2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660323摘要：本團隊系列研究專注於肝臟移植、肺葉切除及開心等手術後之再灌流傷害。先期的臨床觀察發現肝臟移植後，除了局部肝臟傷害之外，遠端的影響更包括肺部的水量增加，嚴重的病患甚至引發肺水腫，不但延長了加護病房照顧和住院的時間，也增加併發症與死亡率。同時，在我們所建立的肝臟的缺血－再灌流動物模式中證明:在肝臟缺血再灌流的過程中，大量氧化自由基的釋放是引發遠端肺功能損傷的主因，若能適時投予具有抗氧化性質的Propofol，可減少肝臟缺血再灌流所產生的氧化自由基，從而減輕整體性的肺部傷害程度。此外，我們也發現從選擇性單肺通氣恢復至雙肺通氣過程中，也會產生了大量的過氧化物，若同時施與Propofol 來維持麻醉深度，則會大幅的降低氧化壓力的產生。手術相關的組織傷害引發的劇烈疼痛是當前臨床醫療品質維護的重要的課題，因為傷口疼痛對人體是一個強大的壓力，缺乏良好的術後止痛會同時引發生理、免疫和心理上的多重變化，連帶影響病患的情緒和睡眠。以往的文獻也指出，越大的傷口會激發越強的免疫反應，產生較多的細胞激素。從組織傷害的全方位角度訊息傳遞鏈來審視，手術介入對於病患產生瞬間的組織破壞會引起三種不同形式的壓力反應(stresses): 術後傷口疼痛引起的傷害性神經反射(physiological stress)、情緒壓力(psychological stress)、發炎反應和前發炎細胞激素的增加(immunological stress)。但是在肝臟移植、肺葉切除及開心等手術後，再灌流傷害會釋放出大量氧化自由基引發一連串氧化壓力(oxidative stress) ，而對身體造成額外壓力傷害。由於充份的研究成果已經証明，良好的術後止痛可以加速術後復原並減輕發炎的反應，是透過傷害性神經反射和情緒感受的壓制所造成。但手術過程中若合併缺血再灌流而引發嚴重發炎反應的傷害時，術後止痛本身對開刀過程中缺血再灌流傷害的影響為何，迄今仍是未知數。本三年期計劃擬延續我們之前的研究，檢驗以下兩個假說:(一)傷口疼痛會加重術後缺血再灌流傷害的影響，(二)不同作用機轉的術後止痛模式會造成缺血再灌流的傷害的差異。本計畫的第一部分是在大白鼠實驗中，以之前建立的肝臟的缺血－再灌流模式，研究止痛藥是否對活體肺功能的變化、肺水腫、氧化傷害以及後續的發炎反應有減少的作用，並進一步探討不同的藥物、不同的給藥時機是否得到不同的結果 第二部份為在肝臟移植和體外循環的病人使用病患自控式止痛來統計所使用止痛藥的量，並使用疼痛評估量表來評估疼痛，來研究肝臟移植後疼痛的程度是否會影響肝臟缺血再灌流引發的全身性的發炎反應。第三部份為在需要單肺呼吸的病人，以不同的止痛藥物與不同的給藥途徑來探討是否會對氧化自由基的產生及後續的發炎反應產生影響。<br> Abstract: Our teamwork has been collaborating on reperfusion injury in both basicand clinical settings of liver transplantation, lung resection and openheartsurgeries requiring cardiopulmonary bypass. In liver transplant recipients, wefound that lung water increased to a variable extent that certain proportion ofpatients may develop pulmonary edema. The extensive adverse effect clearlyleads to longer intensive care unit stay, higher morbidity and eventual mortality.In another study, we demonstrated that the release of large amount of reactiveoxygen species plays a pivotal role in inducing remote lung injury under ourinnovative hepatic ischemia reperfusion animal model. Known as a powerfulantioxidative agent, propofol attenuates the decrease of dynamic compliance andwater content in the lung by decreasing oxidative radicals released from thereperfused liver. In patients switching from one-lung to two-lung ventilation, wedetected a massive superoxide surge which could also be reduced after propofolinfusion.Meanwhile, surgically-related tissue injury is known to trigger a series ofphysiological, immunological and psychological stresses. Cumulative evidencehas shown that surgical injury induces a systemic inflammatorymetabolic-endocrine response that is proportional to the severity of the surgicaltrauma. In patients undergone liver transplantation, intense pain associated withextensive incision and organ exploration could aggravate the concomitantoxidative stress caused by ischemia reperfusion injury. Previous reports haveshown that an adequate postoperative pain control could improve the recoveryand help reducing the subsequent inflammatory cascade by suppressing thephysiological and psychological stresses. However, the effect of postoperativepain management on ischemia reperfusion injury remains largely unclear. In thisongoing proposal, we will extend our earlier work to test two hypotheses: (1)postoperative pain will intensify remote organ injury caused by ischemiareperfusion, (2) various antinociceptive modalities will modify ischemiareperfusion injury at different scale.In the first part, based on our novel hepatic ischemia animal model, wewill compare both opioid and non-opioid analgesic agents on the inflammatoryresponses and remote lung injury in a dose-dependent and mechanistic-basedfashion. In the second part, we will compare the effects of variousmorphine-adjuvants combination formulations in patient-controlled analgesiaand regional analgesia in patients undergoing liver transplantation, lung resectionand open heart surgeries requiring cardiopulmonary bypass. In addition, we wishto clarify the interaction between nociception and various antinociceptivemodalities on ischemia reperfusion injury.缺血再灌流止痛模式病患自控式止痛硬脊膜外病患自控式止痛肝臟移植單肺呼吸ischemia reperufusion injuryantinociceptive modalitiesPCAPCEAliver transplantationone lung ventilation