MINISTRY OF EDUCATION AND TRAINING MINISTRY OF NATIONAL DEFENCE SCIENTIFIC RESEARCH INSTITUTE OF CLINICAL MEDICINE 108 NGUYỄN VI ẾT Q UANG HIỂN RES EARC H VALUE O F PRESEPS IN IN DIAGNOS IS AND PROGNOS IS O F SEVERE S EPS IS AND SEPTIC SHOC K PATIENTS Spe cialism: Aneathesia and resuscitation Code : 62720122 MEDICAL DOC TO RAL THESIS Hà Nội, 2019 Science Instructors: Ass.Prof PhD Le T hi Viet Hoa Ass.Prof PhD Nguyen Phuong Dong Opponent 1: ……………………………………………… Opponent 2: ……………………………………………… Opponent 3: ……………………………………………… The thesis has been defended at University-level Thesis Evaluation Council held in Scientific research Institute of clinical medicine 108 At, (hour), ./ /2019 (date) This thesis may be found at: - National Library - Library of Scientific research Institute of clinical medicine 108 INTRO DUCTIO N The urgency of thesis Septic shock is an acute circulatory failure that reduces the perfusion of organs, promotes systemic inflammatory response and prolonged metabolic disorders, leading to multiple organ failure and death Early identification and effective management reduce mortality in septic shock Biomarkers have an important role in diagnosis as well as prognosis of septic shock Currently there are many biomarkers that help diagnose and prognosis patients with septic shock such as CRP, PCT , presepsin Presepsin is a soluble molecule of CD14, created when the body responds to infection Many studies show that presepsin is valuable in early diagnosis (up to hours after infection) sepsis and septic shock Some meta-analyzes have demonstrated that presepsin has better value than P CT in the diagnosis and prognosis of sepsis and sept ic shock In Vietnam, no studies to evaluated the role of plasma presepsin in diagnosis and prognosis sepsis and septic shock The meaning of thesis The thesis contributes new to theory and practice of using biomarkers presepsin in the direction of diagnosis and prognosis in patients with severe sepsisand septic shock, thereby allowing the use of presepsin as a tool diagnosis, monitoring and prognosis for patients with severe sepsisand septic shock This is the first study in Vietnam Obje ctives - Evaluate concentration changes and the role of plasma presepsin in diagnosing severe sepsisand septic shock - Det ermine the correlation of plasma presepsin with some scales and biomarkers assessing the severity in prognosis of mortality on patients with severe sepsis and septic shock Structure of thesis The thesis has 112 pages including pages of introduction and objectives, 35 pages of overview, research subjects and methods 22 pages, results 22 pages, discussion 22 pages, conclusions and recommendations pages The thesis has 27 tables, 10 pictures and 11 charts The thesis uses 134 references, in which 13 Vietnamese documents, 121 English documents, 03 articles related to the topic have been published Chapte r :OVERVIEW 1.1 Septic shock In 1991, the first consensus conference between the American College of Chest Physicians and the Society of Critical Care Medicine agreed to provide the following definitions of sepsis, severe sepsis and septic shock: Infection: A bacterial infection characterized by a local inflammatory response to microorganisms (bacteria, viruses, fungi, and parasites) or invasion of sterile tissue by these microorganisms Systemic Inflammatory Reponse Syndrome (SIRS): is a global inflammatory response for many different agents characterized by t he presence of at least of the following criteria: - Body temperature> 380C or 90 times / minute; - Breathing frequency> 20 times / minute or PaCO2 12G / L or 10% - Septicemia (sepsis): Systemic inflammatory response syndrome + Positive infection or blood culture positive Severe sepsis: sepsis conditions that manifest organ dysfunction, hypofusion or hypotension Septic shock is a serious infection with prolonged hypotension (systolic blood pressure mmol / l - The conference agreed not to use systemic inflammatory response syndrome in the diagnosis of sepsis and septic shock but instead replaced with qSOFA scale and SOFA 1.2 Role of presepsin in infe ction 1.2.1 The origin and structure of presepsin Presepsin (sCD14-ST ) is a 13 kDa peptide created by soluble protein hydrolysis of the cluster of differentiation CD14 (sCD14) There are forms of soluble CD14 in plasma of healthy people with very low concentrations