Effect of perioperative probiotic therapy on postoperative cognitive dysfunction after non-cardiac surgery under general anesthesia in elderly patients with frailty

Effect of perioperative probiotic therapy on postoperative cognitive dysfunction after non-cardiac surgery under general anesthesia in elderly patients with frailty | 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 Article Effect of perioperative probiotic therapy on postoperative cognitive dysfunction after non-cardiac surgery under general anesthesia in elderly patients with frailty Fu-Mei Wang, Li Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7241135/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, especially those with preoperative frailty. The incidence of preventive and/or therapeutic strategies remains limited. Objective To evaluate the effect of perioperative probiotic therapy on postoperative cognitive dysfunction in frail elderly patients undergoing non-cardiac surgery under general anesthesia. Methods After obtaining ethical approval and written informed consent, this randomised double-blind and placebo-controlled trial included 100 elderly frail patients scheduled for elective general anesthesia non-cardiac surgery were recruited from our hospital. Patients were assigned to receive either probiotics or placebo from admission to discharge. Participants (n = 100) were treated with probiotics or placebo from 2 day before surgery to 5 days after surgery, and participants were assessed by Mini-Mental State Examination (MMSE) before taking the drug and at 1, 7 and 14 days after surgery. The primary endpoint was the incidence of postoperative cognitive dysfunction, defined as a 3-point decrease in MMSE score from baseline to postoperatively. Secondary endpoints included postoperative sleep quality, gastrointestinal function recovery, and length of postoperative hospital stay. Results Compared with the control group, there was no significant difference in MMSE score before taking the drugs in the experimental group, and the MMSE score was higher on the first and seventh days after surgery, the incidence of postoperative cognitive dysfunction was reduced (On the first postoperative day, 11 of 50 patients [22%] vs. 21 of 50 patients [42%] P = 0.03, and on the seventh postoperative day, 4 of 50 patients [8%] vs. 12 of 50 patients [24%]P = 0.03), the postoperative exhaust time was shortened, and the sleep was improved (P < 0.05). Conclusion Perioperative probiotic therapy can reduce the incidence of postoperative cognitive dysfunction and improve the postoperative sleep state of frail elderly patients undergoing general anesthesia non-cardiac surgery. Health sciences/Cardiology Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Health care Health sciences/Medical research Postoperative cognitive dysfunction Probiotics Frailty Noncardiac surgery General anesthesia Figures Figure 1 Figure 2 Figure 3 1. Introduction Postoperative cognitive dysfunction (POCD) refers to the objective decline of cognitive ability after surgery compared with preoperative cognitive function [1] .It is a common complication in elderly patients after surgery, which is closely related to the prolongation of hospital stay and the increase in medical costs in elderly patients, and may even cause a significant increase in long-term disability or mortality [2][3] .Frailty is a clinical syndrome associated with aging, primarily characterized by non-specific dementia, reduced physiological reserves in multiple systems, and decreased resistance to stressors [4–8] .Numerous studies have shown that a state of frailty is associated with various adverse health outcomes, such as falls, fractures, hospitalization or placement in nursing homes, disability, poor quality of life, and dementia [9–14] .It is also strongly linked to an increased risk of death, cardiovascular disease, respiratory disease, and an increased risk of death due to cancer [15] .As a result, frailty is considered an emerging public health challenge [16] .Population aging brings challenges related to age-related diseases like frailty and cognitive dysfunction [17–21] ,leading to increased dependency in later life in many countries [22] ,placing a heavy burden on the elderly, families, and society. Current research indicates that frail patients who undergo surgery have higher rates of postoperative complications, longer hospital stays, greater disability rates, and higher mortality compared to non-frail patients. [23]−[33] .In elderly patients aged 65 and older undergoing elective non-cardiac surgery under general anesthesia, the incidence of postoperative cognitive dysfunction or psychiatric disorders is higher in frail patients compared to non-frail patients [34][35] .However, in recent years, with the aging population and advancements in surgical techniques, an increasing number of frail elderly and critically ill patients are undergoing more complex surgeries, which makes POCD an increasingly important clinical issue [36] ,posing significant challenges for perioperative management.Therefore, improving and preventing postoperative cognitive dysfunction in frail patients has become one of the key goals in elderly healthcare. A large number of studies have shown that the gut microbial system has great potential to influence host health [37] ,and the concept of the microbiome-gut-brain axis is gaining increasing attention [38] .As age advances and frailty progresses, the gut microbiota also undergoes changes, such as a reduction in beneficial bacteria and shifts in dominant microbial specie [39],[40] .These changes can affect the central nervous system through the microbiome-gut-brain axis,which in turn affects cognitive function [41],[42] .Gut microbiota have been shown to be associated with aging-related diseases [43] ,and are inextricably linked to cognitive function [44] ,and have emerged as a powerful target for improving the health status of older adults. Probiotics are active microbial preparations that regulate the host's gut microecology by competitive colonization. Some probiotics have been proven to influence behavior and the central nervous system through the microbiome-gut-brain axis. These probiotics help protect cognitive function in patients with Alzheimer's disease [45] ,and improve depression or anxiety in healthy human volunteers [46] ,These findings suggest that perioperative probiotic therapy may serve as a preventive and corrective measure for postoperative cognitive impairment, leading this study to investigate the impact of perioperative probiotic use on cognitive dysfunction after general anesthesia non-cardiac surgery in elderly frail patients. 2. Patients and methods 2.1. Study design This was a prospective, randomised, double-blind, and placebo- controlled trial which included frail patients over 65 years old who are scheduled to undergo non-cardiac surgery under general anesthesia in the Third People's Hospital of Zigong City from 2024.08 to 2025.03. But one doctor who was not involved in the experimental intervention was retained to closely monitor patient conditions. If any patient experienced intolerance or other issues, the treatment would be promptly terminated to ensure patient safety.The study was designed to assess the superiority of a probiotic intervention compared to placebo in the prevention of postoperative cognitive impairment. This study protocol has been approved by the Research Ethics Committee of the Third People's Hospital of Zigong City(Approval No.: IEC-AF/SW(Research)-10-2.1), and all research was performed in accordance with relevant guidelines/regulations, and registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn;ChiCTR2400087698 ). Written informed consent was obtained from all patients or their legal representatives.MMSE scored fellows were trained and qualified. 2.2. Patients The study focused on elderly frail patients aged ≥ 65 years who were scheduled for general anesthesia non-cardiac surgery at Zigong Third People's Hospital. The main inclusion criteria were: patients with an ASA score of II-III and a preoperative Frailty Assessment Scale score of 3–5; no gender restrictions; and an estimated surgery duration of 2–4 hours. Exclusion criteria included: (1) participants who refused to participate; (2) those with dementia, mental disorders, or communication barriers (such as severe speech, hearing, or vision impairments); (3) patients with significant organ failure, myocardial infarction, cerebral hemorrhage, cerebral infarction, brain tumor, or stroke; (4) patients undergoing cardiac, intracranial, or emergency surgery; (5) patients who had undergone more than one surgery during their hospital stay; (6) patients who used antibiotics, probiotics, or gastric motility drugs within 10 days before admission; (7) patients with chronic constipation; (8) patients participating in other clinical trials or not cooperating with treatment; (9) other reasons unsuitable for this study. Removal criteria included: (1) severe adverse events during surgery that could not be corrected by medication; (2) refusal to continue cooperation due to various reasons; (3) incomplete data collection; (4) ICU stay exceeding 24 hours or mechanical ventilation time exceeding 24 hours; (5) death. 