Association between preoperative systemic immune inflammation index and postoperative sepsis in patients with intestinal obstruction: A retrospective observational cohort study

Abstract Background Sepsis is a severe complication that results in increased morbidity and mortality after intestinal obstruction surgery. This study examined the role of preoperative systemic immune inflammation index (SII) for postoperative sepsis in intestinal obstruction patients. Methods Data on patients who underwent intestinal obstruction surgery were collected. SII was determined and separated into two groups (≤1792.19 and >1792.19) according to the optimal cut‐off value of SII for postoperative sepsis. The odds ratio (OR) is calculated for the correlation between SII and postoperative sepsis. Additional analyses were used to estimate the robustness of SII. Results A total of 371 intestinal obstruction patients undergoing surgery were included in the final cohort, and 60 (16.17%) patients developed postoperative sepsis. Patients with an SII ＞1792.19 had a significantly higher risk for developing postoperative sepsis after multivariable adjustment [adjusted odds ratio = 2.12, 95% confidence interval: [1.02–4.40]]. The analysis of interaction showed no correlation between the preoperative SII and postoperative sepsis regarding age, hypertension, American Society of Anesthesiologists classification, blood loss, albumin, hemoglobin, creatinine, and leukocyte (all interactions p > .05). In subgroup analysis, all statistically significant subgroups showed that SII was a risk factor for postoperative sepsis (all p < .05). The analyses of subgroups and interactions revealed that the interaction effect of a preoperative SII ＞1792.19 and postoperative sepsis remained significant. A sensitivity analysis confirmed the robustness of the results. Conclusions A preoperative SII ＞ 1792.19 was a risk factor for postoperative sepsis in patients undergoing intestinal obstruction surgery.


| INTRODUCTION
Sepsis is described as life-threatening organ dysfunction resulting from a maladjusted response to infection 1 and is a syndrome of physiological, morphological, and metabolic dysfunction caused by infection.Sepsis has a rising documented incidence.Although the actual incidence is unclear, sepsis is the leading cause of global death and critical illness according to a conservative estimate. 2,3The International Guidelines for Management of Sepsis and Septic Shock 4 recommended starting antibacterial treatment within 1 h after the onset of sepsis.However, due to the complexity of the clinical environment 5 and the different clinical presentations of sepsis according to its cause and population, 6 it is challenging to accurately identify sepsis early, while delayed treatment often leads to poor prognosis. 7,8In addition to being the organ in charge of nutritional absorption, the gastrointestinal tract also has immune and metabolic functions and serves as a barrier against bacteria and endotoxins in the intestinal lumen. 9ntestinal obstruction surgery is considered a high-risk procedure for sepsis. 10Although without intestinal perforation and necrosis, patients with intestinal obstruction rarely experience sepsis before surgery.However, intestinal obstruction patients are prone to malnutrition, bacterial translocation, 11,12 changes in bacterial diversity of the obstructed intestinal segments, 13 surgical trauma and the effects of anesthesia on patients, as well as a series of pathophysiological changes caused by complex perioperative factors; as such, sepsis can easily occur after surgery.
In recent years, due to their low cost and straightforward availability, an everbroader range of biological markers have been applied in clinical practice.5][16] However, these predictors tended to become unstable and vulnerable to the effect of additional confounding variables when just one or two characteristics were involved. 17The systemic immune inflammation index (SII), obtained by dividing the product of neutrophils and platelets by lymphocyte count (LYMPH), is a novel biomarker associated with outcomes of bladder cancer, 18 gastroesophageal adenocarcinoma, 19 and colorectal cancer. 20here is also some connection between sepsis and SII.It has been reported that SII can be used in addition to clinical sepsis scores to enhance the accuracy of patient evaluation. 21Meanwhile, a retrospective study showed that SII was associated with short-term mortality in the population of critically ill patients with sepsis. 22However, there have been limited studies on the inflammatory factors in patients with intestinal obstruction who are at a high risk of developing postoperative sepsis.We speculated that SII is a risk factor for sepsis after intestinal obstruction surgery.This retrospective study explored the relationship between preoperative SII and postoperative sepsis in patients with intestinal obstruction.

