MINISTRY OF EDUCATION & TRAINING MINISTRY OF DEFENSE CLINICAL MEDICAL SCIENCE RESEARCH INSTITUTE 108 HOANG DINH TUAN A RESEARCH ON RELATION BETWEEN CLINICAL PARACLINICAL CHARACTERISTICS AND NT proBNP[.]
MINISTRY OF EDUCATION & TRAINING MINISTRY OF DEFENSE CLINICAL MEDICAL SCIENCE RESEARCH INSTITUTE 108 HOANG DINH TUAN A RESEARCH ON RELATION BETWEEN CLINICAL PARACLINICAL CHARACTERISTICS AND NT-proBNP LEVEL WITH DEATH PROGNOSTIC AFTER STROKE Major: Neurology Code number: 62720147 SUMMARY OF MEDICAL THESIS HANOI – 2022 THE STUDY WAS CONDUCTED AT IN INSTITUTE OF CLINICAL MEDICAL SCIENCE RESEARCH INSTITUTE 108 Instructors: Assoc Prof Nguyen Huy Ngoc PHD Nguyen Hong Quan Reviewer: Assoc Prof Dr Mai Duy Ton Assoc Prof Dr Nguyen Hoang Ngoc The thesis will be defended in front of Institute Council, Institute of Clinical Medicine and Pharmaceutical Sciences 108 At Date 2022 The thesis can be accessed at: Vietnam National Library The Library of Institute of Clinical Medicine and Pharmaceutical Sciences 108 INTRODUCTION Cerebral Stroke, the second leading cause of death after cardiovascular disease, has been a topical issue in developing countries It is the leading cause of neurological diseases, which often leaves physically and mentally severe sequelae for the patient, and brings a heavy burden to the family and society The disease is increasing and happens in younger adults, especially in developing countries In the past decades, there have been many advances in the diagnosis, emergency care, treatment, prognosis and prevention of stroke, especially the application of new treatment methods such as: thrombolysis, thrombectomy, endovascular intervention, etc, which significantly reduce the mortality and disability rate after stroke attack However, the study aims to provide predictive models of mortality after stroke, including clinical and paraclinical factors, treatment measures etc, to predict neurological recovery outcomes and motarlity prognosis remains difficult In the world, there are many studies showing that NT-proBNP is a valuable independent factor in the prognosis of severity as well as mortality after stroke In Vietnam, there are no studies on the relationship between NT-proBNP concentrations with stroke mortality With the aim of understanding the role of this biomarker in the prognosis of mortality after stroke, we conducted this study with the following two subjectives: Research on some clinical, paraclinical and NT-proBNP concentration in stroke patients Clarify the roles of NT-proBNP concentration and some clinical and paraclinical factors in the prognosis of motarlity after stroke CHAPTER OVERVIEW 1.1 Cerebral stroke 1.1.1 Summary of cerebral circulation anatomy and physiology The brain is an organ with high metabolic needs, but has no energy reserves, so it requires a large and constant circulation The brain accounts for only 2% of body weight but requires 15% of cardiac supply and 20% of total oxygen consumption in the body The brain is supplied with blood by the internal carotid and vertebral arteries These two arterial systems are connected through the circle of Willis and perfuse different regions of the brain 1.1.2 Definition of cerebral stroke The World Health Organization (WHO) defined stroke as rapidly developed clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than of vascular origin The focal neurological symptoms were consistent with the brain region due to the distribution of damaged arteries without traumatic causes 1.1.3 Ischemic Stroke 1.1.4 Hemorrhagic stroke 1.1.5 Risk factors for cerebral stroke 1.1.5.1 Unchangable risk factors: Age, sex 1.1.5.2 Changable risk factors - Hypertension, Dyslipidemia, Obesity, Diabetes 1.1.6 Clinical and paraclinical symptoms 1.1.6.1 Common clinical features of stroke * The disease usually has a sudden onset, depending on the affected brain area There will be focal neurological symptoms such as Sensory symptoms, Motor symptoms, Cranial nerve paralysis, language