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1 Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia 指導老師:林宏榮 鄭伯智 老師 學生:黃鈴詒 Li Sun, Wei Zhou, Christian.

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Presentation on theme: "1 Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia 指導老師:林宏榮 鄭伯智 老師 學生:黃鈴詒 Li Sun, Wei Zhou, Christian."— Presentation transcript:

1 1 Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia 指導老師:林宏榮 鄭伯智 老師 學生:黃鈴詒 Li Sun, Wei Zhou, Christian Mueller, Clemens Sommer, Sabine Heiland, Alexander T Bauer, Hugo H Marti and Roland Veltkamp Journal of Cerebral Blood Flow & Metabolism 30, 1651–1660, 2010 Impact factor : 5.478

2 2 Introduction

3 3 Stroke Stroke is a brain injury. It occurs when the brain's blood supply is interrupted. Without oxygen and nutrients from blood, brain tissue dies quickly (less than 10 minutes). This causes a sudden function loss.

4 4 Hemorrhagic stroke V.S. Ischemic stroke Hemorrhagic StrokeIschemic Stroke Hemorrhage/ blood leaks into brain tissue Clot stops blood supply to an area of the brain

5 5 Chan P.H., 2001

6 6 The activation and proteolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9, are key factors in the proteolytic disruption of the basal lamina and tight junctions of the BBB. Hawkins and Davis, 2005; Wang et al., 2003.

7 7 Therapy for acute ischemic stroke can be approached in two basic ways: First, by an attempt to restore or improve blood flow in an occluded vascular territory. Nighoghossian and Trouillas. 1997 Therapy for acute ischemic stroke Second, via therapy directed at the cellular and metabolic targets. Tissue plasminogen activator (t-PA) should be given within the first 3 hours after the first symptoms of stroke start.

8 8 Tissue plasminogen activator (tPA) Jaspreet Kaur, et al., 2004 (C)Beneficial effects of tPA are successful thrombolysis and restoration of CBF. (D) The deleterious effects come into play through the NMDA receptors, upregulation of MMPs, enhanced accumulation of PMNLs, and free radicals, which results in exacerbation of ischemic injury via excito-neurotoxicity, edema, and hemorrhage.

9 9 HBO  HBO might be more effective in stroke within the first few hours and at a pressure of 2–3 ATA.  HBO is to increase the solubility of oxygen in plasma to a level sufficient to support tissues with minimal extraction of oxygen carried on hemoglobin. Ann K et al. 2005

10 10 John H. Zhang et al. 2005

11 11 Hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) attenuated BBB permeability, edema and do not increase oxidative stress after focal and global ischemia. (Mink and Dutka, 1995; Singhal et al, 2002; Veltkamp et al., 2005a) NBO and HBO attenuates early BBB disruption and inhibition of MMP-9 mediated occludin degradation is an important mechanism for this protection. (Liu et al., 2009)

12 12 AIMS Examine the differences in the effectiveness of oxygen therapy on postischemic BBB damage and secondary hemorrhage after thrombolysis.

13 13 Materials and Methods

14 14 Brain Ischemia thrombin-induced thromboemboli (TT-tMCAO) calcium-rich thromboemboli (CT-tMCAO) Toomey et al., 2002 It was allowed to coagulate spontaneously for 2 hours at 37 ℃. It was exposed to a 20 mmol/L calcium solution for 1 minute. Mixed with 1.0 National Institutes of Health (NIH) units of human thrombin and 5 μL of 1 mol/L CaCl 2 Twelve thrombi — each 0.35mm in diameter and 1.5mm in length

15 15 Spontaneously hypertensive Rat (300-350g) TT-tMCAO CT-tMCAO 60 minutes air 100% O 2 at ambient pressure (NBO)100% O 2 at 3 bar (HBO) 60 minutes Gelatin ZymographyMRI assay T1W, T2* DWI, PWI MMP-9 and MMP-2 Physiology parameter MABP,heart rate, blood gas Hemoglobin Assay rt-PA (9mg/kg) Histologic staining 30 minutes

16 16 1. MRI assay PWI document the perfusion status after thrombolysis and at the end of the experiment Lesion volume was quantified in Diffusion-weighted imaging (DWI) brain sections at 2.5 and 24h after tMCAO. tMCAO 1hr Air HBO NBO 0hr 24hr 2.5 hr 2hr rt-PA DWI, PWI

17 17 1. MRI assay tMCAO 1hr Air HBO NBO 0hr 24hr 2.5 hr 2hr rt-PA T1w, T2* Postischemic BBB damage was analyzedon postcontrast T1w images. T2* MR imaging was used to detect ‘macroscopic’ intracerebral hemorrhage.