| Data sources and patients
This is a single-center retrospective observational cohort study.Patients with intestinal obstruction who underwent surgery from April 2013 to April 2021 at the Third Affiliated Hospital of Sun Yat-sen University were included in the cohort.Patients who meet the following exclusion criteria were omitted from this study: minors, pregnant women, patients who underwent secondary procedures for intestinal obstruction, and patients who lacked sufficient relevant records.Ethical approval of this study was obtained from the Research Ethics Committee at the Third Affiliated Hospital of Sun Yat-sen University (NO.[2022] 02-004-02).This study was exempted from having to obtain informed consent because the patient identities would not be recognized, and perioperative data were obtained from electrical health records (EHR).All data were collected and verified by three physicians to eliminate potential biases.They independently extracted the data according to the unified inclusion and exclusion standard, and then jointly checked the data to ensure accuracy.All inflammatory indicators were taken from the latest preoperative blood routine test.This report adheres to the strengthening the reporting of observational studies in epidemiology checklist for observational studies.

| Data collection
Based on clinical experience and existing studies, clinical data including demographics, clinical characteristics, laboratory values, or perioperative variables associated with sepsis and intestinal obstruction were derived from EHRs.The demographics and preoperative comorbidities included age, gender, hypertension, coronary disease, diabetes, respiratory disease, American Society of Anesthesiologists (ASA) classification, New York Heart Association classification, preoperative shock, and preoperative organ failure.Characteristics of the disease including obstruction site, cause, nature, degree, and intestinal state.Baseline laboratory findings included white blood cell (WBC) count, hemoglobin (HGB), neutrophil count (NEUT), LYMPH, monocyte count (MONO), platelet count (PLT), albumin (ALB), and creatinine (CR).Intraoperative variables included blood loss, urine volume, operation duration, and anesthesia duration.

| Outcomes and exposures
The main outcome was postoperative sepsis diagnosed according to the Sepsis 3.0 diagnostic criteria. 1Sepsis can be diagnosed if the patient's sequential organ failure assessment (SOFA) score is greater than or equal to 2, based on the infection or suspected infection.The SOFA score is mainly obtained through a comprehensive evaluation of circulation, PLT, TBIL, GCS, Cr, and PaO 2 /FiO 2 .The incidence of sepsis during postoperative hospitalization was recorded.Based on the sepsis criteria, patients were separated into two groups, that is, a sepsis group and a nonsepsis group.The main exposure was computed as the quotient of neutrophils and platelets divided by LYMPHs, that is, the SII.All diagnostic data were derived from EHRs.According to the optimal cutoff value of SII for postoperative sepsis, patients with higher SII were divided into a higher level of SII group, while those with lower SII were divide into a lower level of SII group.

| Statistical analysis
The SPSS Statistics (v.22), MedCalc (v.20.022),PASS software (version 15.0 NCSS), and EmpowerStats (http:// www.empowerststs.com,X&Y Solutions, Inc.) software packages were used to complete the statistical analysis.The median (interquartile range) was used to represent quantitative variables, while number (%) was employed to express qualitative variables.The quantitative data were examined using the student's t test or the Wilcoxon rank-sum (Mann-Whitney) test, and the qualitative data was evaluated using Pearson's χ 2 test.A p < .05 was considered statistically significant.Missing continuous and categorical variables were filled by means and modes, respectively.The Youden index were obtained from the receiver operating characteristic (ROC) curve analysis.And the Youden's index with the greatest sensitivity and specificity was used to calculate the optimal cut-off value of the SII for sepsis and to categorize patients into high or low SII groups.The PASS software (version 15.0 NCSS) was used for post hoc power analysis (two-sided, Z test, and ⍺ = .05).The relationship between the preoperative SII and postoperative sepsis in patients with intestinal obstruction was estimated using binary logistic regression.The adjusted correlations between the SII and postoperative sepsis were then investigated across all groups using multivariate logistic regression, which included the predefined confounders of age, duration of operation, WBC, obstruction cause, and intestinal state.Based on the literature and our clinical experience, interaction, and stratified analyses were performed to assess whether the association between postoperative sepsis and the SII had been influenced by confounding factors.To investigate the robustness of this association between the SII and postoperative sepsis, several sensitivity analyses were conducted.We investigated whether the association would change if patients who had experienced shock or organ dysfunction before surgery were excluded.Given the potential impact of preoperative intestinal perforation on postoperative sepsis, we investigated the relationship between the SII and all patients except for preoperative intestinal perforation.For exploratory purposes, we evaluated the relationship between sepsis and postoperative outcomes such as in-hospital mortality, duration of stay, and total cost.