including molecules weighing 49 KDa and 55 KDa sCD14 plays an important role in mediating immune response to LPS of cells without clustering CD14 such as endothelial and epithelial cells 1.2.2 Kinetics of presepsin Presepsin concentration increased within hours after bacterial infection, peaked after hours This feature makes presepsin molecule become the biomarker that responds quickly to infection when compared with PCT and CRP with activation time of 6-12 hours and 12-24 hours, respectively Plasma half-life is 4-5 hours, compared with 12-24 hours for PCT , allowing early evaluation as well as treatment efficacy Presepsin is mainly excreted by the kidneys 1.2.3 Value of plasma presepsin in infe ction Presepsin is a new biomarker who plays a role in early identification of sepsis and is valuable in the prognosis of severity and mortality in patients with severe sepsis and septic shock 1.2.4 Studies on plasma presepsin in infe ctions on global and Vietnam - Research on the concentration and role of plasma presepsin in diagnosing severe sepsis and septic shock - Research on the role of plasma presepsin in prognosis of patients with severe sepsis and septic shock - In Vietnam, presepsin has also been used in diagnosing infections in some hospitals such as Hue Cent ral Hospital However, there has not been any specific study evaluating the role of plasma presepsin in diagnosis as well as prediction patients with severe sepsis and septic shock Chapte r MATERIALS AND METHO D 2.1 Materials: research on 80 patients with severe sepsis and sept ic shock treated in anesthesia Department of Anesthesia A - Hue Central Hospital from 01/2015 to 01/2017 2.1.1 Criteria for selecting: Patients> 18 years old, having sufficient evidence to diagnose severe sepsis and shock with American College of Chest Physicians and the Society of Critical Care Medicine standard (2001) 2.1.2 Exclusion criteria: Patients or family members not agree to participate in the study, patients with malignancy, HIV infection, immunosuppressive drugs, end-stage chronic renal failure 2.1.3 Standard type out of the study: Patients who are eligible for admission to study but must end treatment because the patient's fam ily wishes 2.2 Research methodology 2.2.1 Study design: Prospective study, cross-sectional description, vertical monitoring and comparison with control group 2.2.2 Calculating example size According to research by Ali (2016) [15], prognostic mortality value of presepin's is 0.89 We choose the current mortality rate of severe sepsis and septic shock based on the study of T ran Xuan Thinh (2016) [11] of 31% n = (FP + T N)/(1-p)= 37,6/0,69 = 54,5 In summary, we need sample size> 55 patients to meet the requirements of the research goal 2.2.3 Re search de vices - Multi-funct ional hemodynamic monitoring system - Blood gas machine, Cardiopulmonary X-ray machine in bed - Presepsin kit 2.2.4 Evaluation crite ria 2.2.4.1 Evaluation criteria for study objectives The e valuation crite ria for obje ctive 1: assessing the concentration change and the role of plasma presepsin in diagnosing severe sepsis and septic shock - Plasma presepsin concentration in patients with severe sepsis and septic shock + Det ermination of plasma presepsin concentration at t he study time: presepsin concentration right after diagnosis of severe sepsis and septic shock (T0), after 24 hours (T1) and after days (T7) + Change the plasma presepsin concentration by age, sex, bacterial culture results (negative or positive) at the time of study + Det ermination of changes in plasma presepsin concentrations at the study t ime between the living and death groups - Value of plasma presepsin in differential diagnosis of severe sepsisand septic shock + Compare presepsin, PCT and CRP concentrations at T0 between severe sepsis and septic shock groups + Analysis of ROC curves of presepsin compared with PCT and CRP in differential diagnosis between severe sepsis and septic shock The e valuation crite ria for obje ctive 2: determining the correlation of plasma presepsin with the severity score in the prognosis of mortality in patients with severe sepsisand septic shock - Evaluate the correlation of presepsin, PCT and CRP with severity scales in patients with severe sepsis and septic shock + Det ermining the correlation between presepsin, PCT and CRP with severity