Clinical Characteristics Of Cardiac Dysfunction In Sepsis And The Intervention Mechanism Of Tongguan Capsule

Objective1.Through retrospective study,analyze the clinical data of sepsis cardiac dysfunction,and explore the risk factors of sepsis cardiac dysfunction.2.To evaluate the risk factors of death in septic patients with cardiac dysfunction and analyze the hemodynamic characteristics of septic patients with cardiac dysfunction through retrospective study.3.Summarize the syndrome differentiation rules of sepsis cardiac dysfunction through the analysis of TCM syndrome elements.4.Based on autophagy,to explore the mechanism of Tongguan capsule,a traditional Chinese medicine for supplementing qi and activating blood circulation,to improve cardiac dysfunction in sepsis,and to provide a new way for the prevention and treatment of cardiac dysfunction in sepsis.Methods1.Clinical research(1)From January 2017 to January 2022,there were 435 consecutive patients who met the sepsis 3.0 diagnostic criteria in the Department of Critical Care Medicine of the General Hospital of Guangdong Hospital of Traditional Chinese Medicine.According to the exclusion criteria,401 patients were finally included,including 336 patients with sepsis cardiac dysfunction(SIMD)and 65 patients with sepsis non cardiac dysfunction(NoSIMD).Collect relevant variables of baseline data.The clinical outcomes of the two groups were compared.Single factor and multi factor logistic regression analysis were conducted for statistically significant indicators to analyze the risk factors of SIMD.Subgroup analysis was carried out to find the risk factors of sepsis with simple left ventricular systolic dysfunction,simple left ventricular diastolic dysfunction and mixed dysfunction by single factor and multiple factor logistic regression analysis.(2)From January 2017 to January 2022,336 patients with septic cardiac dysfunction(SIMD)were admitted to the Department of Severe Medicine of the General Hospital of Guangdong Province.They were divided into death group(96 cases)and survival group(240 cases)according to whether they survived for 28 days.Univariate and multivariate COX regression analysis was conducted for the indicators with statistical difference between the death group and the survival group.24 of 336 patients with SIMD were monitored by transpulmonary thermodilution(PiCCO)to evaluate the cardiac function of SIMD patients from four aspects:cardiac systolic function,preload,afterload,extravascular pulmonary water exudation,and statistical analysis was made.(3)To analyze the data of 401 sepsis patients who continuously stayed in the Department of Critical Care Medicine of the General Hospital of Guangdong Province from January 2017 to January 2022.Refer to Zhu Wenfeng’s Syndrome Differentiation,extract the TCM diagnosis and syndrome differentiation of patients on admission from the electronic medical record system,and screen the standardized four diagnosis information.To analyze the distribution,combination and correlation characteristics of TCM syndrome elements.2.Animal experiment:The rat model of sepsis induced by lipopolysaccharide(LPS)was used.The rats were divided into five groups:control group(CON),model group(LPS),Tongguan capsule group(LPS+TGC),rapamycin group(LPS+TGC+RA),chloroquine group(LPS+TGC+CQ).Tongguan capsule was used to prevent for 7 days,and then 24h after modeling,the rats’ behavior changes,living conditions,cardiac ultrasound,changes of serum myocardial injury markers,cardiac pathological sections,cardiac electron microscopy and protein blot analysis were used to detect the expression level of related proteins.3.StatisticsSPSS 22.0 statistical software package was used to establish the database.The measurement data conforming to the normal distribution were tested by independent sample t test,and the measurement data nonconforming to the normal distribution between the two groups were tested by u test.The chi square test was used to compare the disordered counting data between the two groups,and the non parametric test was used for the non normal measurement data and grade counting data.Single factor and multi factor logistic regression were used for risk factors.The survival analysis used the K-M survival curve.Time related survival analysis was performed using univariate and multivariate COX