前言：即使是在現代醫療，嚴重敗血症或敗血性休克病患的治療仍然是重症照護很大的挑戰，在加護病房的死亡率在不同的報告可達30-60%，其中器官功能的衰竭的出現與病患的死亡率有明顯的關係。但我們對於敗血症引發各種器官功能衰竭的機轉仍不是很了解，同樣的預測各種器官衰竭的發生及預後在臨床上是很困難的。在臨床重症的病患中發現白血球與血管內皮細胞的交互作用在疾病的進程與器官功能衰竭與否扮演關鍵角色。活化的白血球釋放出發炎反應因子，會導致血管內皮的細胞黏著因子表現量上升，進而造成遠端器官的傷害。而白血球細胞發生凋亡，與全身免疫反應的調節中扮演重要的角色。血管內皮前驅細胞與血管內皮細胞新生與修復有關，因此血管內皮前驅細胞數量應能代表嚴重敗血症的嚴重程度。
方法：我們假設1) 上述的生物標記在嚴重敗血症的病患中能夠用於預測疾病的嚴重度及做為臨床治療的指標; 2) 這些體內血液中生物標記的變化與肺、腎臟、腦功能的衰竭存在著相關性。3) 敗血症所致的器官功能衰竭可能後續造成長期性的病變。我們藉由規則性的測定嚴重敗血症病患的血中生物標記及器官衰竭的標記來評估其結果。
結果：研究結果顯示，嚴重敗血症患者不同的白血球其細胞凋亡比例其與疾病嚴重度有，血液不同程度的相關性。血管內皮前驅細胞的比例也與高死亡率有關，而血液中的不同的細胞黏著因子也與敗血症引發的器官衰竭有顯著的關係。
討論：這一系列的研究證實了敗血症的嚴重度與白血球與血管內皮間的交互作用有著明顯的相關性，未來臨床上可用於預測疾病的嚴重度及發展治療策略的重要指標。

Introduction: Severe sepsis and septic shock remain a great challenge in intensive care despite improvements in modern treatment. It stands the major cause of death in patients admitted to the emergency department (ED) and intensive care units (ICU), with a mortality rate varying between 30% and 60% in different reports. But we still did not well known about the mechanism of sepsis and it is very difficult to predict the incidence and outcome of sepsis and sepsis induced organ failure. The inflammatory cytokines and cell adhesion molecules liberated from activated leukocytes and endothelial cells promote further organ damages. Apoptosis is a complex process and white blood cells apoptosis is believed critical relate to inflammation and secondary tissue injury. Circulating endothelial progenitors cells (EPCs) believed critical to negatively correlate to outcome of patients with sepsis since it represent the severity of endothelium injury.
Method: We hypothesize that significantly increased these inflammatory biomarkers, increase leukocyte apoptosis and endothelium progenitor cells in severe sepsis patients would relate to higher mortality rate and connect to specific organ dysfunction. We also speculate that these biomarkers could help in the clinical treatment and severity prediction. We conducted these studies by series checking the serum biomarkers of inflammation and record about their organ dysfunction and try to find their correlation.
Results: The result of these studies showed lymphocyte and monocyte apoptosis, endothelium progenitor cells is significantly higher in severe sepsis patients. Cell adhesion molecules are associated with various organ failures in severe sepsis patients.
Discussion: These series studies revealed that leukocyte and endothelium interaction play an important role on the progression of sepsis. In the future, this will be an important issue on the prediction of disease severity and treatment of sepsis induced organ failure.

目 錄
論文審定書………………………………………………..……………….i
論文公開授權書………………………………………..……………….ii
誌謝…………………………………………………………….………..iii
中文摘要…………………………………………………………….….…iv
英文摘要………………………………………..………….……...…….…v
目錄…………………………………………………..........………………vi
圖次…………………………………………………...…………………ix
表次…………………………………………………….…………….….…x
前言 內容簡介Introduction…………………………...……………….1
核心推論 Central hypothesis………………………………….…………12
第一章 研究對象和實驗方法Patients, methodology and statistics......13 1.1-Baseline characteristics of the study patients………………...…...14
1.2-Methods and Materials……………………………………………17
第 二 章 循環中的內皮前驅細胞可以預測嚴重敗血症病患的預後Circulating endothelial progenitor cells may predict outcome in severe sepsis……………………………………………………………………...25
2.1-Circulating endothelial progenitor cells and sepsis ……….........26
2.2-Material and methods…………….………………..………..........28
2.3-Result………………………………..…………..………………29
2.4-Discussion……………………………………………………….37
2.5-Conculsion….………………..…………………………………41
第 三 章 在急診嚴重敗血症患者以白血球細胞凋亡來預測疾病嚴重度The prognostic value of leukocyte apoptosis in patients with severe sepsis at the emergency department……………………………...…….42
3.1-leukocyte apoptosis and sepsis ……………………………..……43
3.2-Material and methods……….……………………..………..........45
3.3-Result………………………………………………………….…463.4-Discussion………………..……………………………………58
3.5-Conclusion………………..…………………………………63
第 四 章 探討細胞黏著因子和嚴重敗血症患者發生敗血性腦病變的相關性The cell adhesion molecule is associated with septic encephalopathy in severe sepsis patients……………………….………64
4.1-Septic encephalopathy mechanism and related biomarkers……65
4.2-Material and methods……….……………………..………..........68
4.3-Result……………………………………………………………69
4.4-Discussion………………….……………………………….…79
4.5-Conclusion...………………….……………………………….…81
第 五 章 血清中的細胞黏著因子與敗血症誘發的急性腎衰竭的相關性 The value of serial serum cell adhesion molecules in predicting acute kidney injury after severe sepsis …………………...……………82
5.1-Septic kidney injury mechanism and related biomarkers………83
5.2-Material and methods……….……………………..………..........86
5.3-Result…………………………………………………………….88
5.4-Discussion…………………………………………………..…100
5.5-Conclusion...………………….……………………………….104
第 六 章 細胞黏著因子和嚴重敗血症患者發生呼吸衰竭的預後之相關性Serum adhesion molecules as outcome predictors in adult severe sepsis patients requiring mechanical ventilation ………………….…105
6.1-Sepsis induced respiratory failure and related biomarkers……106
6.2-Material and methods……….……………………..………........108
6.3-Result…………………………………………………………108
6.4-Discussion………………………………………………………117
6.5-Conculsion……………………………………………………121
第 七 章 討論 Discussion……………………………………….…....122
第 八 章研究之限制和未來研究方向 Limitation of current study and future research….……………………………………………...……….130
8.1- Limitation of current study……………..………………………131
8.2- Future research………………………...……………………….134
參考文獻 Reference…………..………………………………….……136
附錄…………………………………………………..………………….151
附錄1--英文縮寫全文……………………...…………………………..152
附錄2--Circulating endothelial progenitor cells may predict outcomes in adult patients with severe sepsis in the emergency department….………..
附錄3--The prognostic value of leukocyte apoptosis in patients with severe sepsis at the emergency department…………………………………………
附錄4-- Serum Adhesion Molecules as Outcome Predictors in Adult Severe Sepsis Patients Requiring Mechanical Ventilation in the Emergency Department……………………………………………..…………..……….
附錄5-- Elevated serum vascular cell adhesion molecule-1 is associated with septic encephalopathy in adult community-onset severe sepsis patients…………...…………………………………………..……………..
附錄6-- The value of serial serum cell adhesion molecules in predicting acute kidney injury after severe sepsis in adults ……………………………

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