Summary of medical doctoral thesis: study of the changes of serum nt probnp level and the association with low cardiac output syndrome after coronary artery bypass grafting surgery

MINISTRY OF EDUCATION MINISTRY OF DEFENCEANDTRAINING 108 INSTITUTE OF CLINICAL MEDICINE AND PHARMACY --- BUI DUC THANH STUDY OF THE CHANGES OF SERUM NT-proBNP LEVEL AND THE ASSOCIATION

MINISTRY OF EDUCATION MINISTRY OF DEFENCEANDTRAINING

108 INSTITUTE OF CLINICAL MEDICINE AND PHARMACY

-

BUI DUC THANH

STUDY OF THE CHANGES OF SERUM NT-proBNP LEVEL AND THE ASSOCIATION WITH LOW CARDIAC OUTPUT SYNDROME AFTER CORONARY ARTERY BYPASS

GRAFTING SURGERY

Specialty: Anesthesiology Code: 62.72.01.46

SUMMARY OF MEDICAL DOCTORAL THESIS

Ha Noi – 2020

The work was completed at:

108 INSTITUTE OF CLINICAL MEDICINE AND

PHARMACY

Full name of supervisor:

1 Nguyen Hong Son Assoc Prof

2 Nguyen Thi Quy Assoc Prof

BACKGROUND

Low cardiac output syndrome (LCOS) is a clinical condition caused by a transient decrease in systemic perfusion due to cardiac dysfunction, resulting in an imbalance between supply and demand for cellular oxygen level that le led to metabolic acidosis LCOS is common

in elderly patients, patients with reduced systolic and diastolic left ventricular function, the longer time of aortic cross-clamp orextracorporeal circulation, re-surgery, valve replacement surgery, and coronary artery bypass grafting (CABG) surgeries

The causes of LCOS including reducing myocardial contraction, etiology of pre-load, and afterload Factors leading to impair left ventricular function after LCOS include inflammatory response, myocardial anemia, hypothermia, reperfusion damage, inadequate cardioprotection, and ventricular surgery Reduced cardiac output in heart failure after surgery is a common condition accounting for 30% of CABG cases

In recent years, the role of diuretic peptides (natriuretic peptide) was got attention Many studieshave shown the role of NT-proBNP (N-Terminal pro-B-Type Natriuretic Peptide) in early diagnosis of heart failure, assessment of severity, evaluation of the efficacy of treatment efficacy prognosis of heart failure NT-proBNP is also used to determine the factors associated with heart failure

In Vietnam, the study of NT-pro BNP was mainly internal medicine From a surgical perspective, there has not been any study about NT-pro BNP in patients with CABG surgery For theabove reasons,wehavecarriedout the thesis:“Study of the changes of serum NT-proBNP level and the association with low cardiac output syndrome after coronary artery bypass grafting surgery”withthefollowing objectives:

1 Investigate the changes in serum NT-proBNP level in patients undergoing CABG with extracorporeal circulation

2 Evaluate the association between serum NT-proBNP level and LCOS after CABG

Chapter 1 OVERVIEW 1.1 Coronary artery bypass grafting surgery with extracorporeal circulation

After coronary artery bypass grafting surgery with extracorporeal circulation, the patient underwent the recovery process of an important organ such as a cardiopulmonary organ with an average time was 2-7 days.This period was called the early stage after heart surgery The common complications were seen in this period:

-Blood pressure: Hypotension during the first hours after surgery

- Arrhythmias: bradycardia, sinus tachycardia, atrial fibrillation

- Low cardiac output syndrome: common in about 6-8 hours after surgery

- Right ventricular failure and pulmonary hypertension

- Diastolic dysfunction

- Distribution shock

- Myocardial anemia and myocardial infarction

1.2 Low cardiac output syndrome after heart surgery caused by heart failure

1.2.1 Cardiac Output and Cardiac Index

The activity of the heart is reflected through cardiac output (CO) It is

an average of blood volume that the heart pumps per minute to demand the metabolic needs

CO = Stroke volumex Heart rate

Mean of CO: 5 – 6l/min

The Cardiac Index (CI) is another presentation of cardiac output, defined as CO per skin area This index is not depending on the height, weight, and feasibility to apply in clinical practice

