RES EARCH VALUE OF PRESEPSIN IN DIAGNOSIS AND PROGNOSIS OF SEVERE SEPSIS AND SEPTIC SHOCK PATIENTS

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 pati

MINI STRY OF EDUCATION AND TRAINING MINISTRY OF NATIONAL DEFENCE

SCIENTIFIC RESEARCH INSTITUTE OF CLINICAL MEDICINE 108

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NGUYỄN VI ẾT Q UANG HIỂN

RES EARC H VALUE O F PRESEPS IN

IN DIAGNOS IS AND PROGNOS IS O F

SEV ER E S EPS IS AND SEPTIC SHOC K PATIEN TS

Spe cialism: Aneathesia and resuscitation

Code : 62720122

MEDICAL DOC TO RAL THESIS

Hà Nội, 2019

Science Instructors:

1 Ass.Prof PhD Le T hi Viet Hoa

2 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

INTRO DUC TIO N

1 The urgency of the sis

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 2 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

2 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

4 Structure of thesis

The thesis has 112 pages including 2 pages of introduction and objectives, 35 pages of overview, research subjects and methods 22 pages, results 22 pages, discussion 22 pages, conclusions and recommendations 3 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 1 :OVERVIEW

1.1 Se ptic 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 2 of the following criteria:

- Body temperature> 380C or <360C;

- Heart rate> 90 times / minute;

- Breathing frequency> 20 times / minute or PaCO2 <32 mmHg;

- The number of peripheral blood leukocytes> 12G / L or <4G / L

or leukocytes accounts for> 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 <90 mmHg or a decrease of more than 40 mmHg compared to the initial blood pressure of the patient) and does not respond with fluid replacement

In 2001, the consensus conference between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine proposed adding diagnostic criteria to the definitions but did not provide alternative definitions because it have not enough evidence

In 2016, European and American resuscitation experts agreed to make new updates on infection definition with four main points:

- Agree to remove the term "severe sepsis" because the word

"sepsis" itself means a serious infection

- Sepsis is defined as a life-threatening organ dysfunction due to an uncoordinated response to infection

- Diagnosis of septic shock when the patient meets the criteria for sepsis, even though the circulating volume is sufficient but still requires vasopressors to maintain the mean blood pressure ≥ 65 mmHg and accompanied by increasing the lactate serum> 2 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 2 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 mediat ing 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 2 hours after bacterial infection, peaked after 3 hours This feature makes presepsin molecule become the biomarker that responds quickly to infection when compared with PCT and CRP with act ivation 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 Vie tnam

- Research on the concentrat ion 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 Viet nam, 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 2 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: Pat ients> 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 do 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 m ust end treatm ent 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 2 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 7 days (T7) + Change the plasma presepsin concentration by age, sex, bacterial culture results (negat ive 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 plasm a 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 2 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 pat ients with severe seps is 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: 7 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 7 (after 7 days)

- Monitor patients' response to treatment, record treatment results such as mechanical ventilation time, resuscit ation 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

C HAPTER 3: RESULTS 3.1 General characte ristics in the research group

- Men account for (60%) The average age is 59.0 ± 20.0 years

- The positive blood culture rate in the research group was 27.5%, the rate of blood culture negative was 72.5% Gram negative bacteria dominate (77.3%)

-Infection from the gastrointestinal t ract accounts for a major proportion (73.8%) T he rate of mechanical ventilation is 57.5%, the hospital mortality rate is 28.8%

3.2 The concentration and role of plasma presepsin in the diagnosis of severe infe ctions and septic shock

3.2.1 Plasma pre sepsin concentration in the study group Table 3.10: Plasma presepsin concentration in the stu dy group Pre sepsin

(pg/ml)

Times

Min Max Median Quartile

T0 (n = 80) 78,8 5665,7 420 227,3– 722,8 T1 (n = 80) 75,9 5273,8 345,1 194,9 – 591,1 T7 (n = 72) * 41,9 4257,0 279,4 180,6 – 568,3

Plasma presepsin concentration was highest in the study group

at T0 and tended to decrease gradually at T7

Table 3.14 Plasma pre sepsin concentration in the survival and

de ath in hospital group Group

Time

Survival (n = 57)

Death (n = 23)

p Median

(Qu artile )

Median (Qu artile )

(216,5 – 567,2)

659,9 (423 – 2218) < 0,01

(170,0 – 409,6)

835,8 (468,3 – 1504,9) < 0,01

(138,6 – 448,6)

1033,9 (820,7 – 1578,9) < 0,01

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 7 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 se ptic sh ock

Ta ble 3.15 Plasma conce ntrations of pres e psin, CRP and PC T

in the group of se vere sepsis and se ptic sh ock at T0

Group

Inde x

Se vere sepsis (n = 38)

Se ptic shock (n = 42)

p Median

(Qu artile )

Median (Qu artile ) Pre sepsin

(pg/ml)

313,7 (177,1 – 494,2)

512,6 (288,6 – 1986,0)

< 0,01

(1,6 – 15,5)

15,3 (3,9 – 62,5)

< 0,05

(51,1 – 180,2)

162,0 (60 – 212,5)

> 0,05

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 PC T and CRP at T0

PC T

0,54 – 0,78 p < 0,05

C RP

0,46 – 0,72 p > 0,05

Figure 3.2: Values of plasma presepsin, C RP and PC T in

differen tial 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 <0.01), with a cut-off of 495 pg / ml with a sensitivity of 57.1% and specificity 78.9%

- PCT concentration has a weak differential diagnosis value (AUC 0.66), 6.1 ng / ml cut-off point has sensitivity and specificity> 60% T he concentration of CRP is not valid in differential diagnosis