2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649306摘要：心肺復甦急救的發展改善了心跳停止病患恢復自發性循環的機會，然而缺血再灌流的傷害、發炎反應的進行及多重器官急性失能之合併機轉，使復甦後心臟功能持續惡化並導致死亡，因此改善心臟功能為首要任務。心臟受損過程中，對傳遞收縮及舒張功能的路徑因子，都分別有決定性的影響。近來發展出不須經由β-adrenergic system 之的新藥物，改善心肌對鈣離子的敏感性及粒線體調控之levosimendan，增進心肌filament 於cross bridge 收縮強度之Omecamtiv mecarbil，及經由調控sarcoplasmic reticulum calcium ATPase isoform 2a (SERCA2a)使鈣離子於舒張期更快速移動之istaroxime，都有相當的潛力，然而其對復甦後心臟功能失調之效果仍未明。本計畫第一年將應用心跳停止復甦急救動物模式，檢視不同藥物對於復甦後心臟失調及存活預後的效果，並探討各面向之機轉，找出改善預後之關鍵步驟。由於心肌損傷的多面性，同時經由不同機轉的藥物治療，有進一步改善的潛力，因此將基於初步結果找出的有效藥物，發展合併藥物模式，找出最佳的組合，並於第二年完成。低溫治療現已是治療準則所建議的標準治療，在低溫之下，藥物的效果是否會因此而減少，或因機轉之互補而增加保護效果則未知。第三年則是在新的藥物合併治療模式發展出來之後，釐清其在現行低溫治療下之變化或調整方式，以作為臨床應用的基礎。<br> Abstract: Recent development of cardiopulmonary resuscitation medicine improves the chanceof return spontaneous circulation in cardiac arrest. However, the ischemia reperfusion injuries,progression of inflammatory reactions and acute multiple organ failure keep deteriorating thepost-resuscitation myocardial dysfunction and lead to mortality. Therefore, it is the key issueto improve cardiac dysfunction for achieving better outcomes. Signaling pathways andrelated factors are influenced and damaged after cardiac arrest and during post-cardiac arrestperiod. β-adrenergic system and its downstream pathways play important roles in maintainingthe cardiac function. In addition, there are novel inotropic medications focusing onnon-β-adrenergic system pathways. Levosimendan improves the sensitivity of myocardium tocalcium stimulation and mitochondria integrity. Omecamtiv mercarbil can strengthening thecross bridge in myocardial filament and improve the systolic function. Istaroxime regulatesthe calcium in-and-out of sarcoplasmic reticulum through regulating the sarcoplasmicreticulum calcium ATPase isoform 2a (SERCA2a). These drugs have potentials to improvethe myocardial function, however, their effects on post-cardiac arrest syndrome andmyocardial dysfunction remains unclear.We plan to investigate the responses of different inotropic agents on myocardialdysfunction and survival outcomes in cardiac arrest and resuscitation animal model in thefirst year. The mechanisms and related pathways will be studied to elucidate the criticalpathways of improving cardiac function and survival. Because of the multiple aspects ofmechanisms leading to post-resuscitation myocardial dysfunction, combination of differentdrugs has the potential to improve the cardiac function compared to the single agent treatment.We will combine the effective, but different mechanism, drugs in the study to set a newtreatment modality to ameliorating the post-resuscitation myocardial dysfunction further inthe second year project. Hypothermia treatment has been a guideline-recommended standardtreatment in post-cardiac arrest care. However, whether the effects of drug treatment areinterfered or synergized by hypothermia treatment remains unclear. In the third year, we willinvestigate the influence of therapeutic hypothermia on combined drugs treatment model andthe ways to adjusting the drug treatment model for maintaining the therapeutic effects undertherapeutic hypothermia. The results are the bases for improving clinical managements forcardiac arrest patients.心臟收縮藥物心跳停止復甦後心肌功能失調存活預後心肌收縮功能心肌舒張功能Inotropescardiac arrestpost-resuscitation myocardial dysfunctionsurvival outcomesystolic functiondiastolic function