Nghiên cứu sự thay đổi nồng độ cytokin huyết tương trong lọc máu liên tục bằng màng lọc oxiris ở bệnh nhân sốc nhiễm khuẩn tt tiếng anh

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES - PHẠM QUỐC DŨNG STUDY ON THE CHANGES OF PLASMA CYTOKINE CONCENTRATION IN CONTINUOUS HEMOFILTRATION WITH THE MEMBRANE ADSORBING OXIRIS FILTER IN SEPTIC SHOCK PATIENTS Speciality: Anesthesia and Critical Care Code: 62.72.01.22 ABSTRACT OF MEDICAL PHD THESIS Hanoi – 2020 THE THESIS WAS DONE IN: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Supervisor: M.D., PhD Đo Quoc Huy Ass Prof PhD Le Thi Viet Hoa Reviewer: This thesis will be presented at Institute Council at: 108 Institute of Clinical Medical and Pharmaceutical Sciences Day Month Year The thesis can be found at: National Library of Vietnam Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences INTRODUCTION Septic shock is a common disease in intensive care unit Currently, despite progress in diagnosis and treatment, the fatality rate from septic shock remains as high as 40-55% The "cytokine storm" has been known in the pathophysiology of septic shock and is a condition in which the body's over-immune response to infection causes massive release of cytokines into the bloodstream Treatment of septic shock was agreed by Sepsis-3 (2016) with treatment packages including volume therapy, vasopressor use, infection resolution and other supportive measures Continuous hemofiltration using adsorbing filter that has been recently used helps to remove cytokines (TNF-α, IL-1b, IL-6, IL-8, IL-10) in the hope of stopping the vicious circle of septic shock The oXiris filter has many outstanding advantages compared to other adsorbing filters or devices and is the only filter that adsorbs both bacterial endotoxins and cytokines with safe use and few complications So far, continuous hemofiltration technique using the oXiris adsorbing filters in treatment of septic shock has not been much researched With the value of adsorbing hemofiltration and the advantages of the oXiris filter, the project of "Study on the changes of plasma cytokine concentration in continuous hemofiltration with the membrane adsorbing oXiris filter in septic shock patients" was conducted for two goals: Evaluating changes in plasma cytokine concentrations in continuous hemofiltration with the membrane adsorbing oXiris filter in patients with septic shock 2 Comment on some clinical and subclinical changes in septic shock patients undergoing continuous hemofiltration with the membrane adsorbing oXiris filter Chapter LITERATURE OVERVIEW 1.1 Introduction to cytokine 1.1.1 Definition Cytokines are proteins or glycoproteins produced and released by white blood cells and some other cells Cytokines typically have a molecular weight from to 30 kiloDaltons and act as intercellular chemical messengers All cytokines are involved in the immune response to protect the host against pathogens and/or to regulate the inflammatory response 1.1.2 Classification of cytokine - Interleukin (IL): currently about 40 types of interleukin have been found, denoted from IL-1 to IL-40 - Interferon (IFN): there are three types of IFN: α, β and γ - Tumor necrosis factor (TNF): including 18 types, eg TNF-α, CD40L, FasL, etc - Cerebrospinal fluid (CSF) stimulating factors: including M-CSF, GM-CSF, G-CSF, EPO, SCF, TPO - Chemokine: groups of CC, CXC, C and CX3C 1.1.3 Cytokine release syndrome and cytokine storm - Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome resulting from complications of certain diseases or infections and also a side effect of some monoclonal antibody drugs as well as cancer immunotherapy - Cytokine storm: A cytokine storm is a severe case of CRS 1.1.4 Some types of cytokine in research - Tumor Necrosis Factor-α (TNF-α): tumor necrosis factor is an inflammatory cytokine with molecular weight of 17 kiloDalton TNF-α is selective cytotoxicity to a variety of transgenic cells, especially when the cell is bound to INF-α - Interleukine 1b (IL-1b): lymphocyte activating factor, is an inflammatory cytokine with molecular weight of 18 kiloDaltons, produced by activated macrophages The increased IL-1b remains in patients at high risk of fatality - Interleukine (IL-6): is an inflammatory cytokine with molecular