2.3. Randomisation and masking Random numbers are generated at a 1:1 scale by a researcher who is not involved in data management or statistical analysis using SPSS 27.0 software. The randomization results were sealed in an envelope and kept until the end of the study. During the study, recruited patients received either probiotics or placebo from nurses, depending on the allocation of random numbers. During the study phase, the investigators responsible for follow-up, the surgeon, and the patient were blinded to treatment allocation. However, a doctor who does not participate in the experimental intervention should be retained, and the patient's condition should be closely monitored, and if the patient is intolerant or other conditions, it will be terminated in time to ensure the patient's safety. 2.4. Drugs Eligible patients were randomly divided into probiotic group (group P) and control group (group C). Group P received probiotic treatment (probiotics are "Bifidobacterium Lactobacillus Triple Viable Tablets", 0.5 g/tablet, each tablet containing Bifidobacterium longum viable bacteria should not be less than 0.5x10^7 CFU, and Lactobacillus bulgaricus and Streptococcus thermophilus viable bacteria should not be less than 0.5x10^6 CFU. Group C was treated with placebo (the placebo was a starch pill provided by the nutrition canteen of our hospital, and its appearance and smell were not significantly different from probiotics). The time is from 2 days before the decision to 5 days after surgery, and the dosage is 4 tablets at a time, twice a day (the dosage is recommended according to the drug instructions and the "Chinese Microbial Preparation Clinical Application Guidelines"). 2.5. Outcomes The primary endpoint was the incidence of postoperative cognitive dysfunction on days 1, 7 and 14 after surgery. Cognitive status was determined using the Mini-Mental State Examination (MMSE) before taking the drug and on days 1, 7, and 14 postoperatively. Based on previous studies, postoperative cognitive impairment is defined as a reduction of 3 points or more in the MMSE score between medication and surgery [47–50] . Secondary endpoints included postoperative sleep quality, recovery of gastrointestinal function. The patient's sleep quality was compared with the preoperative one, and it was divided into three grades: good, fair, and poor. Postoperative gastrointestinal function recovery assessment includes the number of hours (h) of first flatus, number of days of first liquid diet (d), number of days of first solid diet (d), and number of days of first bowel movement (d). Other endpoints included length of hospital stay after surgery, type of antibiotic therapy and duration of use after surgery, postoperative complications, and ICU admission. 2.6. Sample size and statistical analysis According to the results of literature search, the POCD rate in placebo group was about 10–40%, and half of them were in probiotics group. Assuming α = 0.05, β = 0.01, according to the formula, and considering sample drop-out, a total of 100 patients (n1 = n2 = 50) were selected to detect the difference, as follows: N1 and N2 represent the sample size of two groups, Zα and Zβ represent the standard normal deviation of α and β, P1 and P2 represent the incidence of two groups ‾P =(P1 + P2)/2。 The analysis was conducted using SPSS27.0 software. All statistical tests are conducted by two-sided test, and the difference tested will be considered to be statistically significant if P < 0.05.The primary outcome measure will be statistically analyzed by chi-square or Fisher exact probability. Secondary outcome measures will be tested by group t-test. The description of quantitative indicators will calculate the mean, standard deviation, median, minimum, and maximum. The number and percentage of patients are used to statistically describe the demographic information, sex,degree of education, combined diseases, preoperative frailty score, type of surgery,use of postoperative analgesia pump,etc. According to the numerical characteristics of variables, t-test is used to compare the quantitative data of age, BMI ,MMSE score between the two groups and so on; chisquare test/exact probability method is used to compare the categorical variables such as gender, medical history,combined diseases and symptoms, physical examination and so on.P < 0.05 was considered statistically significant. 3. Results 3.1. Demographic and perioperative variables A total of 100 patients were initially enrolled after passing the assessment and obtaining informed consent. These 100 participants were equally randomized to either the probiotic group or the control group (n = 50 per group), and all completed the study. None of the patients experienced side effects associated with probiotic treatment. There was no statistically significant difference in baseline characteristics between the two groups (P > 0.05) .(Table 1 ). Table 1 Baseline characteristics of patients. Probiotics(n = 50) Control(n = 50) P-value Age(yr) 73.26 ± 6.73 74.30 ± 5.64 0.4 Sex 0.74 Male 36(72%) 32(64%) Female 14(28%) 18(36%) BMI (kg/m²) 21.35 ± 3.37 22.90 ± 3.44 0.12 Education 0.93 Illiteracy 11 15 Elementary school 17 14 Middle school 18 17 High school 4 4 Preoperative frailty score 0.64 Three score 39(78%) 37(74%) Four score 11(22%) 13(26%) Preoperative MMSE score 25.98 ± 1.86 25.82 ± 1.76 0.66 Preoperative complications Angiocardiopathy 42(84%) 45(90%) 0.37 Diabetes mellitus 14(28%) 13(26%) 0.82 Disease of lung 20(40%) 18(36%) 0.68 Liver and kidney disease 6(12%) 5(10%) 0.74 BMI: body mass index;All data are presented as number (%) or mean ± SD. There were no significant differences in the type of surgery, length of operation and anesthesia,total intraoperative infusion, blood transfusion, intra-operative antibiotic, and incidence of intraoperative complications between the two groups(P > 0.05)(Table 2 ). Table 2 Intraoperative indicators of patients. Probiotics(n = 50) Control(n = 50) P-value Type of surgery 0.97 Orthopaedics surgery 16(32%) 17(34%) Thoracic surgery 17(34%) 16(32%) Gastrointestinal surgery 17(34%) 17(34%) Length of operation (min) Orthopaedics surgery 150.12 ± 20.39 153.71 ± 21.50 0.63 Thoracic surgery 152.35 ± 27.08 151.25 ± 23.22 0.90 Gastrointestinal surgery 162.47 ± 30.68 167.47 ± 25.23 0.61 Length of anesthesia (min) Orthopaedics surgery 203.37 ± 36.39 207.18 ± 32.13 0.75 Thoracic surgery 212.94 ± 35.68 210.81 ± 35.08 0.86 Gastrointestinal surgery 217.18 ± 47.19 223.00 ± 31.49 0.67 Total intra-operative infusion (ml) Orthopaedics surgery 1618.75 ± 316.69 1664.71 ± 524.04 0.76 Thoracic surgery 1629.41 ± 362.31 1640.62 ± 292.81 0.92 Gastrointestinal surgery 1830.88 ± 375.37 1858.82 ± 413.91 0.84 Intra-operative blood transfusion Orthopaedics surgery 1(6.2%) 1(5.9%) 1 Thoracic surgery 0 0 1 Gastrointestinal surgery 1(5.9%) 0 1 Intra-operative antibiotic 0.24 Not used 3(6%) 3(6%) β-lactam 37(74%) 35(70%) quinolones 10(20%) 12(24%) Intraoperative complications 1(2%) 0 1 All data are presented as number (%) or mean ± SD. There was no statistical difference in the use rate of postoperative analgesia pump, the type and time of postoperative antibiotics, and the incidence of postoperative complications between the two groups (P > 0.05), but there was a statistical difference in the length of hospital stay after orthopedic and gastrointestinal surgery (P < 0.05).