disorders, etc 1.1.6.2 Clinical symptoms of stroke types 1.1.7 Paraclinical symptoms * Computerized tomography CT.Scan) * Magnetic resonance imaging (MRI) * Brain angiography 1.1.8 Prognostic factors for stroke 1.1.8.1 Clinical and paraclinical factors - Age: Age was both a risk factor and a predictor of mortality The older the stroke patient was, the higher the mortality rate and the more severe the consequence of stroke - Consciousness status: The patient's consciousness at hospital admission was assessed by the Glasgow scale The lower the Glasgow score (the deeper the level of coma), the worse the prognosis and the higher the risk of motarlity There have been many studies in Vietnam and the world confirming that Glasgow on admission has an independent predictive value of mortality after stroke - Severity of nerve damage (NIHSS Score): NIHSS score is one of the important factors in predicting severity and mortality in stroke patients - Injured brain size: The size of the brain injured or dead is a very important factor in stroke prognosis - Location of the lesion: In general, lesions in the infratentorial area often have a worse prognosis than ones in the supratentorial - Ventricular hemorrhage: Many studies show that ventricular hemorrhage is also a serious prognostic factor 1.1.8.2 Factors associated with disease progression The severity of injured brain cells might got worse within 48 hours of onset and was associated with a poor prognosis if the status was left untreated Some causes were thought to be an increase in the size of the hematoma, hemorrhagic infarction, cerebral edema, or dilated ventricles 1.1.8.3 Comorbidities Stroke patients with comorbidities, especially severe chronic diseases, will have the disease more severe, difficult to treat, often longer hospital stays, and especially a higher mortality rate 1.1.8.4 Biomarkers in stroke prognosis In addition to the prognostic factors mentioned above, biomarkers have been studied and applied in the diagnosis and prognosis of stroke patients such as (MMP)-9, S100β, Lp-PLA2, Protein C, copeptin, BNP and NT-proNBP, etc 1.1.8.5 Factors associated with intervention 1.2 NT-proBNP 1.2.1 Overview 1.2.2 Molecular structure and biological effects of BNP and NTproBNP 1.2.3 Release of BNP and NT-proBNP NT-proBNP is secreted 70% from the ventricular myocytes and a small amount from the atrial ones In addition, NT-proBNP is also secreted from the brain, lungs, kidneys, aorta, and adrenal glands, at lower concentrations than from the atria The release of serum NT-proBNP concentration is regulated by both left ventricular pressure and volume 1.2.4 Clearance of BNP and NT-proBNP 1.2.5 Normal serum NT-proBNP value 1.2.6 Factors affecting secretion of BNP and NT-proBNP Many studies demonstrate that NT-proBNP levels are negatively correlated with left ventricular blood ejection and positively correlated with left ventricular muscle mass In addition, other factors related to serum NT-proBNP levels include age, gender, and obesity, etc 1.2.7 Roles of NT-proBNP in cardiovascular diseases and stroke 1.2.7.1 For cardiovascular diseases 1.2.7.2 For Stroke NT-proBNP levels are often higher than normal in both ischemic and hemorrhagic stroke patients The increased level of this biomarker is related to the extent of damage, and the area of the lesion The level often gets higher in the ischemic stroke group, especially stroke of cardiac origin Many studies demonstrate that the increase of this biomarker is an independent predictor of mortality after stroke Determine the cardiovascular causes of ischemic stroke Prediction of development of atrial fibrillation after hospitalization and risk stratification BNP and NT-proBNP levels may also be used to predict second stroke recurrence, and stroke after TIA One of the reasons thought to increase BNP levels in stroke patients is cardiac dysfunction This includes adaptive vasodilatation during cerebral infarction or activation of the sympathetic nervous system