plasma thrombus III and serum cholinesterase levels in SAE and non-SAE groups (x\u0026macr;\u0026plusmn;s) pg/ml\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":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"inflammatory factor storm, interleukin-6, sepsis-associated encephalopathy, heparin-binding protein, 28-day mortality, Prediction model","lastPublishedDoi":"10.21203/rs.3.rs-5331429/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5331429/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Sepsis related encephalopathy(SAE) is a complication that endangers the nervous function during the development of sepsis. Its occurrence is closely related to severe systemic infection. The increase of serum Interleukin 6 and other inflammatory cytokines has certain clinical significance in the diagnosis of sepsis, However, there is no research at home or abroad indicating whether the high expression of related inflammatory cytokines (inflammatory cytokine storm，ICS) is valuable for the diagnosis and prognosis of SAE patients.\u003c/p\u003e\n\u003cp\u003eObjective: The aim of this study was to analyze serum inflammatory cytokines 6 (IL-2/4/6/10, TNF-α, gamma interferon (IFN-γ)), heparin-binding protein (HBP), serum cholinesterase, and plasma fibrinogen 3 (α2-fibrin inhibitory complex, antithrombin III complex, and fibrinogen TM) levels and their clinical significance in septic patients. In this study, we defined the values of inflammatory storm (IL-6 \u0026gt;5000 pg/ml, IL-10 \u0026gt;1000 pg/ml, and HBP \u0026gt;300 ng/ml) in order to analyze the diagnostic value and 28-day prognostic predictive ability of inflammatory cytokine storm and the severity score in SAE patients\u003c/p\u003e\n\u003cp\u003eMethods: A total of 140 patients with sepsis in the ICU and EICU of the Lianyungang First People's Hospital were included in the present study from Octobet 2021 to March 2023. Based on the Diagnostic criteria for SAE, the 140 cases were divided into 62 cases in the SAE group and 78 cases in the non-SAE group. On admission to the ICU/EICU, the patients gender, age, vital signs, and serum levels of various cytokines were recorded. The Glasgow Coma Scale (GCS), Sequential Organ Failure Scale (qSOFA), and Acute Physiological and Chronic Health Score II (APACHE-II) scores were also assessed to analyze the risk factors for the occurrence of SAE.\u003c/p\u003e\n\u003cp\u003eResults: The age, Sofa score, APACHE-II score, 28-day mortality rate, serological cellular inflammatory factors (IL-2/6/10, INF-α, interferon-gamma), HBP, and antithrombin III complex were significantly higher in the SAE group than in the non-SAE group (P\u0026lt;0.05). In addition, the GCS score and serum cholinesterase levels in the SAE group were lower than in the non-SAE group (P\u0026lt; 0.05). Subsequently, multifactorial logistic regression analysis revealed that ultra-high IL-6 (\u0026gt;5000 pg/ml), IL-10 (\u0026gt;1000 pg/ml), and HBP (\u0026gt;300 ng/ml) levels and elevated qSOFA and APACHE-II scores were risk factors for the development of SAE (P\u0026lt;0.05). Moreover, IL-6/10 and HBP indicators positively correlated with qSOFA and APACHE-II scores (P\u0026lt;0.05). 28-day mortality was significantly higher in patients in the SAE group and in the IL-6 \u0026gt;5000 pg/ml group compared to patients in the USAE and IL-6 \u0026lt;5000 pg/ml groups(P\u0026lt;0.001).The four screened predictors of HBP \u0026gt; 300 ng/ml, IL-6 \u0026gt; 5000 pg/ml, decreased GCS score, and decreased APACHEII score were combined into a new predictive data model (risk score).In the SAE group, patients with high risk scores had a higher 28-day mortality rate compared with the low risk score group (p \u0026lt; 0.001)\u003c/p\u003e\n\u003cp\u003eConclusion: The occurrence of SAE is closely correlated with age, concomitant diabetes, SOFA score, APACHE II score, serum cytosolic inflammatory factor levels (IL-2/6/10, TNF-α, IFN-γ), HBP, and serum cholinesterase levels. Notably, IL-6 \u0026gt;5000pg/ml, IL-10 \u0026gt;1000pg/ml, and HBP \u0026gt; 300ng/ml are diagnostic indicators of SAE, with IL-6 \u0026gt;5000pg/ml also associated with three severe disease scores and increased 28-day mortality rate (p\u0026lt;0.05), suggesting that inflammatory factor storm levels may be associated with the mechanism of sepsis-associated SAEs and 28-day mortality.According to the LASSO results, when SAE patients admitted to the intensive care unit satisfy HBP \u0026gt; 300ng/ml, IL6 \u0026gt; 5000pg/ml, decreased GCS score, and increased APACHEII score, it suggests that the patient's 28-day mortality rate is higher, and it also validates that inflammatory storm can be used as a predictor of prognosis for SAE patients.\u003c/p\u003e","manuscriptTitle":"Analysis of the Inflammatory Storm Response and Heparin Binding Protein Levels for the Diagnosis and Prognosis of Sepsis-Associated Encephalopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 10:29:26","doi":"10.21203/rs.3.rs-5331429/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-01T08:47:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-29T12:39:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-29T08:06:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2024-10-25T09:51:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7f3620fd-513b-4478-a38d-eb57da853f73","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T16:23:35+00:00","versionOfRecord":{"articleIdentity":"rs-5331429","link":"https://doi.org/10.1186/s40001-025-02369-x","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2025-02-18 15:57:09","publishedOnDateReadable":"February 18th, 2025"},"versionCreatedAt":"2024-11-20 10:29:26","video":"","vorDoi":"10.1186/s40001-025-02369-x","vorDoiUrl":"https://doi.org/10.1186/s40001-025-02369-x","workflowStages":[]},"version":"v1","identity":"rs-5331429","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5331429","identity":"rs-5331429","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}