regression analysis.When P<0.05,there is statistical difference.Results1.Clinical research(1)A case-control study of cardiac dysfunction in sepsisThe in-hospital mortality and 28 day mortality of 401 sepsis patients were 31.4%and 28.4%,respectively.In SIMD group,the in-hospital mortality was 31.8%,and the 28 day mortality was 28.6%.In NoSIMD group,the in-hospital mortality was 29.2%,and the 28 day mortality was 27.7%.Compared with NoSIMD group,SIMD group had fewer hospital stay,more invasive mechanical ventilation(P<0.05)and CRRT treatment(P<0.05).In terms of risk factors of SIMD,single factor logistic regression analysis showed that hypertension,heart failure,stroke,heart rate and systolic blood pressure were related to the occurrence of SIMD patients(P<0.05).In the multivariate logistic regression model,the above indicators were not risk factors of SIMD(P>0.05).Subgroup analysis of SIMD risk factors and single factor logistic regression analysis showed that left ventricular end systolic diameter(LVESD)was related to systolic dysfunction(P<0.05);Single factor logistic regression analysis showed that systolic blood pressure(SBP),mean blood pressure(MAP)and ejection fraction(EF)were correlated with the occurrence of diastolic dysfunction(P;Single factor logistic regression analysis showed that heart failure,malignant tumor,SBP,DBP,MAP,left ventricular end diastolic diameter(LVEDD),LVESD,total cholesterol(TC),high-density lipoprotein(HDL),and serum creatinine(Cr)were associated with mixed dysfunction(P,The increase of LVEDD value will increase the risk of mixed dysfunction(P<0.05),and the increase of TC value will increase the risk of mixed dysfunction(P<0.05).(2)Risk factors and hemodynamic characteristics of cardiac dysfunction death in sepsisSIMD patients were divided into death group and control group according to whether they died on the 28th day.Single factor COX regression analysis showed that the risk factors for death included APACHE2,SOFA,shock,dopamine use,norepinephrine use,adrenaline use,blood lactic acid(Lac),creatine kinase isoenzyme(CK-MB),and C-reactive protein(CRP).Therefore,high APACHE2 score,high SOFA score,shock occurrence,dopamine use,norepinephrine use,epinephrine use,high Lac level,high CK-MB level,and high CRP level are risk factors for death of septic cardiac dysfunction.The HR of SBP,diastolic pressure(DBP),MAP,TC,HDL,and low-density lipoprotein(LDL)were less than 1,so they were protective factors.Therefore,the increase of SBP,DBP and MAP are protective factors,while the increase of TC level,HDL level and LDL level are protective factors.Multivariate COX regression analysis showed that the effects of increased Lac level,CRP level and adrenaline use on survival time were statistically significant.In terms of hemodynamic monitoring,in patients with SIMD,the cardiac index(CI)of the survivors showed a downward trend within 72 hours,and gradually returned to normal after 72 hours;In the death group,CI was basically normal within 72 hours,and began to decline after 72 hours.The stroke volume index(SVI)was lower than the normal reference value throughout the observation period,but gradually recovered.After 72 hours,SVI of patients in the survival group continued to recover,while SVI of patients in the death group showed a downward trend.The whole heart ejection fraction(GEF)was lower than the normal reference value throughout the observation period,but gradually recovered.After 72 hours,GEF in the survival group continued to recover,while GEF in the death group showed a downward trend.The initial cardiac function index(CFI)of SIMD patients was low,especially in the survival group.The whole heart end diastolic volume index(GEDVI)and intrathoracic blood volume index(ITBVI)of SIMD patients were within the normal range,regardless of the survival group or the death group.Compared with the patients in the death group,the SVV of the patients in the survival group was small,and the difference was not statistically significant(P>0.05).During the observation period,the peripheral circulation resistance index(SVRI)of patients with SIMD was at a high level,and gradually decreased to the normal range 72 hours later.In the survival group,the resistance of peripheral circulation was relatively high and gradually decreased to the normal range on the 5th day.In the death group,the peripheral circulation resistance was still low even if vasoactive drugs were used.The extravascular lung water index(EVLWI)of SIMD patients was more than 10ml/kg,while the pulmonary vascular permeability index(PVPI)was less than 3,which belonged to cardiogenic pulmonary edema.The peak period of this pulmonary edema is on the 3rd and 4th days.Compared with the death group,the pulmonary edema in the survival group was more obvious,but decreased earlier.