| Relationship between SII and sepsis
The box plot shows that the median, 75th percentiles, and maximum values of SII in the sepsis group are higher than those in the nonsepsis group (1923.92 vs. 1180.98,5146.31 vs. 2771.65,16842.43 vs. 13306.53,p = .0072,Figure 2).The ROC analysis determined 1792.19 as the ideal cut-off value for the SII.Following Figure 3, the SII for postoperative sepsis had a cut-off value of 1792.19,AUC of 0.610, a sensitivity of 56.67%, and a specificity of 69.45%.To explore the relationship between the SII and postoperative outcomes, we found that those with a preoperative SII ＞1792.19 were associated with a higher incidence of postoperative sepsis (26.15% vs. 10.79%,p < .05;Table 1), longer time of drainage tube retention, longer postoperative hospitalization days and a longer ICU length of stay (all p < .05;Table 1).Post hoc power analysis demonstrated a study power of 0.96, which shows study was sufficiently powered.The correlation analysis revealed that individuals with a preoperative SII ＞1792.19 were at a higher risk of developing postoperative sepsis (odds ratio [OR] = 2.92, 95% confidence interval [CI]: [1.67-5.15],p < .05).We adjusted the results taking into account confounding factors such as age, WBC, surgical duration, cause of obstruction, and intestinal state.After multivariable adjustment, further correlation analysis revealed that individuals with a preoperative SII ＞1792.19 were at a higher risk of developing postoperative sepsis (adjusted odds ratio [aOR] = 2.12, 95% CI: [1.02-4.40],p < .05; Figure 4).Furthermore, the analysis of interaction showed no correlation between the preoperative SII and postoperative sepsis regarding age, hypertension, ASA classification, blood loss, ALB, HGB, CR, and leukocyte (all interactions p > .05).In subgroup analysis, all statistically significant subgroups showed that SII was a risk factor for postoperative sepsis, such as age ≥65 years old (OR = 5.52, 95% CI:

| DISCUSSION
In this retrospective observational cohort study, intestinal obstruction patients with a preoperative SII ＞ 1792.19 had a significantly increased risk of developing postoperative sepsis, with an aOR of 2.12 (95% CI: T A B L E 1 Baseline characteristics between patients with and without sepsis.The SII combines NLR with PLT to represent the balance between the inflammation, immune response, and thrombotic pathways.Large quantities of proinflammatory cytokines are released during the complicated pathophysiological process of sepsis, which causes inflammatory reactions throughout the body and promotes its progression. 23Additionally, the various antiinflammatory cytokines released into the circulation may induce immunosuppression, subsequently leading to many lymphocytes undergoing apoptosis. 24The NEUT increases sharply during sepsis because neutrophils react rapidly to microbial infection.These neutrophils then migrate to the affected area, but they have also transitioned from powerful antibacterial protectants to potentially dangerous mediums that can cause tissue damage and organ dysfunction. 25More than 40 years ago, thrombocytopenia and sepsis were first shown to be related. 26In patients with sepsis, thrombocytopenia is a potent prognostic indicator that is considered to arise from platelet activation and consumption. 27,28Because the NEUT and PLT in the numerator and lymphocytes are included in the denominator, a higher neutrophil or PLT or a lower LYMPH will result in a higher SII value.