CI = CO / S

Mean ofCI: 2.5 – 3.5 l/min/m2

1.2.2 Low cardiac output syndrome caused by heart failure

Low cardiac output syndrome caused by heart failure is a clinical condition resulted from decreasing in systemic perfusion pressure,which led to a decrease in myocardial function with imbalance cellular oxygen supply and consumption and formed metabolic acidosis

There is no definition consensus of LCOS after cardiac surgery with extracorporeal circulation According to many authors, LCOS after

3cardiac surgery with extracorporeal circulation is a condition that patient needs to used post-operative intra-aortic balloon pumpe or cardiovascular medication such as vasomotor (dopamine dose > 5 µg/kg/min or dobutamine, adrenalin, noradrenalin, milrinone at any doses) from ≥ 30 minutes after surgery to maintain systolic blood pressure> 90 mmHg and CI > 2.2 L/min/m2, after optimizing the preload, afterload, and hemostatic condition (electrolyte and blood gas) Recommendation of Vela aboutLCOS after cardiac surgery with extracorporeal circulation:

- Cardiac index <2.2 L/min/ m2 without reducing blood volume The etiology maybe are the failure of right, left, or both ventricles with

or without pulmonary congestion Blood pressure maybe normal or decreased

-The clinical manifestations of LCOS: using when unable to monitor cardiac output: oliguria (urine <0.5 ml/kg/h), central venous oxygen saturation <60% (with normal arterial oxygen saturation), and/or lactate > 3 mmol/l, without the insufficiency blood volume

- In severe cases: cardiac index <2 L/min/m2, systolic blood pressure <90 mmHg, oliguria, and sufficient blood volume

1.2.3.Hemodynamic monitoring in cardiac surgery from an anesthesiologist

- Invasive arterial blood pressure measures

- Swan-Ganz Catheter: measuring pulmonary pressure, cardiac output, and other values

-Echocardiography:Trans-thoracicortrans-esophageal

echocardiography

- Monitor cardiac output using a PiCCO or Flotrac system

1.3 N-Terminal pro-B-type natriuretic peptide (NT-proBNP)

1.3.1 Structure and formation of NT-proBNP

Formation of NT-proBNP: In cardiomyocytes, preproBNP divide into proBNP (108 amino acid) and signal peptide (26 amino acids) ProBNP secreted into the blood by ventricles of the heart in response to myocardial injury or excessive stretching of the heart muscle cell (pressure or volume) In blood, undergoing the catalysis process ofcorin/furin enzyme, proBNP divide into BNP (32 amino acid) and NT-proBNP (76 amino acid)

1.3.2 Serum NT-proBNP level

The value 125 pg/ml ofNT-proBNP is considered a baseline in patients at risk for heart failure with a very high negative predictive value However, It is useful when dividing by age:Under 50 years old:

50 pg/ml; From 50 to 75 years: 75 - 125 pg/ml; Over 75 years: 125 pg/ml

The US Food and Drug Administration (FDA) certified a value of 250-300 pg/ml for people  75 years old

1.3.3 Identify the serum NT-proBNP level

NT-proBNPwas performed by luminescent electrochemical immunization according to the principle of sandwich onCobase601 (Roche Elecsys 2010) using ECLIA (Electro chemiluminescence immunoassay).Analyzing the immunological test by MODULAR ANALYTICS E170 The principleof luminescentelectrochemical immunization Principle of sandwiches:

- The first incubation period: the antigen in the test specimen sandwiched between a biotinized NT-proBNP-specific monoclonal antibody and a ruthenium-marked NT-proBNP-specific monoclonal antibody forming a sandwich complex (sandwich)

- The second incubation period: After adding the microparticles coated with Streptavidin, the sandwich complex becomes cohesive and converts to the solid phase by the reaction of Biotin and Streptavidin This mixture is sucked into the measuring chamber, where the particles are magnetically attracted to the surface of the electrode The unbound substances will then be rejected with the procell solution Applying voltage to the electrode produces chemical luminescence The luminescent signal is received and measured with a magneto-optical amplifier The results are determined based on a standard machine curve

*ReagentM: microparticles surrounded by streptavidin; R1: biotinized monoclonal anti-NT-proBNP (from mouse) antibody; R2: NT-proBNP (sheep) monoclonal antibody labeled with a ruthenium complex

