Kết quả điều trị nhồi máu não trong giai đoạn từ 3 đến 4,5 giờ bằng thuốc tiêu huyết khối alteplase liều thấp tt tiếng anh

1 INTRODUCTION BACKGROUND Stroke is the third leading cause of death after cardiovascular disease and cancer, and is also the leading cause of disability in developed countries The burden of strokes has increased steadily, mainly in developing countries, with deaths accounting for 75.2% of the world, including Vietnam Therefore, the goal of reducing the mortality and morbidity due to stroke is constantly urgent and challenging Up to now, the strategy of recanalision treatment with the intravenous thrombolysis by Alteplase remains the cornerstone in the emergent management of acute ischemic stroke within 4.5 hour from symptom onset The recommendations of up-to-date international guidelines show that the thrombolytic treatment as a standard option, in a maximum time window of 4.5 hours, with the highest level of evidence Studies in Asia had demonstrated the outcomes of low-dose administration was noninferior to those with standard dose thrombolytic trials in the United States and Europe, while the complications are much lower, especially intracranial hemorrhage Domestic and international studies had indicated that the treatment of low-dose Alteplase within hours after stroke onset had high rate of patients with favorable outcome at months ENCHANTED, a international randomised control trial was conducted to compare the results of low-dose and standard-dose intravenous Alteplase in acute ischemic stroke within 4.5 hours after the onset, did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days However, symptomatic intracranial hemorrhage was significantly higher in the standard dose group (2.1% vs 1.0%) In addition, when analyzing the subgroup of to 4.5 hours treatment, the outcome in both groups were similar (51.1% versus 50.1%) To date, there have not been any study specifically mentioned the treatment of intravenous low dose Alteplase between to 4.5hour after onset Therefore, we conducted the study: "The treatment outcome of acute ischemic stroke between to 4.5 hours with low dose Alteplase thrombolysis", with objectives as follow: To describe the clinical features and brain CT scans presentation of ischemic stroke patients between to 4.5 hours after symptom onset To evaluate the outcome of acute ischemic stroke treating with low dose Alteplase thrombolysis (0.6 mg / kg) between to 4.5 hours after symptom onset, during hospital stay period , at months and adverse events To find out the predictive factors for neurological recovery at months THE LAYOUT OF THESIS: There are pages, including: Introduction (3 pages); Chapter Overview (43 pages); Chapter Objectives and methods (22 pages); Chapter Results (40 pages); Chapter Discussion (40 pages); Conclusion (2 pages) ; Recommendtion (1 page) ; Limitation ( page) There are also 170 references section, appendices, tables, charts, illustrations NEW CONTRIBUTIONS The thesis assessed the outcome and adverse events of treatment for acute ischemic stroke patients at window time from to 4.5 hours with low dose Alteplase (0.6 mg/kg) during inpatient period and at months This publication does not overlap with those of other studies in and out of the country The thesis identified independent outcome predictors and the role of prognostic scores for unfavorable neurological recovery at months The study has simultaneously applied multiple score (ASPECT, NIHSS, DRAGON, ASTRAL, HAT), which other studies have not mentioned simultaneously CHAPTER 1: OVERVIEW 1.1.1 Cerebral autoregulation during ischemic stroke Cerebral autoregulation is impaired during some disease conditions, including ischemic stroke As cerebral perfusion pressure falls, cerebral blood vessels dilate to increase cerebral blood flow A decrease in perfusion pressure beyond the ability of the brain to compensate results in a reduction in cerebral blood flow Initially, the oxygen extraction fraction is increased in order to maintain levels of oxygen delivery to the brain As the