scales (APACHE II, SOFA, SAPS 2, MODS) + Det ermine the correlation between presepsin, PCT and CRP with plasma lactate - Determine t he mortality prognostic value of plasma presepsin in patients with severe sepsis and septic shock + Analysis of ROC curve in presepsin mortality prognosis at the time of study + Analyzing the ROC curve in presepsin’s mortality prognosis at time T0 compared with APACHE II, SOFA, SAPS and MODS scale + Analysis of the ROC curve in presepsin mortality prognosis in combination with the severity scales (SOFA, APACHE II, SAPS 2, MODS) at time T0 compared to presepsin alone + Analyzing the ROC curve in presepsin mortality prognosis compared to the biomarkers of PCT, CRP and lactate at the time of T0 + Multivariat e regre ssion analysis to identify independent risk factors in mort ality prognosis in patients with severe sepsis and septic shock 2.2.4.2 Other evaluation criteria - Det ermine general characteristics of age, gender, bacteria access path, circulation, rating scale - Describe characteristics of hematological testing, liver, kidney, blood sugar, lact ate, blood gas, IL-6, microbiological characteristics - T reatment results (number of days resuscitation, mechanical ventilation rate, mechanical ventilation time, rate and death) 2.2.4 Study proce dure 2.2.4.1 The time of conducting research - T ime T 0: time of diagnosis of severe sepsis and septic shock - Time T1: 24 hours after diagnosis of severe sepsis and septic shock - Time T7: days after diagnosis of severe sepsis and septic shock 2.2.4.2 Acquiring patients into the study: Patients who are eligible for diagnosis or are eligible for inclusion in the control group are enrolled in the study after obtaining the consent of the patient, or the patient's family members if the patient is not alert 2.2.5.3 Prepare research sheets for each patient 2.2.5.4 Applying a treatment regimen for severe sepsis and septic shock according to SSC 2012 guidelines 2.2.5.5 Monitor and record research parameters - Continue to monitor and treat patients daily The clinical symptoms were recorded and the presepsin, PCT , IL-6 and lactate tests were performed at times T0 (diagnosis time), T1 (after 24 hours) and T (after days) - Monitor patients' response to treatment, record treatment results such as mechanical ventilation time, resuscitation period, hospital stay - Patients who die: are patients who die in hospitals or patients who are too heavy to be sent home 2.3 Data processing: The data are processed according to the medical statistical calculations, SPSS software 20.0 10 Signific ant presepsin levels in death groups were signif icantly higher than in the live group Presepsin concentrat ion in mortality group increased gra dually from time T0 to T In the living group, presepsin concentration decreases 3.2.2 The role of pl asma pres psin in differe ntial diagnosis of severe se psis and septic shock Ta ble 3.15 Plasma conce ntrations of pres e psin, CRP and PCT in the group of severe sepsis and septic shock at T0 Group Severe sepsis Se ptic shock (n = 38) (n = 42) Median Median p Inde x (Qu artile) (Qu artile) 313,7 512,6 Pre sepsin < 0,01 (177,1 – 494,2) (288,6 – 1986,0) (pg/ml) 4,0 15,3 < 0,05 PC T (ng/ml) (1,6 – 15,5) (3,9 – 62,5) 110,6 162,0 > 0,05 CRP (mg/L) (51,1 – 180,2) (60 – 212,5) Plasma concentrations of presepsin and PCT in septic shock groups were significantly higher than those in severe infections There were no statistically significant differences in CRP levels in the two groups Table 3.16: Diagnosis value of severe sepsis and septic shock of presepsin compare d with PCT and CRP at T0 Inde x Cut- Sensitivity Spe cificity AUC KTC p off 95% 0,59 Pre sepsin 495 57,1% 78,9% 0,7 p < 0,01 (pg/ml) 0,82 0,54 – PC T 6,1 72,5% 63,9% 0,66 p < 0,05 (ng/ml) 0,78 0,46 – CRP 183,7 40% 83,3% 0,59 p > 0,05 (mg/l) 0,72 11 Figure 3.2: Values of plasma presepsin, CRP and PCT in differential diagnosis of NKN and SNK - Plasma presepsin concentration has a differential diagnostic value of severe sepsis and sept ic shock, the area under ROC 0.7 curve (p 60% T he concentration of CRP is not valid in differential diagnosis of NKN and SNK 3.3 Value of plasma presepsin in prognosis in patients with severe sepsis and se ptic shock 3.3.1 Value of plasma presepsin in prognosis of seve rity in patients with seve re sepsis and septic shock - T he