* Specimen tube and storage: Blood tubes that contain K2- or EDTA plasma The blood is centrifuged and serous Blood samples were stable for 3 days at a temperature of 200C – 250C, 6 days at 20C – 80C,

K3-24 months at –200C

CHAPTER 2 MATERIALS AND METHODS 2.1.Study subjects

We conducted this prospective study on 107 patients who underwent CABG surgery withextracorporeal circulationat Ho Chi Minh Heart Institute from October 2012 to June 2014

2.1.1 Inclusion criteria

- Aged 18 and older regardless of gender

- Indication for CABG surgery with extracorporeal circulation

2.1.2 Exclusion criteria:

- Aged <18

- Concomitant cardiac surgery

- Renal function insufficiency (Creatinin > 1.6 mg/dl)

- Myocardial infarction

- Severe COPD

- Do not agree to participate in the study

2.1.3 Discontinuation from study

- Death within 24h after surgery

- Do not agree to participate in the study

2.2 Methodology

2.2.1 Study design:Prospective, longitudinal descriptivestudy with

comparison

2.2.2 Materials

- The arterial catheter (20G, Vygon, French)

- Central venous catheter (7Fr B.Braun, Germany)

- Colour Echocardiography(Philips Bothel.WA, USA)

- Flotrac/Vigileo System USA)

- Monitor (Philips MP40, USA)

- Immunology test (Cobas e602, Roche)

-Dobutamine (Bivid Co, Germany): 250 mg/20ml

- Noradrenalin (Levonor, Poland): 1mg/ml

- Adrenalin (Minh Dan, Viet Nam): 1mg/ml

2.2.3 Study process

2.2.3.1 Before surgery:

Recording the patient history and general characteristic, diagnosis

of chronic heart failure according to Framingham, heart failure

6classification according to NYHA, EuroSCORE scale, taking blood tests, X-ray, electrocardiography, Doppler echocardiography, coronary artery image, consultation decision on CABG surgery with cardiopulmonary bypass

2.2.3.2 In surgery:

- Setup monitor to follow the vital signs

- Arterial catheter to monitor arterial blood pressure

- Monitoring central venous pressure using catheter: Central-line catheter number 16 was placed through the internal jugular vein The position of the catheter was the position of the aortic vein in the right atrium (depth of the catheter about 15 cm) Central venous pressure measured by Truwave sensor (mmHg), The zero point is the intersection

of the medial axillary line and the 4th intercostal space

- Using Flotrac System to monitor cardiovascular indexes: Cardiac Output (CO), Cardiac Index (CI), Stroke Volume (SV), Stroke Volume Index (SVI), Stroke Volume Variations (SVV), Stroke Volume Resistants (SVR)

- Testing NT-proBNP before going to the operative room, before the procedure

2.2.3.3 After surgery (in ICU)

- Continous following vital signs on monitoring: heart rate, invasive blood pressure, respiratory rate, respiratory pattern, SpO2, central venous pressure CVP, and temperature

- Following CI, CO, SVI through Flotrac System

- Following LCOS after cardiac surgery

- Transthoracic echocardiography: assessment of left ventricular function (EF), systolic pulmonary arterial pressure (PAPs), regional movement disorders, pleural effusion, and pericardium effusion (if any)

- Monitoring and treatment LCOS after heart surgery

- Serum NT-proBNP test at postoperative days:

+ Sample preparation: Taking 1ml of blood from the vein into a tube containing K2- or K3-EDTA plasma Tubes are marked with the full name and age of the study patient and are barcoded After taking the blood, the specimen tube was put in an icebox and bring it to the laboratory The maximum time from taking blood to putting the tube in the machine is 30 minutes The assay was performed on Roche Cobas e602 automated immunoassay

7+ Performing test: Using pipettes Roche CARDIAC to take blood from a sample tube with a rubber lid Before removing the blood sample from the tube, press the piston completely and then pierce the needle through the rubber tube cap Always ensure homogeneity of blood specimens before inserting the test strip (by gently shaking the tube several times before taking the sample) Taking exactly 150 ml of blood from the tube into the pipette (according to the mark on the pipette) and ensure that there are no bubbles

+ The analyzer automatically calculates the analyte concentration

of each sample (either in pmol/ L or pg/mL)

2.2.3.4 Data collection

The results were collected at the time points:

- No: the day before surgery(NT-proBNP and hemodynamic index using Flotrac system were evaluated before going to the operating roo m

to operate)

- N1: Postoperative day 1 (2 hours after surgery)

- N2: Postoperative day 2(8 a.m.)