cerebral blood flow continues to fall, other mechanisms come into play Neuronal electrical failure occurs at 16 to 18 mL/100 g per minute, and failure of membrane ion homeostasis occurs at 10 to 12 mL/100 g per minute This level typically marks the threshold for the development of infarct 1.1.2 Ischemic penumbra Ischemic penumbra is a localized ischemic area with impaired function and at risk of infarction, but it is likely to be saved by reperfusion or other strategies If not, the ischemic zone would be progressively infarcted until it reaches its maximum volume, that was the original volume of risk 1.1.3 Mechanism of ischemic stroke Embolic Mechanism: Embolism refers to clot or other material formed elsewhere within the vascular system that travels from the site of formation and lodges in distal vessels causing blockage of those vessel and ischemia The heart is a common source of this material, although other arteries may also be sources of this embolic material (artery to artery embolism) In the heart, clots may form on valves or chambers Tumors, venous clots, septic emboli, air, and fat can also embolize and cause stroke Embolic strokes tend to be cortical and are more likely to undergo hemorrhagic transformation, probably due to vessel damage caused by the embolus Hemodynamic Mechanism: Thrombosis refers to obstruction of a blood vessel due to a localized occlusive process within a blood vessel The obstruction may occur acutely or gradually In many cases, underlying pathology such as atherosclerosis may cause narrowing of the diseased vessel This may lead to restriction of blood flow gradually, or in some cases, platelets may adhere to the atherosclerotic plaque forming a clot leading to acute occlusion of the vessel Atherosclerosis usually affects larger extracranial and intracranial vessels In some cases, acute occlusion of a vessel unaffected by atherosclerosis may occur because of a hypercoagulable state 1.1.4 Etiologic classification of ischemic stroke Acute ischemic stroke subtypes are often classified in clinical studies using a system developed by investigators of the TOAST trial, based upon the underlying cause Under this system, strokes are classified into the following categories: Large artery atherosclerosis; Cardioembolism; Small vessel occlusion; Stroke of other, unusual, determined etiology; Stroke of undetermined etiolog 1.2 Mechanisms of Thrombus Formation and the impact of the tissue plasminogen activator on thromboembolism 1.2.1 Mechanisms of Thrombus Formation The main cause of clot formation for ischemic stroke is endothelial cell injury of atherosclerotic plaque and it can also be established from the heart chambers In addition, the composition of the thrombus may depend on a number of factors, including the extent of blood vessel damage, intravascular pressure, and the presence of thrombotic agents 5 1.2.2 Thrombolysis Plasmin formation plays a central role in thrombolytic processes Endogenous fibrinolytic system includes plasminogen, plasminogen activator, and fibrinolytic inhibitory factor Fibrin degradation requires plasmin activation Plasminogen, its activating factor, and fibrinolytic suppression factor contribute to the balance between hemorrhaging and thrombosis 1.2.3 The impact of the tissue plasminogen activator on thromboembolism (Alteplase) Alteplase is a specialized plasminogen activator with fibrin, which has a good thrombolytic activity, does not reduce systemic clotting factors, and has a short half-life This is a remarkable advantage of Alteplase compared with non-specific plasminogen activators with fibrin 1.3 The roles of neuroimaging in acute ischemic stroke 1.3.1 Computed tomography (CT) Computed tomography plays a very important role in acute ischemic stroke The main advantage of computed tomography in comparison with MRI is the availability and the technique could be done quickly, cost-effectively For hyperacute stroke, computed tomography without contrast is often indicated for the exclusion or identification of intracranial hemorrhage