18 18 2. Spectrophotometric Hemoglobin and Gelatin Zymography Assay Spectrophotometric assay  the hemoglobin content of brains. Gelatin zymography  protein expression of MMP-2 and MMP-9 at ischemic and nonischemic hemispheres. tMCAO 1hr Air HBO NBO 0hr 24hr 2hr rt-PA Hemoglobin content MMP-2 and MMP-9

19 19 3. Histologic staining- secondary hemorrage Coronal cryosections  the secondary hemorrage of brains was compared with T2* on corresponding sections. Erythrocytic extravasations  assess the severity of erythrocytic extravasations 24hr after CT-tMCAO. tMCAO 1hr1hr Air HBO NBO 0hr0hr 24hr 2hr2hr rt-PA coronal cryosections Erythrocytic extravasations

20 20 Results

21 21

22 22 Figure 1. Hyperintense lesion volumes on magnetic resonance diffusion-weighted images at 2.5 and 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO) (mm3). TT-tMCAO CT-tMCAO MRI-DWI (Lesion volume)

23 23 In TT-tMCAO, NBO and HBO significantly reduced lesion volume on DWI compared with air. In CT-tMCAO, only a transient trend toward reduced lesion volume was detected in the HBO group at 2.5 hours but no differences were seen at 24 hours after tMCAO. Oxygen therapy can reduce lesion volume after thrombolysis. SUMMARY 1

24 24 Figure 2. Volume of enhancement on postcontrast T1w magnetic resonance images 2.5 and 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO) (mm3). MRI-T1w (BBB damage) TT-tMCAO CT-tMCAO

25 25 In TT-tMCAO, HBO significantly reduced postischemic BBB damage on T1w images. In CT-tMCAO, HBO also significantly reduced postischemic, at 24 hours after tMCAO, whereas NBO failed to attenuate the enhancing volume on T1w Images. Hyperbaric oxygen therapy significantly reduces BBB damage after thrombolysis. SUMMARY 2

26 26 TT-tMCAO Figure 3. Correspondence of blood–brain barrier damage, infarct lesion, and secondary hemorrhage. T1w T2* cryosections BBB damage intracerebral hemorrhage 2.5hr24hr

27 27 Figure 4. Multimodal magnetic resonance imaging images showing the topography of the parenchymal infarct (diffusion weighted imaging (DWI) at 24 hours), blood–brain barrier permeability (postcontrast T1w at 2.5 hours), and hemorrhage (T2* at 24 hours). 24 hr 2.5 hr 24 hr Hemorrhage BBB damage Lesion volume TT-tMCAO MRI assay

28 28 Figure 5. Erythrocytic extravasation on trichrome-stained coronal brain sections at the level of the bregma +0.26mm (anterior commissure) 24 hours after calcium-induced thromboemboli-middle cerebral artery occlusion without recanalization. CT-tMCAO 24hr Ischemic striatum (score 4) Contralateral cortex without erythrocytic extravasation Ischemic cortex (score 2) Histologic staining- erythrocytic extravasation

29 29 Figure 6. Hemoglobin spectrophotometry of perfused ischemic brain hemisphere after thromboembolic middle cerebral artery occlusion (tMCAO). Hemoglobin content

30 30 Figure 7. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO). TT-tMCAO 24hr Expression of MMP-2 and MMP-9 MMP-9 MMP-2

31 31 Thus, both NBO and HBO induced a significant reduction in macroscopic hemorrhage on T2* MR image. The area of hypointense T2* signal at 24 hours after MCAO was located within the area of intense postcontrast enhancement on T1w images at 2.5 hours after MACO. In TT-t MCAo and CT-tMCAO, HBO significantly decreased the mean hemoglobin volume. 1.Early increase in BBB permeability appeared to indicate a risk for later secondary hemorrhage. 2.HBO significantly reduces infarct volume, BBB permeability, hemorrhage and MMP-9 activity after thrombolysis. SUMMARY 3

32 32 Conclusion

33 33 Oxygen therapy can decrease infarct size and BBB damage after thromboembolic ischemia and reduce postthrombolytic intracerebral hemorrhage.