(3)TCM Syndrome Elements of Sepsis Heart DysfunctionThe distribution of TCM syndrome elements in patients with SIMD is different from that in patients with NoSIMD.The top ten TCM syndrome elements of SIMD patients are blood stasis,phlegm,fire and heat,spleen,lung,qi deficiency,dampness,kidney,meridians,and water stagnation.The top ten TCM syndrome elements of NoSIMD patients are blood stasis,phlegm,fire and heat,spleen,dampness,qi deficiency,lung,kidney,water stagnation and meridians.Blood stasis syndrome was the most frequent syndrome element in the two groups,followed by phlegm turbidity and fire heat.Qi deficiency is the most frequent deficiency syndrome element in the two groups.The organs with the highest frequency were spleen,lung and kidney.The meridians are also the most common TCM syndrome elements of sepsis.In the combination of syndrome elements of patients in SIMD and NoSIMD groups,the proportion of three syndrome elements is the highest(30.36%and 36.92%).The most common combination of syndrome elements is meridian+phlegm+blood stasis+qi deficiency.From the correlation of syndrome elements,the three combinations of syndrome elements with the highest degree of support in SIMD patients are lung→phlegm,qi deficiency→blood stasis,lung,spleen→ phlegm,and their confidence levels are 94.82%,81.65%,98.82%respectively.The three combinations of syndrome elements with the highest degree of support in NoSIMD patients were lung→sputum,kidney→spleen,dampness,spleen→blood stasis,and their confidence levels were 93.33%,80.00%,81.82%respectively.2.Animal experiment:24 hours after LPS injection,the model rats showed sluggish reaction,curling up,fatigue,yellow and lusterless hair color,cyanosis,abdominal distension and feces excretion.In terms of survival rate,the survival rate of rats in LPS+TGC group was higher than that in LPS group(90%vs.60%).In terms of myocardial injury,compared with CON group,the levels of serum troponin Ⅰ(cTn-Ⅰ and type B brain natriuretic peptide(BNP)in LPS group increased(P<0.05),and the levels of serum cTn-Ⅰ and BNP in LPS+TGC group decreased(P<0.05).In terms of cardiac function,compared with CON group,left ventricular ejection fraction(LVEF)and left ventricular short axis shortening fraction(LVFS)in LPS group were significantly increased,and left ventricular end systolic volume(LVESV)and left ventricular end diastolic volume(LVEDV)were significantly decreased(P<0.05).Compared with LPS group,LPS+TGC group showed improvement of LVEDV and LVESV,recovery.of LVEF and LVFS 24 hours after LPS modeling(P<0.05).In terms of pathological damage,obvious pathological changes were observed in myocardium of LPS group,and the pathological damage of LPS+TGC group was the least.Electron microscopy showed that the production of autophagosomes decreased in LPS group,but increased after Tongguan capsule intervention.Compared with CON group,autophagy related proteins Atg5,Beclinl and LC3-Ⅱ in LPS group were down regulated,suggesting that LPS can inhibit autophagy in septic rats.LC3-Ⅱ,Atg5 and Beclinl of rats in LPS+TGC group increased,indicating that Tongguan capsule enhanced autophagy in myocardial cells to respond to the stimulation of LPS.Even with Tongguan capsule,the levels of Atg5,Beclinl and LC3-Ⅱ in LPS+TGC+CQ group decreased.Conclusion1.Different types of sepsis cardiac dysfunction have different risk factors.Elevated blood lactate and C-reactive protein levels increase the risk of death in patients with septic cardiac dysfunction.2.The heart funion of patients with sepsis cardiac dysfunction decreased and gradually recovered after 72 hours.3.The occurrence of cardiac dysfunction in sepsis is mostly due to blood stasis caused by deficiency,which is closely related to the lung and spleen.4.Animal experiments showed that Tongguan capsule alleviated cardiac insufficiency caused by sepsis by inducing autophagy.