醫學院: 臨床醫學研究所指導教授: 孫維仁; 陳朝峰詹光政Chan, Kuang-ChengKuang-ChengChan2017-03-062018-07-062017-03-062018-07-062016http://ntur.lib.ntu.edu.tw//handle/246246/277321肝臟移植手術被廣泛接受是對很多不可逆的急性或慢性肝臟疾病最有效的治療方式，最早進行肝臟移植這種手術時通常是被認為在臨床情況非常嚴重的時候才當成最後一線的治療方式。然而到了現在，這種手術已經成為常規手術而且在存活品質和存活時間方面都有很好的結果。肝臟移植手術結果改善與進步的原因包括整個圍術期技術的成熟與進展、對嚴重肝病的病程有更清楚完整的了解、更有效的免疫抑制劑的進步以及更完善的術後照顧。然而即使有這麼多實質上技術性、內科醫學以及外科手術的進展，肝臟移植手術仍然是會伴隨著很多嚴重的致病率和致死率的複雜手術。肝臟是一個跟全身所有的生理系統都有相互作用的重要器官，所以當一個病人接受了肝臟的移植片時身體就會面臨一連串巨大的生理變化，這些巨大的生理變化和反應可能會導致非常不同的後果或併發症。主要的手術後併發症跟手術的技術以及全身性的內科疾病有關，例如肺部、腎臟、心臟或神經系統的問題。手術後很快就出現併發症的風險，跟病患手術前的狀況、捐贈者肝臟的好壞、捐贈者和受贈者手術的品質、一開始移植肝臟作用的情形、以及圍術期麻醉和加護病房的照顧和處理有很大的關連性。肝臟移植後產生的疾病，很重要一部分是缺血再循環傷害的結果。身為一位麻醉醫師，本論文的首要目的是將利用已建立肝臟缺血再循環引發肺損傷的動物模式，來探討肝臟缺血再循環與產生的氧化自由基之間的關聯性，以及這些損傷對肺功能的影響。更進一步在病人身上也會探討肝臟移植後常見的肺部併發症，以及利用檢驗脈衝輪廓連續心輸出量系統肝臟移植後發生急性肺損傷和血管外肺水量之間的關聯性。脈衝輪廓連續心輸出量系統是利用經肺熱稀釋的方式來測定心輸出量，和胸腔的容積指標例如胸腔內血容量指數，血管外肺水量指標，以及肺部血管通透性指數等參數，這些參數的變化可能可以反映肺部的水量和受傷害的情形。再者，麻醉藥物如麻醉藥物如揮發性和非揮發性的麻醉藥物可以透過不同的機轉來減少氧化傷害，Propofol由於有類似維他命E酚環的構造而有類似的清除氧化自由基的效用，而揮發性麻醉氣體則可透過麻醉劑預適應的作用來減少氧化傷害，本論文的第二個目的是探討不同的麻醉方式在肝臟缺血再循環動物模式和肝臟移植手術中所產生的遠端肺部損傷是否有差異。肝硬化合併之心肌病變是發生在肝硬化的臨床狀況，包含在有壓力的情況下心臟收縮異常、心肌舒張異常、以及在沒有已知心臟疾病下的電生理學異常。本論文的第三個目的是利用心率多尺度熵來評估末期肝病並將接受移植病患的心臟電生理學術前和術後的變化。此外，為了更進一步清楚這些胸腔的容積指標是否為潛在造成術後急性肺損傷的危險因子，我們將會用多變數邏輯回歸分析來檢查。最後我們假定足夠的心率變異分析值可以預測肝臟移植病患有較好的心臟反應和存活率。 肝臟缺血再循環引發遠端肺損傷的大鼠動物模式實驗的結果顯示，動態順應性在肝臟再循環後隨著時間顯著的下降，而這個肺功能降低的情況可能跟產生大量的氧化自由基有關。而在肝臟移植的臨床試驗中顯示出手術後發生急性肺損傷的病人在肝臟移植前的血管外肺水量指標以及肺部血管通透性指數都比沒有發生急性肺損傷的病人要來的高。圍術期監測這些胸腔的容積指標可能在臨床上可以提供更多的資訊來幫助圍術期肝臟移植的照護。 而探討不同麻醉藥物對肝臟缺血再循環引發遠端肺損傷的動物研究中顯示出Propofol的輸注可以藉由一開始減少由肝臟釋放出的氧化自由基的產生來減少遠端的肺損傷。而臨床試驗顯示在肝臟移植手術中利用兩種不同麻醉藥物來維持手術中的麻醉深度，兩組的臨床結果並不會有差異，而且兩種麻醉術中和術後的氧化自由基也沒有顯著的上升。 臨床試驗研究肝臟移植病患的心臟電生理學試驗中顯示心率多尺度熵可以用來評估肝臟疾病的嚴重度，心率多尺度熵在評估自主神經失調的狀況可能比傳統線性的心率變異分析有更好的敏感度。心率多尺度熵在肝病較嚴重的病患(末期肝病評分系統分數≧25 )在第七天時就跟嚴重度較低的病患沒有差別了。 臨床試驗探討肝臟移植後產生術後急性肺損傷的研究中顯示肝臟移植病患在手術前的肺部血管通透性指數大於1.7時可能在肝臟移植手術後有較高的產生急性肺損傷的風險。 在肝臟移植病患的心律變異分析預測術後結果的臨床試驗中顯示末期肝病評分系統分數加上心臟血管的生物標記包含心跳減速能力和心率複雜度會比單純使用末期肝病評分系統分數有較好的預測肝臟移植一年存活率的能力。心率調控能力較差的病人在肝臟移植術後有比較高的死亡率。 因此，具備這些在肝臟移植追蹤期可能產生的併發症的完整知識，早期且正確地建立診斷，而立刻採用適當的治療方法是對病患和移植到病人身上的肝臟是非常重要的，也可因此更加提高病患的存活率和移植手術後的生活品質。Liver transplantation is the treatment of choice for a variety of irreversible end-stage liver disease. The results of liver transplantation have improved in recent years due to advances in perioperative technique, a better understanding of the course of several liver disease, improved immune-suppressive therapy and more effective postoperative care. However, despite substantial technological, medical and surgical advances, liver transplantation remains a complex procedure that is accompanied by significant morbidity and mortality. The main complications in the postoperative period are related to surgical techniques and systemic medical problems such as pulmonary and cardiovascular complications. The risk of developing early postoperative complications is associated with the patient’s preoperative condition, the quality of the donor and recipient procedure, and perioperative anesthesiological and intensive care management. The morbidity associated with liver transplantation is partly a result of ischemia and reperfusion (I/R) injury. As an anesthesiologist, the first aim of this thesis is to investigate the relationship of oxidative injury and remote respiratory function by an I/R maneuver of the liver in a rat model. Furthermore, we also investigated the commonly seen pulmonary complications following liver transplantation and to determine the relationship between postoperative acute lung injury and extravascular lung water index following liver transplantation by using pulse contour cardiac output (PiCCO) system. The PiCCO system uses the transpulmonary thermodilution technique to determine the cardiac index (CI) and thoracic fluid indices such as the intrathoracic blood volume index (ITBVI), extravascular lung water index (EVLWI), and pulmonary vascular permeability index (PVPI), all of which may reflect pulmonary fluid and injury status. Moreover, to further clarify that whether the thoracic