Non-contrast CT should be performed as soon as possible in order to initiate the thrombolytic therapy in the best way The early signs of ischemic stroke on noncontrast computed tomography: In hyperacute phase, early ischemic signs on CT scans would hardly be found on noncontrast CT The sensitivity of standard noncontrast CT for cerebral infarction increases over time, particularly after 24 hours ASPECT score in assessing early ischemic changes on head CT scan: ASPECT score (the Alberta stroke program early CT score) is a simple and reliable method for assessing ischemic cerebral lesions on CT scans Currently, the score is applied in specialized neurodiagnostic units and plays an important role in thrombolytic treatment and endovascular interventions for stroke patients CT angiography (CTA): CTA is considered as a standard practice in managing acute ischemic stroke The CTA evaluation of cerebral blood vessels has high reliability In addition, it is possible to multiphase CT and CT perfusion 1.3.2 Magnetic Resonance Imaging (MRI) MRI characteristics of early changes in acute ischemic stroke including increased (hyperintense) DWI signal, hypointense signal on ADC maps and increased signals on FLAIR Diffusion-weighted imaging (DWI): This technique can detect ischemic abnormalities within to 30 minutes after stroke onset, meanwhile CT and standard MRI are not sensitive enough to expose the lesion MRI can be a good alternative for CT or in some cases, the combination of both models is the best option Magnetic Resonance Imaging (MRI): A magnetic resonance imaging (MRI) scan for narrowing or embolism is commonly performed as part of pulse trainings for patients with acute cerebral infarction MR angiography (MRA): MRA to detect vascular stenosis or occlusion is routinely done as part of a fast MRI protocol for acute ischemic stroke 1.4 Studies of intravenous Alteplase treatment International trials: An important breakthrough appeared in 1995, the National Institute of Neurological Disorders and strokepublicized NINDS trial It showed that the intravenous use of tissue plasminogen activator recombinant (rtPA) improve neurological function in patients with ischemic stroke after three months In 2008, the ECASS trial in Europe demonstrated the safety and efficacy of Alteplase when given at to 4.5 hours after the onset of stroke Since then, treatment window has been accepted from to 4.5 hours In Asia, Japan routinely uses low doses after approval by the Ministry of Health in 2006 By 2016, the ENCHANTED trial compared the outcome of standard dose and low-dose Alteplase within treatment window 4.5 hours The results shows that low doses (0.6mg/kg) was safer than the standard dose (0.9 mg/kg) with significantly fewer symptomatic intracerebral hemorrhages And in the low dose group, favorable outcome at months was equivalent to standard dose at the treatment window from to 4.5 hours However, the study did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days By now, many efforts have been made to develop a more efective drugs than Alteplase, but there is still not enough evidence Alteplase studies in Vietnam: The first case of intravenous rtPA treatment for acute ischemic stroke patients were reported by Phan Cong Tan from 2005 In 2006, the first study to evaluated the safety and efficacy of rtPA was done in three facilities: 115 People's hospital, Gia Dinh People's hospital and An Binh hospital At three months, the rate of good clinical outcome (modified Rankin 0-1) was 43%, symptomatic intracranial hemorrhage was 4%, mortality was 8% In 2013, Nguyen Huy Thang published the results of 152 patients treated with intravenous standard dose alteplase within hours after onset in 115 People's Hospital Good outcome rate(modified Rankin 0-1) at 90 days was 45% Symptomatic intracranial hemorrhage(sICH) was 4.6% The risk of death due to sICH was 71.4% Mortality rate at three months was 11.8% A research of Mai Duy Ton (2013), assessed the safety and effectiveness of treatment for acute ischemic stroke by intravenous low dose