(Table 3 ) Table 3 Postoperative indicators of patients. Probiotics(n = 50) Control(n = 50) P-value Postoperative analgesic pumps Orthopaedics surgery 12(75%) 12(71%) 0.54 Thoracic surgery 14(82%) 13(81%) 0.64 Gastrointestinal surgery 11(65%) 12(71%) 0.59 Postoperative antibiotic 0.23 β-lactam 40(80%) 38(76%) quinolones 10(20%) 12(24%) Postoperative antibiotic duration(d) Orthopaedics surgery 2.50 ± 0.52 2.47 ± 0.51 0.16 Thoracic surgery 5.18 ± 0.73 5.12 ± 0.81 0.85 Gastrointestinal surgery 4.76 ± 0.56 4.82 ± 0.73 0.79 Postoperative complications Orthopaedics surgery 1(6.2%) 1(5.9%) 1 Thoracic surgery 2(11.8%) 1(6.2%) 1 Gastrointestinal surgery 3(17.6%) 2(11.8%) 1 Postoperative hospital stay duration (d) Orthopaedics surgery 6.94 ± 0.68 7.88 ± 0.86 0.01 Thoracic surgery 7.47 ± 1.12 7.87 ± 1.09 0.30 Gastrointestinal surgery 9.76 ± 1.09 10.47 ± 0.80 0.04 All data are presented as number (%) or mean ± SD. 3.2. Postoperative cognitive impairment Mean MMSE score on admission did not differ significantly between the probiotic and control groups (25.98 ± 1.86 vs.25.82 ± 1.76, P = 0.66) (Fig. 1 ). Compared with the preoperative period, the incidence of cognitive dysfunction in the probiotic group on the first and seventh postoperative days was lower than that in the control groupFig. 2, and there was no significant difference on the 14th postoperative day.The incidence of postoperative cognitive impairment in the probiotic group (4% vs.8%) (Fig. 3 ). 3.3. postoperative sleep quality, and gastrointestinal function recovery Compared with the control group, the sleep was improved, and the postoperative exhaust time was shortened,the incidence of POCD decreased in the experimental group 1 and 7 days after surgery. (P < 0.05)(Table 4 ) Table 4 Indicators of postoperative recovery. Probiotics(n = 50) Control(n = 50) P-value Admitted to the ICU after surgery (number, percentage) Orthopaedics surgery 2(12.5%) 2(11.8%) 0.67 Thoracic surgery 2(11.8%) 3(18.8) 0.66 Gastrointestinal surgery 3(17.6%) 4(25.3%) 0.5 Sleep quality 0.04 Good 34(68%) 22(44%) Average 9(18%) 13(28%) Poor 7(14%) 15(28%) Gastrointestinal function recovered Hours to first flatus Non-gastrointestinal surgery 5.45 ± 0.99 6.94 ± 0.98 < 0.01 Gastrointestinal surgery 9.00 ± 1.25 10.67 ± 1.19 < 0.01 Days to first fluid diet Non-gastrointestinal surgery 1.10 ± 0.30 1.09 ± 0.30 0.97 Gastrointestinal surgery 3.32 ± 0.88 3.78 ± 1.11 0.17 Days to first solid diet Non-gastrointestinal surgery 2.35 ± 0.55 2.44 ± 0.50 0.54 Gastrointestinal surgery 6.37 ± 1.77 6.16 ± 1.54 0.71 Days to first defecation Non-gastrointestinal surgery 1.71 ± 0.59 1.91 ± 0.64 0.21 Gastrointestinal surgery 4.32 ± 0.75 4.33 ± 1.19 0.96 All data are presented as number (%) or mean ± SD. 4. Discussion The WHO's "World Report on Ageing and Health" shows that the world population is aging severely, with a significant increase in the elderly population. It is projected that by 2050, the number of elderly people will double [51] 。As a country's population continues to age, the demand for surgical services is gradually increasing. Elderly patients typically require higher levels of care and more meticulous perioperative management compared to younger patients, leading to higher healthcare costs [52] 。With the progression of population aging, the proportion of frail patients undergoing surgical treatment is gradually increasing, and the incidence of postoperative cognitive dysfunction remains high. Current research has shown that postoperative cognitive dysfunction is closely related to neuroinflammation, oxidative stress, β-amyloid deposition, and excessive phosphorylation of Tau protein [53],[54] 。 Surgical trauma and anesthetic drugs (such as opioids and inhalation anesthetics) can disrupt the blood-brain barrier, activate microglia, release pro-inflammatory factors (such as IL-6, TNF-α), and exacerbate central inflammatory responses through gut microbiota dysbiosis [55] 。 Thespecific pathogenesis of frailty are not fully understood, but studies have shown that frailty is closely associated with malnutrition, sarcopenia, and gastrointestinal inflammation [56],[57] , and is closely related to gut microbiota dysbiosis [58] 。Frailty and POCD are inseparable from intestinal dysbiosis, therefore, using probiotics or prebiotics to improve gut microbiota dysbiosis may significantly reduce the incidence and severity of POCD in preoperative frail patients. There are hundreds of millions of doses of microorganisms in the human gut, which are collectively referred to as the gut microbiota system.The gut microbiota has tremendous potential in influencing host health, playing significant roles in digestion and absorption, cognitive function, inflammation, and immune regulation [37],[59] 。This has led to the concept of the "gut-brain axis" [38] , which refers to the human "second brain" formed by the intestines, the gut nervous system, and gut microbiota.The gut microbiota is closely related to cognitive function; it can synthesize various neurotransmitters or modulators that are absorbed into the bloodstream and cross the blood-brain barrier to regulate the activity of glial cells and neurons [60] 。Dysbiosis of the gut microbiota can affect the levels of these neurotransmitters in the central nervous system, thereby impacting cognitive function [61] 。These influencing factors include, but are not limited to, surgical procedures, antibiotics, anesthetics, intraoperative hemodynamic instability, hypoxemia, etc [54] 。Animal experiments have shown that abnormal intestinal microbiota composition after abdominal surgery may contribute to the occurrence and development of postoperative delirium. Therapeutic strategies that target the gut microbiota can provide a new alternative to postoperative delirium treatment [62] 。Another study showed that perioperative probiotic therapy could significantly improve the incidence of cognitive dysfunction after cardiac surgery in mice [63] 。Hu et al. showed that probiotics could be used in the perioperative period to prevent the development of POCD and improve speech and memory in older patients undergoing hip or knee arthroplasty [64] ;Wang et al. found that the use of oral probiotics perioperatively may prevent postoperative cognitive impairment in elderly patients after non-cardiac surgery by limiting peripheral inflammation and stress responses [50] 。 Currently, some research reports have explored the link between gut microbiota and frailty, suggesting that certain gut microbiota may be another risk factor for frailty. Compared to healthy elderly individuals, those who are frail exhibit differences in gut microbial abundance and dominant bacterial species. The abundance of Prevotella and Enterobacteriaceae is notably lower in frail elderly individuals, while beneficial bacteria such as Sutterella, Bifidobacterium, Lactobacillus, and Klebsiella are more abundant in non-frail elderly individuals [65] 。A study involving 85 community-dwelling adults showed that modules of coexisting microbial genera, including Ruminococcus, Erysipeloides, and Enterobacteriaceae, were positively correlated with frailty indice [66] ,and so on.Frail elderly patients often experience dysbiosis of gut microbiota, with the abundance of Bacteroides decreasing with age, whereas Prevotella increases in contrast [67] , Dysbiosis can exacerbate frailty state [43] ,creating a vicious cycle. Probiotics may help reduce inflammation levels in the elderly, enhance anti-inflammatory effects, improve frailty status, and cognitive function [43], [68][69] 。 Intestinal dysbiosis is inseparable from frailty and postoperative cognitive dysfunction, and perioperative improvement of intestinal dysbiosis may improve the incidence and severity of postoperative cognitive dysfunction in frail patients. According to our results, the incidence and severity of postoperative cognitive dysfunction in the probiotic group were significantly lower than those in the placebo group on the first and seventh days after surgery, suggesting that perioperative probiotic therapy can improve the incidence of cognitive dysfunction after elective general anesthesia noncardiac surgery in frail patients. Moreover, the data showed that perioperative probiotic treatment can also improve patients' sleep status and shorten the time of exhaust. According to the admission time of our patients, in our experiment, a protocol from 2 days before surgery to 5 days after surgery was used, which not only ensured the effective cultivation of probiotics, but also ensured the accuracy of patients taking drugs in the hospital, and reduced the relevant heterogeneity. However, this study has limitations: it is a single-center trial with a small sample size, and no fecal or other biological samples were collected for microbial monitoring., and the follow-up time of cognitive function is limited to 14 days after surgery, and no long-term follow-up is performed. However, according to the data search, this is also the first time that the effect of perioperative probiotic therapy on postoperative cognitive dysfunction