concentration of plasma presepsin at diagnosis time of severe sepsis and sept ic shock is positively correlated, the average level of SOFA scale (r = 0.39; p 0,05 Presepsin + APACHE II (AUC = 0,87) p < 0,05 (*) Presepsin + SOFA (AUC = 0,77) p > 0,05 Presepsin + SAPS (AUC = 0,82) p > 0,05 Presepsin + MODS (AUC = 0,78) p > 0,05 PCT (AUC = 0,52) p < 0,05 (*) CRP (AUC = 0,53) p < 0,05 (*) 14 Lactat (AUC = 0,65) p > 0,05 (*) Test DeLong - The concentration of presepsin at T0 has an area under the curve (AUC) in the prognosis of death equivalent to the scale of APACHE II, SOFA, SAPS 2, MOD S and Lactat (p> 0.05) When combining Presepsin with APACHE II scale, the area under the ROC curve in t he mortality prognosis is higher than presepsin alone (p 22 score 0,009 8,4 1,7– 41,9 Pre sepsin > 488,1 (pg/ml) 0,01 5,7 1,4 – 22,5 SO FA > score 0,56 1,3 0,3 – 6,5 Lactat > 5,4 (mmol/L) 0,14 2,8 0,7– 11,3 Plasma presepsin concentration and APACHE II score are independent predictors of mortality in patients with severe infections and septic shock Chapte r 4: DISCUSSIO N 4.1 General characte ristics of research patients 4.1.1 Gene ral characteristics of the re search te am Charact eristics of age and gen der in the research group: T he average a ge of patients in the study group is 59.0 ± 20.0 years Men in the research group accounted for 60% Compared with other studies: According to Bui T hi Huong Giang (2016), the average age in sept ic shock group is 55.6 ± 16.5 years, male 15 accounts for 67.9% T ran Xuan T hinh (2016), men account for 63%, the average age is 59.8 ± 19.8 years old (t he lowest is 18 years and the highest is 98 years old) Characteristics of infection origins: Infection from the gastrointestinal tract accounts for the highest percentage of 73.8% Respiratory tract infections accounted for 7.5% Compared with other studies: Pham Thi Ngoc Thao (2013), gastrointestinal infections accounted for a major proportion of 56.1%, respiratory tract 21.1%, urinary tract 7.3% and unknown route of entry accounting for 7.3% T he mortality rate in the respiratory tract infections group was 61.5% Sturgess et al (2010) found the main source of infection from the gastrointestinal tract (38%) and respiratory tract (33%) Characteristics of pathogenic bacteria: Positive blood culture rate of 27.5%, in which gram-negative bacteria dominate (77.3%) Compared with other studies: Pham T hi Ngoc Thao (2013), positive blood culture rate 33.9%, gram negative bacteria accounted for 83.8%, gram positive bacteria mainly Staphylococcus aureus accounted for 13.5% Bui Thi Huong Giang (2016), blood culture rate is 21% positive Treatment results: T he rate of mechanical ventilation in the study group accounted for 57.5%, the average mechanical ventilation time was 3.7 days In the subgroup analysis, the rate of mechanical ventilation in t he group of septic shock was 78.6% higher t han that of the severe sepsis group of 34.2% The average duration of treatment in the intensive care unit was 12.4 days, the hospital mortality rate was 28.8% In the group of septic shock, the death rate was 42.9% higher than the severe infection group of 13.2% Compared with other research: Tran Xuan Thinh (2016): the proportion of patients with mechanical ventilation accounted for 42%, the average hospital stay was 18.7 days, the hospital death rate 16 was 31% Bui T hi Huong Giang (2016): patients with septic shock, hospital death rate of 42% [4] Sturgess DJ et al (2010): 76% of patients had mechanical ventilation at admission, the average resuscitation time was 12.5 ± 12.3 days, the hospital stay was 29.6 ± 29.3 days and the rate was hospit al death rate is 29% Klouche et al (2016), the average resuscitation period is days and the hospital mortality rate is 28% 4.2 Variation in concentration and role of plasma presepsin in the diagnosis of severe infections and septic shock 4.2.1 Plasma presepsin concentration in patients with severe infections and septic shock Plasma presepsin concentration in the study group: The highest presepsin plasma concentration in the study group at the time of diagnosis was 420 pg / mL ( quart ile 227.3 - 722.8 pg / ml) and decreased gradually at T 345.1 pg / mL (quart ile 194.9 - 591.1 pg / ml), and T7 was 279.4 pg / mL (quartile 180.6 - 568.3 pg / ml), there was a difference in presepsin concentration at T compared to T (p