fluid indices are potential risk factors to postoperative ALI, we calculated a multiple logistic regression model which aimed to include possible risk factors in our patients. Volatile and non-volatile anesthetics can exert their antioxidant capacity through different mechanisms. Propofol (2,6-diisopropylphenol) has been reported to provide antioxidant capacity by scavenging free radicals, whereas volatile anesthetics can reduce the oxidative damage through anesthetic preconditioning. The second aim of this thesis is to investigate the different anesthetic strategy on remote lung injury following hepatic I/R and liver transplantation. Cirrhotic cardiomyopathy is a clinical condition in liver cirrhosis consisting of systolic incompetence under condition of stress, diastolic dysfunction related to altered diastolic relaxation, and electrophysiological abnormalities in the absence of any known cardiac disease. The third aim of this thesis is to evaluate the cardiac electrophysiological abnormalities of transplantation candidates with end-stage liver disease by using heart rate multiscale entropy (MSE) before and after liver transplantation. Lastly, we hypothesized that sufficient heart rate variability (HRV, as represented by the deceleration capacity (DC) value) and heart rate complexity (HRC) are suggestive of better cardiac responsiveness and survival for liver transplant recipients. The results of animal research of remote lung injury following hepatic I/R revealed that dynamic compliance was significantly decreased with time after reperfusion, which may be associated with the production of reactive oxygen species (ROS). The results of clinical research of liver transplantation revealed that pretransplant EVLWI and PVPI are higher in recipients who develop postoperative ALI. Monitoring thoracic indices perioperatively may provide clinicians with helpful information facilitating their delivery of postoperative care. The results of clinical research of risk factors of postoperative pulmonary complication following liver transplantation revealed that recipients with the pretransplant PVPI > 1.7 may be at higher risk to develop postoperative ALI. The results of animal research of anesthetic strategy on remote lung injury following hepatic I/R revealed that Propofol infusion was shown to attenuate remote pulmonary dysfunction through an initial reduction of ROS production from the reperfused liver. The results of clinical research of anesthetic strategy on pulmonary complication following liver transplantation revealed that the clinical outcome of the two commonly used anesthetics group were comparable and the ROS production didn’t change significantly during the period of investigation in both groups. The results of clinical research of cardiac electrophysiological abnormalities of transplantation candidates revealed that cardiac electrophysiological alterations in end stage liver disease can be assessed by MSE. MSE may be a more sensitive method to evaluate autonomic dysfunction in end stage liver disease than conventional linear HRV analysis. MSE in patients with MELD score ≧ 25 can improve with no difference compared to MELD < 25 in 7 days. The results of clinical research of HRV analysis in liver transplant recipients revealed that adding cardiovascular biomarkers including DC value and HRC to MELD score improved the ability of the model to predict one-year survival after liver transplantation. Thus, knowledge of complications that emerge during follow up period, early and accurate establishment of diagnosis, and prompt institution of appropriate interventions are essential for optimal patient and graft outcome.6184109 bytesapplication/pdf論文公開時間: 2016/2/24論文使用權限: 同意有償授權(權利金給回饋學校)肝臟移植肝臟缺血再循環遠端器官傷害血管外肺水量指標肺部血管通透性指數心律變異分析心率多尺度熵Liver transplantationhepatic ischemia reperfusionremote organ injuryextravascular lung water indexpulmonary vascular permeability indexthesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/277321/1/ntu-105-D92421010-1.pdf