Characteristics
The SII was associated with the prognosis of patients with hepatocellular carcinoma after curative resection in the beginning. 29][32] Meanwhile, most studies have shown that a higher SII is associated with the occurrence and poor prognosis of sepsis. 21,33However, a retrospective study showed that not only is a higher SII associated with the death of critically ill patients with sepsis, but a lower SII also led to an increased risk of short-term death. 22Low SII levels theoretically signal that the body may be suffering from significant inflammation and immune suppression disorder.However, intestinal obstruction patients who are about to undergo surgical treatment rarely experience these conditions before surgery.The SII is also a potential biomarker for other diseases.Man Xu et al. reported in a retrospective cohort study of 13,929 middle-aged and elderly people that SII can be used as a useful indicator to clarify the interaction between thrombocytosis and immune inflammation in the occurrence and development of cerebral vascular disease in middle-aged and elderly people. 346][37] A higher SII has also been associated with an increased risk of POCD, 38 rheumatoid arthritis, 39 and postoperative pulmonary complications. 40he PLT, neutrophil, and LYMPHs could all be examined routinely and easily in patients undergoing selective and emergency procedures, making the marker available to doctors in our daily practice.Additionally, SII can easily be integrated into hospital information systems and EHRs, allowing it to be used as a clinical decision-making support tool for patients with postoperative intestinal obstruction.Preoperative SII may present anesthesiologists with diagnostic and prognostic evidence to identify sepsis in patients undergoing intestinal obstruction surgery, allowing them to better avoid and treat it.It should be clarified that preoperative SII evaluation only begins when patients have determined the need for surgery.SII is not a tool for determining the timing of surgery, it is used to quickly identify high-risk patients who are prone to sepsis after intestinal obstruction surgery.Preoperative use of antibiotics and anti-inflammatory drug can improve the systemic inflammatory response status of patients and reduce SII levels, which helps to reduce the risk of postoperative sepsis in such patients.Intraoperative fluid resuscitation for high-risk patients can also reduce the risk of postoperative sepsis.This will also help with research into how the immune-inflammatory response can lead to sepsis, which will provide a better understanding of the pathophysiology of a range of dysfunctions produced by sepsis.However, it should be clarified that this study only confirmed that SII ＞1792.19 may be F I G U R E 3 Receiver operating curve of the systemic inflammatory index.The systemic immune inflammation index for postoperative sepsis had an AUC of 0.610 (p = .012).
F I G U R E 4 Forest plot for subgroup analysis.Unadjusted model: using the univariate logistic model; adjusted model: using multivariate logistic regression including the predefined confounders of age, duration of surgery, and white blood cell count; P for interaction: result of the interaction analysis.ASA, American Society of Anesthesiologists physical status classification system; ALB, albumin; CR, creatinine; HGB, hemoglobin; WBC, white blood cell count.a potential risk factor for postoperative sepsis in patients with intestinal obstruction, but failed to confirm that SII can predict the incidence of postoperative sepsis, despite its AUC of 0.610 and sensitivity of 56.7% indicates moderate predictive or diagnostic performance.Due to the limitations of retrospective study designs, we could not determine the precise impact of anti-inflammatory therapy on patients with the same condition.Further prospective clinical studies should be conducted to determine whether preoperative anti-inflammatory medication might improve patients' results and when and how to manage them.
Our study has some limitations.First, it was a single-center study with limited sample size, resulting in a small number of cases in subgroup analysis and insignificant results.This may have led to failure to identify populations in which it may be more suitable to use the SII to identify and predict postoperative sepsis in patients with intestinal obstruction.Second, only the variables present in the EHR system were used in the analysis.Therefore, it is impossible to entirely rule out additional potentially significant confounding factors.Third, although this study first discovered a correlation between preoperative SII and postoperative sepsis in patients with intestinal obstruction surgery, its AUC and sensitivity were not outstanding enough.Whether SII has better guidance value and predictive ability in a certain subgroup population (combined with preoperative diseases, preoperative intervention measures, etc.) still needs to include more cases and conduct more research.Fourth, further analysis of any correlation between SII and SOFA scores is valuable for the conclusion that SII can identify high-risk patients with sepsis.This requires further analysis in the future.Fifth, more studies are needed in the future to confirm the prognostic value of the components, as it will enhance the importance and potential use of SII as a more valuable clinical tool than its sum.Sixth, our study did not compare with other inflammatory markers, so we cannot determine if there is a better correlation between other inflammatory markers and postoperative sepsis in such patients.Finally, to investigate the effect of preoperative anti-inflammatory medication on postoperative sepsis, the findings still require further verification through prospective randomized controlled trials.
(grant No. 2023B110006) and the Young Talent Support Project of Guangzhou Association for Science and Technology (Grant No. QT20220101257).

T A B L E 2
Abbreviation: ICU, intensive care unit.