leading to increased arterial pressure and higher left ventricular wall tension Stroke is an acute stress response involving a neuronal and systemic inflammatory response that can increase BNP, NT-proBNP levels The level increases due to the activation of the hypothalamic-pituitary-adrenal axis in ischemic stroke It is also hypothesized that it may be due to brain damage that increases the biomarker secretion 1.2.8 Some studies on the association of NT-proBNP and stroke - Teresa García et al analyzed a meta-study including 3498 stroke patients from 16 studies to investigate the association between BNP levels and mortality after stroke The authors concluded that BNP/NT-proBNP played a role as an independent prognostic factor of death after stroke - Author Joan Montaner in a study used the two biomarkers, BNP and D-dimer to diagnose embolic stroke of cardiac origin The author concluded that BNP and D-dimer climbed up high in the group of embolic stroke of cardiac origin and the author also recorded a high positive diagnostic value when combining both factors with sensitivity and specificity of 66.5% and 91.3%, respectively - To evaluate the role of NT-proBNP and NHISS score in ischemic stroke, Xing Yong Chen et al studied 122 ischemic stroke patients and found that NT-proBNP level > 1,583.50 pg and NIHSS score > 12.5 were independent factors associated with hospital mortality - Kensaku Shibazaki et al studied 335 patients with acute ischemic stroke admitted to hospitals within 24 hours of onset: After multivariate logistic regression analysis, the author concluded that NIHSS score > 13 and plasma BNP levels >240 pg/mL were two independent factors associated with in-hospital mortality - Gregorio T et al studied 201 patients with cerebral hemorrhage, the research team concluded: The concentration of NTproBNP at admission time was independently related to the size of the hematoma NT-proBNP was an independent predictor of disease severity in patients with cerebral hemorrhage - To evaluate the role of NT-proBNP in predicting stroke risk after TIA, Rodríguez-Castro E and colleagues conducted a study on 381 patients with TIA The author concluded, “early determination of NT-proBNP levels is a simple and very useful alternative for predicting and forecasting stroke occurring after TIA - Hoang Khanh and Tran Thi Phuoc Yen in a study in 2011 summarize that the mean NT-proBNP concentration increased significantly compared with the control group in both ischemic and hemorrhage stroke; the mean serum NT-proBNP concentration went up to the highest in the group of patients with NIHSS score > 20 while Huynh Thi Thanh Thuy and Nguyen Thi Minh Duc concluded that the concentration of NT-proBNP increased in both ischemic and hemorrhage groups There is a positive relationship between NTproBNP concentration and severity of nerve damage with NIHSS > 20 points CHAPTER RESEARCH SUBJECTS AND METHODS 2.1 Research subjects 300 patients diagnosed with cerebral stroke, treated at the Acute Stroke Unit, Stroke Center, Phu Tho Provincial General Hospital from October 2015 to August 2019 2.1.1 Inclusion criteria - Age: Patients over 18 years old - Have diagnosis of acute cerebral stroke based on clinical and laboratory criteria - Hospitalization within 72 hours of stroke onset 2.1.2 Exclusion criteria - Patients with a brain tumor, traumatic brain injury, encephalitis, infection, immune diseases - Patients with a transient ischemic attack (TIA) - Patients with a history of cardiovascular diseases such as heart failure, valvular disease, atrial fibrillation, dilated cardiomyopathy, ischemic heart disease, and myocardial infarction - Patients with serious diseases: liver failure, severe kidney failure - Patients with ischemic stroke have been successfully treated with mechanical thrombectomy - Patients who died after 30 days of hospitalization - Patients whose death did not cause by a stroke - Pregnant women - Patients who did not agree to participate in the study 