has been verified in frail populations. In conclusion, we believe that perioperative probiotic therapy can reduce the incidence and severity of postoperative cognitive dysfunction in elderly frail patients undergoing general anesthesia non-cardiac surgery. It can also improve sleep quality to some extent, shorten postoperative gas elimination time, and does not affect the quality of postoperative recovery. Perioperative probiotic therapy, by regulating gut microbiota and neuroinflammation at multiple targets, holds promise as a new strategy to improve postoperative cognitive function in elderly frail patients. Future research should combine relevant basic and biochemical studies, use more experimental data, optimize intervention protocols, and verify their long-term safety to ultimately enhance the overall prognosis of elderly surgical patients. Declarations Conflicts of interest The authors declare no competing interests. Correspondence All data generated or analyzed by this study are included in this paper and its supplemental information, which can be obtained from the first author( [email protected] ). Funding This study was not supported by a fund. Author Contribution Wang wrote the main manuscript text prepared figures and tables. Liu was responsible for revising and directing this article.All authors reviewed the manuscript. Data Availability All data generated or analyzed by this study are included in this paper and its supplemental information, which can be obtained from the first author（ [email protected] ）. References A L E ,S B S .Postoperative Cognitive Dysfunction and Noncardiac Surgery.[J].Anesthesia and analgesia,2018,127(2):496-505. A L E ,V T M C ,Ruquan H , et al. Anaesthetic depth and delirium after major surgery: a randomised clinical trial. [J]. British journal of anaesthesia, 2021, 127 (5): 704-712. E ,K. A ,B. S , et al. 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1","display":"","copyAsset":false,"role":"figure","size":102741,"visible":true,"origin":"","legend":"\u003cp\u003eThere was no difference in MMSE scores between the preoperative probiotic group and the control group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7241135/v1/ac7ebd8d0d5039b6c090204e.png"},{"id":97654502,"identity":"80cfce1b-5a00-435c-91c9-e5043eccf4db","added_by":"auto","created_at":"2025-12-08 07:00:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":186155,"visible":true,"origin":"","legend":"\u003cp\u003eChange in cognitive function score on the first and seventh postoperative days compared to preoperatively.If the difference is ≥ 3 points, it is judged to have postoperative cognitive dysfunction. （A）Scatter plot of changes in MMSE score on the first postoperative day compared to preoperatively. On the first day after surgery, the incidence of POCD in the probiotic group was significantly lower than that in the control group（11/50 patients [22%] vs. 21/50 patients [42%], P =0.03）.(B）Scatter plot of changes in MMSE score on the seventh postoperative day compared to preoperatively. On the seventh day after surgery, the incidence of POCD in the probiotic group was significantly lower than that in the control group（4/50 patients [8%] vs. 12/50 patients [24%], P =0.03）.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7241135/v1/1c9dc97bdf8094216ff2983c.png"},{"id":97654498,"identity":"e7339a64-c1c9-468d-b7cf-250d647fc76b","added_by":"auto","created_at":"2025-12-08 07:00:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32767,"visible":true,"origin":"","legend":"\u003cp\u003eChange in cognitive function score on the 14th postoperative days compared to preoperatively.If the difference is ≥ 3 points, it is judged to have postoperative cognitive dysfunction. On the 14th day after surgery, there was no significant difference in the incidence of postoperative cognitive dysfunction between the probiotic group and the control group.（2/50 patients [4%] vs. 4/50 patients [8%], P =0.67）.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7241135/v1/c92a33f097470836337076bc.png"},{"id":97678834,"identity":"f9a0032d-4f61-4d99-ba59-f297de499d73","added_by":"auto","created_at":"2025-12-08 09:56:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1090614,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7241135/v1/c010eece-6ed1-42df-86eb-c58a64dee812.pdf"},{"id":97673794,"identity":"6ce9a099-c43c-4a92-88cf-c7ee53dcf157","added_by":"auto","created_at":"2025-12-08 09:41:25","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":32031,"visible":true,"origin":"","legend":"","description":"","filename":"rawdata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7241135/v1/79f269dfe4feb38258b3c798.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of perioperative probiotic therapy on postoperative cognitive dysfunction after non-cardiac surgery under general anesthesia in elderly patients with frailty","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePostoperative cognitive dysfunction (POCD) refers to the objective decline of cognitive ability after surgery compared with preoperative cognitive function\u003csup\u003e[1]\u003c/sup\u003e.It is a common complication in elderly patients after surgery, which is closely related to the prolongation of hospital stay and the increase in medical costs in elderly patients, and may even cause a significant increase in long-term disability or mortality\u003csup\u003e[2][3]\u003c/sup\u003e.Frailty is a clinical syndrome associated with aging, primarily characterized by non-specific dementia, reduced physiological reserves in multiple systems, and decreased resistance to stressors \u003csup\u003e[4\u0026ndash;8]\u003c/sup\u003e.Numerous studies have shown that a state of frailty is associated with various adverse health outcomes, such as falls, fractures, hospitalization or placement in nursing homes, disability, poor quality of life, and dementia\u003csup\u003e[9\u0026ndash;14]\u003c/sup\u003e.It is also strongly linked to an increased risk of death, cardiovascular disease, respiratory disease, and an increased risk of death due to cancer\u003csup\u003e[15]\u003c/sup\u003e.As a result, frailty is considered an emerging public health challenge\u003csup\u003e[16]\u003c/sup\u003e.Population aging brings challenges related to age-related diseases like frailty and cognitive dysfunction\u003csup\u003e[17\u0026ndash;21]\u003c/sup\u003e,leading to increased dependency in later life in many countries\u003csup\u003e[22]\u003c/sup\u003e,placing a heavy burden on the elderly, families, and society. Current research indicates that frail patients who undergo surgery have higher rates of postoperative complications, longer hospital stays, greater disability rates, and higher mortality compared to non-frail patients.\u003csup\u003e[23]\u0026minus;[33]\u003c/sup\u003e.In elderly patients aged 65 and older undergoing elective non-cardiac surgery under general anesthesia, the incidence of postoperative cognitive dysfunction or psychiatric disorders is higher in frail patients compared to non-frail patients\u003csup\u003e[34][35]\u003c/sup\u003e.However, in recent years, with the aging population and advancements in surgical techniques, an increasing number of frail elderly and critically ill patients are undergoing more complex surgeries, which makes POCD an increasingly important clinical issue\u003csup\u003e[36]\u003c/sup\u003e,posing significant challenges for perioperative management.Therefore, improving and preventing postoperative cognitive dysfunction in frail patients has become one of the key goals in elderly healthcare.\u003c/p\u003e\u003cp\u003eA large number of studies have shown that the gut microbial system has great potential to influence host health\u003csup\u003e[37]\u003c/sup\u003e,and the concept of the microbiome-gut-brain axis is gaining increasing attention\u003csup\u003e[38]\u003c/sup\u003e.As age advances and frailty progresses, the gut microbiota also undergoes changes, such as a reduction in beneficial bacteria and shifts in dominant microbial specie\u003csup\u003e[39],[40]\u003c/sup\u003e.These changes can affect the central nervous system through the microbiome-gut-brain axis,which in turn affects cognitive function\u003csup\u003e[41],[42]\u003c/sup\u003e.Gut microbiota have been shown to be associated with aging-related diseases\u003csup\u003e[43]\u003c/sup\u003e,and are inextricably linked to cognitive function\u003csup\u003e[44]\u003c/sup\u003e,and have emerged as a powerful target for improving the health status of older adults. Probiotics are active microbial preparations that regulate the host's gut microecology by competitive colonization. Some probiotics have been proven to influence behavior and the central nervous system through the microbiome-gut-brain axis. These probiotics help protect cognitive function in patients with Alzheimer's disease\u003csup\u003e[45]\u003c/sup\u003e,and improve depression or anxiety in healthy human volunteers\u003csup\u003e[46]\u003c/sup\u003e,These findings suggest that perioperative probiotic therapy may serve as a preventive and corrective measure for postoperative cognitive impairment, leading this study to investigate the impact of perioperative probiotic use on cognitive dysfunction after general anesthesia non-cardiac surgery in elderly frail patients.