weight of 21 kiloDaltons IL-6 regulates B and T cell functions, hematopoiesis, and acute phase response IL-6 is the most effective stimulant in the production of proteins in hepatic acute phases It is the second messenger released by macrophages, endothelial cells or fibroblasts and other cells in response to IL-1b and TNF-α cytokines - Interkeukine (IL-8): is an inflammatory cytokine with molecular weight of kiloDaltons IL-8 is an inflammatory chemokine produced by multiple cells, especially mononuclear cells, and functions as an activating and chemical attracting factor in polymorphonuclear leukocytes IL-8 is a very powerful vascular agent The presence of IL-8 causes neutrophils to attach to the capillary endothelial cells and move into the tissues - Interkeukine 10 (IL-10): is a potent anti-inflammatory cytokine, with molecular weight of 18 kiloDaltons IL-10 is a cytokine secreted by Th0 and Th2 cells, a subset of T lymphocytes (CD4) IL10 inhibits the activation of cytokine synthesis of Th1 cells, activated mononuclear cells and NK cells 1.2 Septic shock 1.2.1 Definition - Septic shock is considered a subtype of sepsis, in which circulatory and cellular metabolic abnormalities are severe enough to increase mortality (Sepsis-3, 2016) - Septic shock is diagnosed based on criteria for diagnosis of sepsis together with persistent hypotension, which requires the use of vasopressors to maintain mean arterial blood pressure ≥ 65 mmHg and serum lactate ≥ mmol/l (18mg/dl) despite full volume compensation 1.2.2 Mechanism of pathogenesis Immune mechanisms (cytokine storms: an increase in blood cytokines such as TNF-α, IL-1, IL-6, IL-8, IL-10 ) is a major factor in the pathogenesis of septic shock There are three important components involved in this pathogenesis, including: - Pattern recognition receptor (PRRs): are proteins expressed on cells of the innate immune system to recognize pathogen associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) - Pathogen associated molecular patterns (PAMPs): are antigenic types associated with etiologic groups (gram-negative bacteria are LPS, gram-positive bacteria are LTA) identified by cells of the innate immunity system - Damage-associated molecular patterns (DAMPs): are multistructural, multi-functional host proteins released in response to infection or tissue damage 1.2.3 Treatment of septic shock Early diagnosis, settlement of septic foci, appropriate antibiotics and initial resuscitation are the cornerstones of the treatment 1.3 Continuous hemofiltration using oXiris filter 1.3.1 Continuous Veno-Venous Hemofiltration (CVVH) in supporting treatment of septic shock - Continuous veno-venous hemofiltration is a method using only the ultrafiltration - convection mechanism in which blood runs through the filter with replacement fluid inserted in front or after the filter and without using dialysis Fluid Due to the ultrafiltration convection mechanism and large enough rate of replacement fluid, it is also possible to remove very well substances with high molecular weight such as inflammatory mediators of TNF-α, IL-1, IL-6, IL-8, IL-10, in addition to removing solutes - Hemoperfusion is a method of filtering the blood extracorporeally that uses devices containing adsorbents (adsorbent devices) An adsorbent device can be an adsorption filter that can adsorb and/or adsorbent cartridges/columns to eliminate toxins or pathogens (endotoxins, cytokines, etc) Hemoperfusion is performed in the same way as regular continuous hemofiltration, but the blood is passed through a filter that adsorbs or through a sorbent container, in which "toxins" like cytokines, bacterial endotoxins, etc are adsorbed into the surface of filter or adsorbing cartridges/columns 1.3.2 oXiris filter - oXiris filter is manufactured based on AN69 filter (Figure 1.9) 1.3.3 Domestic and international hemofiltration using oXiris filter studies on continuous International studies: Currently, researches in the world on continuous hemofiltration using oXiris filter with endotoxin and cytokine absorption properties in the treatment of septic shock are quite rare Through literature reference, only about 13 studies are found, of which there are quantitative studies about cytokines in the blood Fig.9 The layers