34 34 Thank you for attention

35 35 Oxygen therapy in combination with thrombolytic therapy only affects infarct size if recanalization is successful. Oxygen therapy reduce size and frequency of gross parenchymal hemorrhage after thrombolysis- induced reperfusion. HBO and NBO reduce early BBB permeability after tMCAO, which is a marker for subsequent hemorrhagic complications of thrombolysis. Oxygen therapy improves microvascular integrity even in regions that undergo parenchymal infarction

36 36 缺血性中風阻塞之機轉不同可分為腦 血栓 (cerebral thrombosis) 腦血栓原發 於血管壁,因血液凝固 (coagulation) 而 阻塞,並不移動 。腦栓塞 (cerebral embolism) 而腦栓塞則是血管壁沒有太 大的問題,乃血管上游的漂流物漂下 來把血管阻塞。 cerebral thrombosis cerebral embolism

37 37 血栓的種類與溶解血栓的種類 一、血栓的種類  1. 靜脈血栓 由於靜脈流速慢、血壓低。 血栓之成因是活化纖維蛋白、攔住血球細胞形成,因為有紅血 球的參與,故呈現紅斑狀。 臨床以抗凝血劑為主。  2. 動脈血栓 動脈管壁厚而有彈性,血流速度變快、血液壓力大。 血栓的形成主要是因血小板附著凝集。 臨床以抗血小板藥物為主。 

38 38 抗血栓藥物 1. 抗凝血劑 (anticoagulant drugs) 2. 血栓溶解藥物 (thrombolytic drugs) 3. 抗血小板藥物 (antiplatelet drugs)

39 39 血液凝固路徑及抗凝血藥物的作用部位

40 40 血栓的溶解機制  人體內有一連串的血栓溶解酶存在,即胞漿素 (plasmin) , 它是一種強力的纖維蛋白溶解酶 (fibrinolysin) ,平常不具活性的胞 漿素原 (plasminogen) 經活化成胞漿素後才有溶解纖維蛋白作用。

41 41 血栓溶解劑血栓溶解劑 血栓溶解劑 (thrombolysis agents) 可活化胞漿素原 (plasminogen) ,又稱為纖維蛋白溶解劑 (fibrinolytics) 。 當血栓形成後,必須在 3~6 小時內給藥,血塊的溶解機率 很高,超過 72 小時則無效。 臨床用途:治療深部靜脈栓塞(如肺栓塞)和急性動 脈栓塞,特別是急性心肌梗塞病患的冠狀動脈栓塞。

42 42 Alteplase Recombinant 1. 來源及作用機轉 利用基因重組工程製造之人體的蛋白質,為常用之組織型胞 漿素活化劑 (t-PA) 其特點是 只活化已和血栓結合之胞漿 素原,對纖維蛋白具有高度選擇性 ,不易引起全身性 的出血現象,靜脈注射給藥,半衰期短,無抗原性。 2. 臨床用途:主要用於治療急性心肌梗塞和急性肺栓塞,另 改善腦中風病人的後遺症。

43 43 V O 2 /V B = 1.39  Hb  S O 2 Oxygen Content in Blood on HBO PO 2, mmHg O 2 content, ml/dl Dissolved Hgb-bound   PO 2 + 1.39  Hb  SO 2 Dissolved O 2 =   P O 2 = 0.003 x 2000 [3 ATA] = 6.0 ml/dl Hb bound O 2 = 1.39  Hb  SO 2 = 1.39 x 14 x 100%  19.7 ml/dl 3 ATA Total

44 44 高壓氧治療( Hyperbaric Oxygen Therapy , HBO ) 1. 定義: HBO 是指將病人置於大於一大氣壓的高壓艙內(壓力通常介 於 1 至 3 大氣壓),給予 100% 的氧氣使病患吸入的一種治療方式。 2. 應用:藉以 提高體內含氧濃度,改善組織缺氧、減少腦水腫, 並對厭氧菌產生抑菌、殺菌的功能,促進嗜中性白血球殺菌力, 降 低缺血再灌流中白血球吸附的情形 ( Leach et al., 1998 ),促進 傷口癒合,進而達到治療目的。

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