\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. \u003cem\u003eStudy design\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eThis was a prospective, randomised, double-blind, and placebo-\u003c/p\u003e\u003cp\u003econtrolled trial which included frail patients over 65 years old who are scheduled to undergo non-cardiac surgery under general anesthesia in the Third People's Hospital of Zigong City from 2024.08 to 2025.03. But one doctor who was not involved in the experimental intervention was retained to closely monitor patient conditions. If any patient experienced intolerance or other issues, the treatment would be promptly terminated to ensure patient safety.The study was designed to assess the superiority of a probiotic intervention compared to placebo in the prevention of postoperative cognitive impairment. This study protocol has been approved by the Research Ethics Committee of the Third People's Hospital of Zigong City(Approval No.: IEC-AF/SW(Research)-10-2.1), and all research was performed in accordance with relevant guidelines/regulations, and registered with the Chinese Clinical Trial Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.chictr.org.cn;ChiCTR2400087698\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn;ChiCTR2400087698\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Written informed consent was obtained from all patients or their legal representatives.MMSE scored fellows were trained and qualified.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. \u003cem\u003ePatients\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eThe study focused on elderly frail patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years who were scheduled for general anesthesia non-cardiac surgery at Zigong Third People's Hospital. The main inclusion criteria were: patients with an ASA score of II-III and a preoperative Frailty Assessment Scale score of 3\u0026ndash;5; no gender restrictions; and an estimated surgery duration of 2\u0026ndash;4 hours. Exclusion criteria included: (1) participants who refused to participate; (2) those with dementia, mental disorders, or communication barriers (such as severe speech, hearing, or vision impairments); (3) patients with significant organ failure, myocardial infarction, cerebral hemorrhage, cerebral infarction, brain tumor, or stroke; (4) patients undergoing cardiac, intracranial, or emergency surgery; (5) patients who had undergone more than one surgery during their hospital stay; (6) patients who used antibiotics, probiotics, or gastric motility drugs within 10 days before admission; (7) patients with chronic constipation; (8) patients participating in other clinical trials or not cooperating with treatment; (9) other reasons unsuitable for this study. Removal criteria included: (1) severe adverse events during surgery that could not be corrected by medication; (2) refusal to continue cooperation due to various reasons; (3) incomplete data collection; (4) ICU stay exceeding 24 hours or mechanical ventilation time exceeding 24 hours; (5) death.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. \u003cem\u003eRandomisation and masking\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eRandom numbers are generated at a 1:1 scale by a researcher who is not involved in data management or statistical analysis using SPSS 27.0 software. The randomization results were sealed in an envelope and kept until the end of the study. During the study, recruited patients received either probiotics or placebo from nurses, depending on the allocation of random numbers. During the study phase, the investigators responsible for follow-up, the surgeon, and the patient were blinded to treatment allocation. However, a doctor who does not participate in the experimental intervention should be retained, and the patient's condition should be closely monitored, and if the patient is intolerant or other conditions, it will be terminated in time to ensure the patient's safety.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. \u003cem\u003eDrugs\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eEligible patients were randomly divided into probiotic group (group P) and control group (group C). Group P received probiotic treatment (probiotics are \"Bifidobacterium Lactobacillus Triple Viable Tablets\", 0.5 g/tablet, each tablet containing Bifidobacterium longum viable bacteria should not be less than 0.5x10^7 CFU, and Lactobacillus bulgaricus and Streptococcus thermophilus viable bacteria should not be less than 0.5x10^6 CFU. Group C was treated with placebo (the placebo was a starch pill provided by the nutrition canteen of our hospital, and its appearance and smell were not significantly different from probiotics). The time is from 2 days before the decision to 5 days after surgery, and the dosage is 4 tablets at a time, twice a day (the dosage is recommended according to the drug instructions and the \"Chinese Microbial Preparation Clinical Application Guidelines\").\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. \u003cem\u003eOutcomes\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eThe primary endpoint was the incidence of postoperative cognitive dysfunction on days 1, 7 and 14 after surgery. Cognitive status was determined using the Mini-Mental State Examination (MMSE) before taking the drug and on days 1, 7, and 14 postoperatively. Based on previous studies, postoperative cognitive impairment is defined as a reduction of 3 points or more in the MMSE score between medication and surgery\u003csup\u003e[47\u0026ndash;50]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSecondary endpoints included postoperative sleep quality, recovery of gastrointestinal function. The patient's sleep quality was compared with the preoperative one, and it was divided into three grades: good, fair, and poor. Postoperative gastrointestinal function recovery assessment includes the number of hours (h) of first flatus, number of days of first liquid diet (d), number of days of first solid diet (d), and number of days of first bowel movement (d).\u003c/p\u003e\u003cp\u003eOther endpoints included length of hospital stay after surgery, type of antibiotic therapy and duration of use after surgery, postoperative complications, and ICU admission.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6. \u003cem\u003eSample size and statistical analysis\u003c/em\u003e\u003c/h2\u003e\u003cp\u003eAccording to the results of literature search, the POCD rate in placebo group was about 10\u0026ndash;40%, and half of them were in probiotics group. Assuming α\u0026thinsp;=\u0026thinsp;0.05, β\u0026thinsp;=\u0026thinsp;0.01, according to the formula, and considering sample drop-out, a total of 100 patients (n1\u0026thinsp;=\u0026thinsp;n2\u0026thinsp;=\u0026thinsp;50) were selected to detect the difference, as follows:\u003c/p\u003e\u003cp\u003e\u003cimg 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width=\"555\" height=\"89\"\u003e\u003c/p\u003e\u003cp\u003eN1 and N2 represent the sample size of two groups, Zα and Zβ represent the standard normal deviation of α and β, P1 and P2 represent the incidence of two groups\u003c/p\u003e\u003cp\u003e\u0026oline;P =(P1\u0026thinsp;+\u0026thinsp;P2)/2。