of the oXiris membrane PEI, polyethyleneimine Domestic studies: Continuous hemofiltration was transferred into Vietnam in 2002 Since then, this technique has been routinely used in a number of major hospitals across the country There, however, are few studies in Vietnam OXiris membrane has just appeared in the Vietnamese market Currently, only one report by Le Huu Nhuong (2017) on the effectiveness of continuous hemofiltration using oXiris filter is found but not on subjects of septic shock Chapter RESEARCH SUBJECTS AND METHODOLOGY 2.1 Research subject 31 patients in 03 intensive care units (ICU) of Thu Duc District Hospital, 115 People's Hospital, Bach Mai Hospital from September 2014 to October 2018 2.1.1 Criteria for selecting patients - Patients ≥ 18 years of age who were diagnosed with septic shock according to Sepsis-3, maintained systolic blood pressure ≥ 90 mmHg by infusion and vasopressors in ICU and had APACHE II score at admission ≥ 25 or acute kidney damage or mechanical ventilation The patient's relatives agreed to participate in the study 2.1.2 Criteria for exclusion - Patients who did not agree to participate in the study - Patients who had contraindications to continuous hemofiltration techniques, irreversible shock unresponding to therapy and vasopressors 2.1.3 Venue of study The intensive care units of Thu Duc District Hospital, 115 People's Hospital, Bach Mai Hospital 2.2 Research methodology 2.2.1 Research design: prospective study, intervention study, case control study 2.2.2 Research equipment and tools 15 Chapter RESEARCH FINDINGS 3.1 Common characteristics of patients - The study was made on 31 patients with septic shock, mean age of 62.03 ± 15.79 (26-97) Patients> 60 years old accounted for a high rate of 67.3% of age Male/female ratio = 0.72/1 The SOFA score at the beginning of hemofiltration was 16.2 ± 4.8 points The most common primary infection was the respiratory tract, followed by the digestive tract, urinary tract and other organs Among infectious agents, the rate of Acinetobacter baumannii was most commonly encountered In addition, some other types such as Escherichia coli, Klebsiella spp, etc were also encountered - The time of hospitalization was 13.6 ± 11.3 days; the time in intensive care unit was 11.0 ± 11.4 days; 72 oXiris filter were used for 31 patients, the mean lifespan of oXiris filter was 16.2 ± 10.3 hours Continuous hemofiltration with oXiris filter was safe with very few complications - The survival rate was 48.4%, the mortality rate was 51.6% 3.2 Evaluating changes in plasma cytokine concentrations in continuous hemofiltration (CHF) with the membrane adsorbing oXiris filter in patients with septic shock Table 0.20 Concentration of cytokine at the beginning of CHF Cytokine Normal (pg/ml) median (25th-75th), n=31 TNF-α < 11 13.06 (6.34 – 22.41) IL-1b < 14.5 5.0 (1.7 – 7.65) IL-6 < 1.23 665.1 (147.73 – 1095.0) IL-8 – 159.4 710.2 (198.0 – 1351.0) IL-10 < 1.9 21.91 (7.88 – 51.4) 16 Most plasma cytokin concentrations before continuous hemofiltration are higher than normal values Comment: Table 0.1 The change of plasma TNF-α concentration Cytokine TNF-α, median (25th- Friedman Test Times 75th), n=31 T1 13.06 (6.34 – 22.41) T2 12.05 (5.82 – 19.76) χ2 = 6.34 T3 9.76 (6.25 – 29.43) p = 0.096 (>0.05) T4 9.84 (5.70 – 19.00) Comment: The median value of the TNF-α concentration tends to decrease during continuous hemofiltration, but this change is not statistically significant Table 0.2 The change of plasma IL-1b concentration Cytokine IL-1b, median (25th- Friedman Test Times 75th), n=31 T1 5.0 (1.7 – 7.65) T2 5.0 (1.9 – 5.95) χ2 = 12.938 T3 5.0 (2.1 – 7.22) p = 0.005 (0,05) T4 371.23 (70.8 – 1207.54) Comment: The median value of the IL-6 concentration tends to decrease gradually during hemofiltration, but this difference is not statistically significant Table 0.5 The change of plasma IL-8 concentration Cytokine IL-8, median (25th- Friedman Test Times 75th), n=31 T1 710.2 (198.0 – 1351.0) T2 342.86 (80.7 – 1351.0) χ2 = 22.878 T3 110.7 (41.0 – 600.27) p = 0.000 ( 0.05 (tables 3.43, 3.46 and 3.47) Median values of IL-1b and IL-6 concentrations differ between the mortality group and the survival group: in the mortality group it is higher than that in survival group, p