- N3: Postoperative day 3(8 a.m.)

- N4: Postoperative day 4(8 a.m.)

- N5: Postoperative day 5(8 a.m.)

Besides,we also recorded data about clinical characteristics, cardiovascular indexes, NT-proBNP,and dosage of cardiovascular medication at a time when patients showed cardiac impairment or when LCOS occurred

2.2.4 Criteria in our research

2.2.4.1 Criteria in general characteristics:

- Age (years) divided into three groups : < 50 years, from 50 – 75 years and > 75 years

- Gender: Male, female and % male/ female ratio

- Central venous pressure (CVP): Using Flotrac

+ Cardiac index (CI):

Normal CI: 2.5 – 4.0 L/min/m2 Decreased CI: ≤ 2.4 L/min/m2 + Cardiac output (CO):

Normal CO: 4.0 – 8.0 L/min Decreased CO: < 4.0 L/min + Stroke volume index (SVI):

Normal SVI: 33 – 47 ml/m2 Decreased SVI: ≤ 32 ml/m2

2.2.4.3 Criteria in the association between NT-proBNP and LCOS after surgery:

- The association between NT-proBNP and the prognosis ability of LCOS

Criteria for diagnosing LCOS after surgery:

+ Cardiac index <2.2 L/min/ m2 without reducing blood volume The etiology maybe are the failure of right, left, or both ventricles with

The cut-off value was determined as the value that the NT-proBNP level had the maximal sensitivity and specificity, calculated by maximal

J index (Youden Index) J = max (Sensitivity + Specificity -1)

- The association between NT-proBNP and the ability of profnosis

of LCOS after cardiac surgery

In our study, we used EuroSCOREto prognose the risk of acute heart failure after CABG surgery This is quite simple based on 17 index according to patients, heart or surgery It has three level of EuroSCORE:

 EuroSCORE 0-2 score: low risk

 EuroSCORE 2-5 score: moderate risk

 EuroSCORE > 5 score: high risk

- The association betweenNT-proBNP level with Vasoactive Inotropic Score (VIS) after surgery:

IS = dopamin dosage (µg/kg/min) + dobutamin dosage (µg/kg/min) +

100 x epinephrin dosage (µg/kg/min)

VIS = IS + 10 x milrinon dosage (µg/kg/min) + 10000 x vasopressin dosage (UI/kg/min) + 100 x norepinephrin dosage (µg/kg/min) The medication did not use, its dosage was calculated as 0.We evaluated VIS at N1, N2, N3, N4, N5 VIS > 15 was considered as high value and VIS ≤ 15 was considered as low value

2.3 Statistical analysisData collected using Epi Data 6 and using STATA14.0 to analyze

Figure 2.1 Study design

Indication for CABG surgery

N0: Clinical characteristics, Echocardiography, NT-proBNP Hemodynamic indexes

CABG

ICU

Clinical characteristics, Echocardiography, NT-proBNP Hemodynamic indexes

Objective 1 Objective2

Chapter 3 RESULTS 3.1 Demographic characteristics

- The mean age in the research group is 60.7 ± 9.4 Patients aged 50-75 years were major with 87.8% The percentage of males was higher than females (72 male versus 35 female)

- There were 36/107 cases (33.64%) diagnosed with chronic heart failure before surgery NYHA II and NYHA III were dominant in classification accounting for 55.6% and 33.3% respectively

- Patients with EuroScore 3-5 were mainly with 58% before surgery

- CABG with 3 and 4 bridges was mainly with 48.6% and 33.6% The mean of ECMO and clipped aorta artery time were 126.8 ± 27.1 minutes and 87.7 ± 23.4 minutes, respectively

3.2.Evaluating the changes in the level of serum NT-proBNP in patients with CABG

Table 3.11 Level of serum NT-proBNP at time points

Comment:After surgery, the mean of NT-proBNP level increased

slightly at N1 with 972.5 pg/ml, then increased fastly and peaked at N3 with 4057.26 pg/ml, and then tending decreased gradually at N5 with 3457.81 pg/ml The difference in the NT-proBNP level between pre- and post-operative time was statistically significant with a p-value

<0.05