\u003c/p\u003e\u003cp\u003eThe analysis was conducted using SPSS27.0 software. All statistical tests are conducted by two-sided test, and the difference tested will be considered to be statistically significant if P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.The primary outcome measure will be statistically analyzed by chi-square or Fisher exact probability. Secondary outcome measures will be tested by group t-test. The description of quantitative indicators will calculate the mean, standard deviation, median, minimum, and maximum. The number and percentage of patients are used to statistically describe the demographic information, sex,degree of education, combined diseases, preoperative frailty score, type of surgery,use of postoperative analgesia pump,etc. According to the numerical characteristics of variables, t-test is used to compare the quantitative data of age, BMI ,MMSE score between the two groups and so on; chisquare test/exact probability method is used to compare the categorical variables such as gender, medical history,combined diseases and symptoms, physical examination and so on.P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Demographic and perioperative variables\u003c/h2\u003e\u003cp\u003e A total of 100 patients were initially enrolled after passing the assessment and obtaining informed consent. These 100 participants were equally randomized to either the probiotic group or the control group (n\u0026thinsp;=\u0026thinsp;50 per group), and all completed the study. None of the patients experienced side effects associated with probiotic treatment. There was no statistically significant difference in baseline characteristics between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) .(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003eBaseline characteristics of patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProbiotics(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge(yr)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73.26\u0026thinsp;\u0026plusmn;\u0026thinsp;6.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e74.30\u0026thinsp;\u0026plusmn;\u0026thinsp;5.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36(72%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32(64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18(36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21.35\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEducation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIlliteracy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElementary school\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMiddle school\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHigh school\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative frailty 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=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThree score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39(78%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37(74%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFour score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11(22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13(26%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative MMSE score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative complications\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAngiocardiopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42(84%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45(90%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13(26%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease of lung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20(40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18(36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver and kidney disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6(12%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5(10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.74\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\u003eBMI: body mass index;All data are presented as number (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e\u003cp\u003eThere were no significant differences in the type of surgery, length of operation and anesthesia,total intraoperative infusion, blood transfusion, intra-operative antibiotic, and incidence of intraoperative complications between the two groups(P\u0026thinsp;\u0026gt;\u0026thinsp;0.05)(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIntraoperative indicators of patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProbiotics(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\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 surgery\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\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16(32%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17(34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16(32%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17(34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of operation (min)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e150.12\u0026thinsp;\u0026plusmn;\u0026thinsp;20.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e153.71\u0026thinsp;\u0026plusmn;\u0026thinsp;21.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e152.35\u0026thinsp;\u0026plusmn;\u0026thinsp;27.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e151.25\u0026thinsp;\u0026plusmn;\u0026thinsp;23.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e162.47\u0026thinsp;\u0026plusmn;\u0026thinsp;30.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e167.47\u0026thinsp;\u0026plusmn;\u0026thinsp;25.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of anesthesia (min)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e203.37\u0026thinsp;\u0026plusmn;\u0026thinsp;36.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e207.18\u0026thinsp;\u0026plusmn;\u0026thinsp;32.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e212.94\u0026thinsp;\u0026plusmn;\u0026thinsp;35.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e210.81\u0026thinsp;\u0026plusmn;\u0026thinsp;35.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e217.18\u0026thinsp;\u0026plusmn;\u0026thinsp;47.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e223.00\u0026thinsp;\u0026plusmn;\u0026thinsp;31.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal intra-operative infusion (ml)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1618.75\u0026thinsp;\u0026plusmn;\u0026thinsp;316.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1664.71\u0026thinsp;\u0026plusmn;\u0026thinsp;524.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1629.41\u0026thinsp;\u0026plusmn;\u0026thinsp;362.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1640.62\u0026thinsp;\u0026plusmn;\u0026thinsp;292.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1830.88\u0026thinsp;\u0026plusmn;\u0026thinsp;375.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1858.82\u0026thinsp;\u0026plusmn;\u0026thinsp;413.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntra-operative blood transfusion\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntra-operative antibiotic\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\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot used\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-lactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37(74%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35(70%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003equinolones\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntraoperative complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\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\u003eAll data are presented as number (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e\u003cp\u003eThere was no statistical difference in the use rate of postoperative analgesia pump, the type and time of postoperative antibiotics, and the incidence of postoperative complications between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), but there was a statistical difference in the length of hospital stay after orthopedic and gastrointestinal surgery (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePostoperative indicators of patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProbiotics(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative analgesic pumps\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12(75%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(71%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13(81%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11(65%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(71%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative antibiotic\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\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eβ-lactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40(80%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38(76%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003equinolones\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative antibiotic duration(d)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative complications\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(11.