2.2 Research Methods 2.2.1 Research Design Descriptive prospective study, the study population was divided into 02 groups: The fatal group and the survival group (survival) for comparison 2.2.2 Population size calculation Z(1-α/2)2p (1-p) n= ᴈ2 With: - P: Estimated stroke mortality rate: P = 0,2 - Z(1-α/2): With confidence 95% = > Z(1-α/2) = 1,96 - ᴈ: Relative error, take 5% = > ᴈ = 0,05 2.2.3 Research design 2.2.3.1 Collect data All stroke patients admitted to the Stroke Center of Phu Tho Provincial General Hospital within 72 hours of onset were asked about their illness, history, and under clinical examination based on a common medical record The patients were applied a general, standard treatment regimen according to the acknowledged Guideline * Variables used in the study: - Age, sex, pulse, blood pressure, weight at admission - Time from onset to initiation of treatment - High blood pressure - History of stroke, hypertension, smoking, drinking alcohol, - Blood count with 18 indexes, blood biochemical indicators - Coagulation tests (PT, APTT, etc.) - NT-proBNP concentration test: 11 STUDY DIAGRAM The patient was diagnosed with cerebral stroke and met inclusion criteria Ischemic Stroke Hemorrhage Stroke Evaluate and comment on some general characteristics, clinical and subclinical characteristics such as age, gender, risk factors, onset symptoms Analysis to find out the relationship between NT-proBNP concentration with some clinical and subclinical characteristics Group II:Nonfatal Group I: Fatal Assess the association of NT-proBNP and clinical, paraclinical factors with mortality after stroke by univariate logistic analysis After univariate Logistic analysis, insert factors related to mortality after stroke into multivariable Logistic analysis to identify factors which were independently associated with mortality after stroke CONCLUSION 12 CHAPTER RESEARCH RESULTS 3.1 Some clinical, paraclinical, and NT-proBNP levels in stroke patients Stroke patients were mainly over 60 years old, and the average age of the study group was 70,2 ± 13,2 years old The current rate of stroke in Men (62,3%) was higher than in Women (37,7%) Ischemic stroke accounted for a higher rate (63,3%) than hemorrhagic stroke (36,7%) Hemiplegia was the most common onset symptom (92%), followed by dysphasia/aphasia (72,3%) The most common risk factor was hypertension, accounting for 79,3%, followed by dyslipidemia The most common clinical symptoms were: Hemiplegia (95,3%); Headache (87,7%) 7th Nerve Palsy (68%) There were 67 (22,3%) patients with respiratory failure requiring ventilation The mortality rate in the group with hemorrhage stroke (28,1%) was higher than that of the group with ischemic stroke (9,5%), (p < 0,001) The overall mortality rate of the study patients was 16,3% 3.1.6 The relationship between NT-proBNP levels and some clinical and paraclinical factors in cerebral stroke Table 14 The relation between NT-proBNP levels with types of stroke Number of p Stroke type NT-proBNP Patients Hemorrhage 110 422,63 ± 567,53 0,932 Ischemic 190 429,87 ± 780,97 Sum types 300 422,21 ± 709,20 There was no difference in NT-proBNP levels between stroke 13 Table 15 The relation between NT-proBNP levels and age and gender Characteristics Pulse (n) NT-proBNP p < 60 years old 67 353,23 ± 605,01 0,334 ≥ 60 years old 233 448,47 ± 736,24 Man 187 371,93 ± 623.03 Gender 0,082 Woman 113 518,70 ± 827,37 There was no statistically significant difference between NTproBNP levels in women younger than 60, and men older than 60 Table 17 The relation between NT-proBNP levels with clinical symptoms Age Characteristics 15 score Glasgow NIHSS Number of patients (n) NT-proBNP 89 184,59 ± 277,29 187 527,34 ± 837,47 ≤ score 24 546,78 ±498,28 - score 101 169,19 ± 251,02 - 15 score 119 449,91 ± 831,51 > 15 score 80 719,19 ±786,68 104 209,28 ± 303,30 143 507,96 ± 833,97 53 636,98 ± 807,95 fast 46 563,06 ± 686,20 Normal 254 402,61 ± 711,82 Yes 81 637,71 ± 401,49 From - 14 score p 0,001