alteplase within hours window in 66 patients, at Bach Mai hospital, Hanoi The rate of good clinical outcome (Rankin 0-1) was 51.51% at 90 days; symptomatic brain hemorrhage was 1.52%; mortality was 3:03% This result showed that low dose Alteplase was safe and could be as efective as the standard dose regimen Currently, Alteplase remains the standard therapy for acute ischemic stroke for up to 4.5 hours after symptom onset Thrombolytic trials are ongoing to increase benefits, reduce risk and widen treatment windows to increase the number of patients using tPA 1.5 Predictive factors and scores 1.5.1 Predictive factors: To date, many studies have shown that factors that may be associated with prognosis include: Age, sex, treatment windows, blood glucose, history of diabetes mellitus, occlusion sites and causes of stroke 1.5.2 Predictive Scores: Neurologists and radiologysts have recently developed several diagnostic and prognostic scores for better dicision in stroke treatment Scores can be integrated multiple symptoms and signs, both clinical presentation and neuroimaging including, most importantly, ASPECT scores (CT), DRAGON, HAT (Clinical and CT combination), ASTRAL, NIHSS (Clinical only) CHAPTER 2: METHODS 2.1 Subjects Patients who admitted to Emergency department, Bach Mai hospital, diagnosis of acute ischemic stroke within 4.5 hours after the symptom onset, eligible individuals was to participate in the study, in the period from 20th of November 2014 to 1st of October 2017 The follow up ended in 02/2018 All patients who were eligible for the thrombolytic treatment by Alteplase generally had done urgent medical treatment on a rule of "time is brain" In cases the treatment indicated within hours after symptom onset, it was not allowed to delay Alteplase administration Only patients with objective, unforeseeable causes leading to the time of Alteplase injection have fallen into the window period of to 4.5 hours were eligible to included in this study Selection criteria were based on the sampling protocol of the NINDS and ECASS trials 2.2 Methods A longitudinal, prospective, descriptive study The variables and indexs were collected according to the purpose of study Stroke specialist and fellow had implemented the study The fellow collected data according to given medical record forms Data calculation and processing by STATA 14.0 Sample size was calculated by formula: Z21-α/2 p ( 1- p) n = d2 In which: n was minimal sample size; Z 1-α/2 = 1,96, was level of confidence; p = 52.4% was the rate of favorable outcome ( modified Rankin score ≤ 1) at months (52.4%) in ECASS trial that has criteriors and subjects similar to the study d was deviation = 0.1 Replace to the formula above,:we had n = 1.96 x 1.96 x 0.524 x 0.476/ 0.1 x 0.1 = 95.8 So, minimal sample size was 96 patients 2.3 Ethical issues in medicine The treatment protocol has been approved by the Bach Mai Hospital, the Ministry of Health and the Scientific Council The study did not alter the existing treatment regimens and procedures and did not generate any costs or any disturbance for the patient Patients and relatives were explained about the purpose of the study, the steps taken and their voluntary participation in the study Information regarding the patients was kept confidential 10 CHAPTER 3: RESULTS 3.1 Baseline clinical characteristics, CT scan presentations and stroke classification Table 3.1: Baseline clinical and CT characteristics Age (yrs) Mean 64.79 ± 9.75 Median 64 Male (%) 58.59 Time from onset to Alteplase treatment (mins) Mean 207.87 ± 26.5 Median 195 NIHSS Mean 11.93 ± 4.23 Median 11 DRAGON score Mean 4.68 ± 1.68 Median ASTRAL score Mean 25.83 ± 5.45 Median 25 HAT score Mean 1.24 ± 1.07 Median Pretreatment blood pressure (mmHg) Systolic 152.79 ± 21.73 Diastolic 84.65 ± 10.1 Neurologic clinical presentation (%) Impared level of consciousness 22.22 Hemiparesis 92.93 Hemisensory deficit 64.65 Cranial nerve paresis 92.93 11 Language impairment/aphasia Disarthria Extinction and inattention 35.35 63.64 30.30 History of diseases (%) Hypertension Diabetes mellitus Dislipidemia Athorosclerosis Atrial fibrillation Stroke Valvular heart diseases Heart failure Cigarette smoking Concomitant diseases (%) Mitral valve stenosis Heart failure (EF < 55) Mitral valve stenosis/ Heart failure Left ventricle thickness Baseline CT scan presentation ASPECT score (63 pts) Mean Median ASPECT = 10 ASPECT = ASPECT = ASPECT = Early signs on CT (%) Cortical sulcal effacement Focal parenchymal attenuation Loss of grey – white matter differentiation Loss of the insular ribbon 78.79 19.19 72.73 60.60 22.22 6.07 6.07 8.08 24.24 6.06 8.08 4.04 77.77 8.6 ± 1.11 (7 – 10) 26.98 % 23.81 % 28.57 % 20.64 % 16.16 54.55 40.40 28.28 12 MCA hyperdense sign - M1 segment MCA dot sign - M2 segment Normal CT Abnormal CT Occlusion positions (%) Middle cerebral artery (MCA) - M1 segment Middle cerebral artery (MCA) - M2 segment Middle cerebral artery (MCA) - M1 plus M2 Intracranial carotid artery ( ICA) plus M1 Intracranial carotid artery ( ICA) Anterior cerebral artery ( ACA) Posterior cerebral artery ( PCA) Basilar artery ( BA) Small vessels Total Etiologic classification (%) Large-artery atherosclerosis Small-vessel occlusion Cardioembolism Undetermined etiology Other determined etiology Total (99 pts) 3.2 Treatment Results Table 3.2: Treatment Results NIHSS changes after Alteplase administration NIHSS Mean Alteplase Pretreatment 11.93 ± 4.23 One hour after Alteplase loading 8.38 ± 5.11 24 hours after Alteplase loading 7.64 ± 5.69 At discharge 7.21 ± 5.32 NIHSS changes after 24 hours No of Patients 18.18 22.22 28.28 71.72 25.25 34.34 2.02 2.02 2.02 3.03 2.02 1.01 28.28 100 36.37 28.28 22.22 13.13 0.00 100 Median 11 7 Rate (%) 13 NIHSS improvement ≥ points 58 58.59 NIHSS worsening ≥ points 3.03 NIHSS changes within points 38 38.38 Total 99 100 Recanalisation rate at 24h according to MORI classification Mori score No of Patients Rate (%) Grade 35 49.30 Grade 11.27 Grade 12.67 Grade 19 26.76 Tổng số 71 100.00 Clinical Outcome at months Modified Rankin Scale (mRS) No of Pts Rate (%) mRS - 52 52.53 mRS - 31 31.31 mRS - 8.08 mRS = (death) 8.08 Total 99 100.00 Barthel Index (BI) ≥ 95 points 53 53.54 GOS (Glasgow Outcome Scale) = 48 48.48 Adverse events Symptomatic ICH No of pts Rate(%) According to ECASS definition 3.03 According to NINDS definition 5.05 According to ECASS definition 4.04 According to SITS - MOST 2.02 ICH subtype Hemorrhagic infarction - HI Hemorrhagic infarction2 - HI Parenchymal hematoma - PH Parenchymal hematoma - PH 10 2 10.10 2.02 1.01 2.02 14 Others Reocclusion Cardiac infartion Pneumonia Urinary tract infection Skin and mucous bleeding Ureter and bladder bleeding Alteplase allergy 3.3 Predictive factors and scores 1 2 3.03 1.01 1.01 1.01 2.02 2.02 0.00 3.3.1 Prediction related factors and the role of predictive scores Table 3.3: Univariate analysis of the relationship between factors and predictive scores with clinical outcome at months Factors/predictive scores Modified Rankin ≤ 1, n (%) > 1, n (%) Male 31 (59.62) 27 (57.45) Female 21 (40.38) 20 (42.55) < 50 (9.62) (6.38) ≥ 50 47 (90.38) 44 (93.62) < 60 17 (32.69) 11 (23.40) Genders Ages (years) ≥ 60 35 (67.31) 36 (76.60) < 70 34 (65.38) 29 (61.70) ≥ 70 18 (34.62) 18 (38.30) OR p 1.09 0.827 1.56 0.558 1.58 0.307 1.17 0.704 15 Baseline NIHSS Time from onset to treatment (mins) Diabetes mellitus History of hypertetion Atrial fibillation < 16 48 (92.31) 32 (68.09) ≥ 16 (7.69) 15 (31.91) < 210 31 (59.62) 25 (53.19) ≥ 210 21 (40.38) 22 (46.81) < 240 39 (75) 39 (83.98) ≥ 240 13 (25) (17.02) No 51 (98.08) 28 (59.57) Yes (1.92) 19 (40.43) No (17.31) (12.77) Yes 43 (82.69) 41 (87.23) No 45 (86.54) 32 (68.09) Yes (13.46) 15 (31.91) No (17.65) 12 (25.53) Dyslipidemia Yes 42 (82.35) 35 (74.47) No 29 (55.77) 10 (21.28) Yes 23 (44.23) 37 (78.72) Cardioembolic No 45 (86.54) 32 (68.09) stroke Yes (13.46) 15 (31.91) Abnormal No 26 (50) (4.26) MCA occlusion 5.63 0.004 1.3 0.520 1.625 0.335 34.61 0.001 1.43 0.530 3.01 0.031 1.6 0.344 4.67 0.001 3.01 0.031 22.5 0.001 16 Brain CT scan Yes 26 (50) 45 (95.74)