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(17.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(11.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative hospital stay duration (d)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.04\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\u003eAll data are presented as number (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Postoperative cognitive impairment\u003c/h2\u003e\u003cp\u003eMean MMSE score on admission did not differ significantly between the probiotic and control groups (25.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.86 vs.25.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76, P\u0026thinsp;=\u0026thinsp;0.66) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Compared with the preoperative period, the incidence of cognitive dysfunction in the probiotic group on the first and seventh postoperative days was lower than that in the control groupFig. 2, and there was no significant difference on the 14th postoperative day.The incidence of postoperative cognitive impairment in the probiotic group (4% vs.8%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3. postoperative sleep quality, and gastrointestinal function recovery\u003c/h2\u003e\u003cp\u003eCompared with the control group, the sleep was improved, and the postoperative exhaust time was shortened,the incidence of POCD decreased in the experimental group 1 and 7 days after surgery. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05)(Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\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\u003eIndicators of postoperative recovery.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProbiotics(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdmitted to the ICU after surgery (number, percentage)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrthopaedics surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(11.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(11.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(17.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(25.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSleep quality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34(68%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22(44%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAverage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13(28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePoor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7(14%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15(28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal function recovered\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHours to first flatus\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-gastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDays to first fluid diet\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-gastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDays to first solid diet\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-gastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDays to first defecation\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-gastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.96\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\u003eAll data are presented as number (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe WHO's \"World Report on Ageing and Health\" shows that the world population is aging severely, with a significant increase in the elderly population. It is projected that by 2050, the number of elderly people will double\u003csup\u003e[51]\u003c/sup\u003e。As a country's population continues to age, the demand for surgical services is gradually increasing. Elderly patients typically require higher levels of care and more meticulous perioperative management compared to younger patients, leading to higher healthcare costs\u003csup\u003e[52]\u003c/sup\u003e。With the progression of population aging, the proportion of frail patients undergoing surgical treatment is gradually increasing, and the incidence of postoperative cognitive dysfunction remains high. Current research has shown that postoperative cognitive dysfunction is closely related to neuroinflammation, oxidative stress, β-amyloid deposition, and excessive phosphorylation of Tau protein\u003csup\u003e[53],[54]\u003c/sup\u003e。 Surgical trauma and anesthetic drugs (such as opioids and inhalation anesthetics) can disrupt the blood-brain barrier, activate microglia, release pro-inflammatory factors (such as IL-6, TNF-α), and exacerbate central inflammatory responses through gut microbiota dysbiosis\u003csup\u003e[55]\u003c/sup\u003e。 Thespecific pathogenesis of frailty are not fully understood, but studies have shown that frailty is closely associated with malnutrition, sarcopenia, and gastrointestinal inflammation\u003csup\u003e[56],[57]\u003c/sup\u003e, and is closely related to gut microbiota dysbiosis\u003csup\u003e[58]\u003c/sup\u003e。Frailty and POCD are inseparable from intestinal dysbiosis, therefore, using probiotics or prebiotics to improve gut microbiota dysbiosis may significantly reduce the incidence and severity of POCD in preoperative frail patients.\u003c/p\u003e\u003cp\u003eThere are hundreds of millions of doses of microorganisms in the human gut, which are collectively referred to as the gut microbiota system.The gut microbiota has tremendous potential in influencing host health, playing significant roles in digestion and absorption, cognitive function, inflammation, and immune regulation \u003csup\u003e[37],[59]\u003c/sup\u003e。This has led to the concept of the \"gut-brain axis\" \u003csup\u003e[38]\u003c/sup\u003e, which refers to the human \"second brain\" formed by the intestines, the gut nervous system, and gut microbiota.The gut microbiota is closely related to cognitive function; it can synthesize various neurotransmitters or modulators that are absorbed into the bloodstream and cross the blood-brain barrier to regulate the activity of glial cells and neurons \u003csup\u003e[60]\u003c/sup\u003e。Dysbiosis of the gut microbiota can affect the levels of these neurotransmitters in the central nervous system, thereby impacting cognitive function\u003csup\u003e[61]\u003c/sup\u003e。These influencing factors include, but are not limited to, surgical procedures, antibiotics, anesthetics, intraoperative hemodynamic instability, hypoxemia, etc\u003csup\u003e[54]\u003c/sup\u003e。Animal experiments have shown that abnormal intestinal microbiota composition after abdominal surgery may contribute to the occurrence and development of postoperative delirium. Therapeutic strategies that target the gut microbiota can provide a new alternative to postoperative delirium treatment\u003csup\u003e[62]\u003c/sup\u003e。Another study showed that perioperative probiotic therapy could significantly improve the incidence of cognitive dysfunction after cardiac surgery in mice\u003csup\u003e[63]\u003c/sup\u003e。Hu et al. showed that probiotics could be used in the perioperative period to prevent the development of POCD and improve speech and memory in older patients undergoing hip or knee arthroplasty\u003csup\u003e[64]\u003c/sup\u003e;Wang et al. found that the use of oral probiotics perioperatively may prevent postoperative cognitive impairment in elderly patients after non-cardiac surgery by limiting peripheral inflammation and stress responses\u003csup\u003e[50]\u003c/sup\u003e。\u003c/p\u003e\u003cp\u003eCurrently, some research reports have explored the link between gut microbiota and frailty, suggesting that certain gut microbiota may be another risk factor for frailty. Compared to healthy elderly individuals, those who are frail exhibit differences in gut microbial abundance and dominant bacterial species. The abundance of Prevotella and Enterobacteriaceae is notably lower in frail elderly individuals, while beneficial bacteria such as Sutterella, Bifidobacterium, Lactobacillus, and Klebsiella are more abundant in non-frail elderly individuals\u003csup\u003e[65]\u003c/sup\u003e。A study involving 85 community-dwelling adults showed that modules of coexisting microbial genera, including Ruminococcus, Erysipeloides, and Enterobacteriaceae, were positively correlated with frailty indice\u003csup\u003e[66]\u003c/sup\u003e,and so on.Frail elderly patients often experience dysbiosis of gut microbiota, with the abundance of Bacteroides decreasing with age, whereas Prevotella increases in contrast\u003csup\u003e[67]\u003c/sup\u003e, Dysbiosis can exacerbate frailty state\u003csup\u003e[43]\u003c/sup\u003e,creating a vicious cycle. Probiotics may help reduce inflammation levels in the elderly, enhance anti-inflammatory effects, improve frailty status, and cognitive function\u003csup\u003e[43], [68][69]\u003c/sup\u003e。\u003c/p\u003e\u003cp\u003eIntestinal dysbiosis is inseparable from frailty and postoperative cognitive dysfunction, and perioperative improvement of intestinal dysbiosis may improve the incidence and severity of postoperative cognitive dysfunction in frail patients. According to our results, the incidence and severity of postoperative cognitive dysfunction in the probiotic group were significantly lower than those in the placebo group on the first and seventh days after surgery, suggesting that perioperative probiotic therapy can improve the incidence of cognitive dysfunction after elective general anesthesia noncardiac surgery in frail patients. Moreover, the data showed that perioperative probiotic treatment can also improve patients' sleep status and shorten the time of exhaust. According to the admission time of our patients, in our experiment, a protocol from 2 days before surgery to 5 days after surgery was used, which not only ensured the effective cultivation of probiotics, but also ensured the accuracy of patients taking drugs in the hospital, and reduced the relevant heterogeneity. However, this study has limitations: it is a single-center trial with a small sample size, and no fecal or other biological samples were collected for microbial monitoring., and the follow-up time of cognitive function is limited to 14 days after surgery, and no long-term follow-up is performed. However, according to the data search, this is also the first time that the effect of perioperative probiotic therapy on postoperative cognitive dysfunction has been verified in frail populations.\u003c/p\u003e\u003cp\u003eIn conclusion, we believe that perioperative probiotic therapy can reduce the incidence and severity of postoperative cognitive dysfunction in elderly frail patients undergoing general anesthesia non-cardiac surgery. It can also improve sleep quality to some extent, shorten postoperative gas elimination time, and does not affect the quality of postoperative recovery. Perioperative probiotic therapy, by regulating gut microbiota and neuroinflammation at multiple targets, holds promise as a new strategy to improve postoperative cognitive function in elderly frail patients. Future research should combine relevant basic and biochemical studies, use more experimental data, optimize intervention protocols, and verify their long-term safety to ultimately enhance the overall prognosis of elderly surgical patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of interest\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eCorrespondence\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed by this study are included in this paper and its supplemental information, which can be obtained from the first author([email protected]).\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis study was not supported by a fund.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eWang wrote the main manuscript text prepared figures and tables. Liu was responsible for revising and directing this article.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed by this study are included in this paper and its supplemental information, which can be obtained from the first author（[email protected]）.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eA L E ,S B S .Postoperative Cognitive Dysfunction and Noncardiac Surgery.[J].Anesthesia and analgesia,2018,127(2):496-505.\u003c/li\u003e\n\u003cli\u003eA L E ,V T M C ,Ruquan H , et al. Anaesthetic depth and delirium after major surgery: a randomised clinical trial. [J]. British journal of anaesthesia, 2021, 127 (5): 704-712.\u003c/li\u003e\n\u003cli\u003eE ,K. A ,B. S , et al. Acute peri-operative neurocognitive disorders: a narrative review [J]. Anaesthesia, 2022, 77 (1): 34-42.\u003c/li\u003e\n\u003cli\u003eD S H ,Shubham B ,E S H . Frailty Assessment in Animal Models. 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Journal of the American College of Nutrition, 2015, 34 (6): 459-69.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Postoperative cognitive dysfunction, Probiotics, Frailty, Noncardiac surgery, General anesthesia","lastPublishedDoi":"10.21203/rs.3.rs-7241135/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7241135/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePostoperative cognitive dysfunction (POCD) is a common complication in elderly patients, especially those with preoperative frailty. The incidence of preventive and/or therapeutic strategies remains limited.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo evaluate the effect of perioperative probiotic therapy on postoperative cognitive dysfunction in frail elderly patients undergoing non-cardiac surgery under general anesthesia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eAfter obtaining ethical approval and written informed consent, this randomised double-blind and placebo-controlled trial included 100 elderly frail patients scheduled for elective general anesthesia non-cardiac surgery were recruited from our hospital. Patients were assigned to receive either probiotics or placebo from admission to discharge. Participants (n\u0026thinsp;=\u0026thinsp;100) were treated with probiotics or placebo from 2 day before surgery to 5 days after surgery, and participants were assessed by Mini-Mental State Examination (MMSE) before taking the drug and at 1, 7 and 14 days after surgery. The primary endpoint was the incidence of postoperative cognitive dysfunction, defined as a 3-point decrease in MMSE score from baseline to postoperatively. Secondary endpoints included postoperative sleep quality, gastrointestinal function recovery, and length of postoperative hospital stay.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCompared with the control group, there was no significant difference in MMSE score before taking the drugs in the experimental group, and the MMSE score was higher on the first and seventh days after surgery, the incidence of postoperative cognitive dysfunction was reduced (On the first postoperative day, 11 of 50 patients [22%] vs. 21 of 50 patients [42%] P\u0026thinsp;=\u0026thinsp;0.03, and on the seventh postoperative day, 4 of 50 patients [8%] vs. 12 of 50 patients [24%]P\u0026thinsp;=\u0026thinsp;0.03), the postoperative exhaust time was shortened, and the sleep was improved (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePerioperative probiotic therapy can reduce the incidence of postoperative cognitive dysfunction and improve the postoperative sleep state of frail elderly patients undergoing general anesthesia non-cardiac surgery.\u003c/p\u003e","manuscriptTitle":"Effect of perioperative probiotic therapy on postoperative cognitive dysfunction after non-cardiac surgery under general anesthesia in elderly patients with frailty","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 07:00:45","doi":"10.21203/rs.3.rs-7241135/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"46981702428763496998291986567788632050","date":"2025-12-14T08:51:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-02T17:22:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"107502802693774355277762450656711792225","date":"2025-12-02T17:09:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-02T16:40:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-13T05:30:14+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-12T19:30:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-29T02:37:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-29T02:33:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f7dca35-7c62-4da8-8b52-385210f0948e","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":58999391,"name":"Health sciences/Cardiology"},{"id":58999392,"name":"Health sciences/Diseases"},{"id":58999393,"name":"Health sciences/Gastroenterology"},{"id":58999394,"name":"Health sciences/Health care"},{"id":58999395,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-12-08T07:00:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 07:00:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7241135","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7241135","identity":"rs-7241135","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}