對於複雜性副肺炎積水(complicated parapneumonic effusion)正在形成膿胸(empyema)的過程中，是否只使用抗生素，或是需要何時該去做引流，或是採用何種方式的引流處理，目前對臨床醫師來說仍然是有很大的挑戰性。應用肋膜間施予纖維溶解激酶治療術(intrapleural fibrinolytic therapy)來治療複雜性副肺炎積水在臨床上是一種可能有效的治療方式，但是在孩童病患的使用上卻沒有足夠的資訊。因此，在我的博士論文裡，我嘗試去闡述對於兒童副肺炎積水，採用肋膜間施予纖維溶解激酶治療術，評估其臨床上的經驗與成果，並進一步探討其使用纖維溶解激酶治療術的實驗室證據。
我研究的特殊目的包括：一、研究在肋膜間施予鏈球菌激酶纖維溶解治療兒童複雜性副肺炎積水的臨床治療成果；二、設計一個前瞻性研究來探討比較施予肋膜間纖維溶解激酶的頻次，以提供未來治療方法的依據；三、收集病患在接受肋膜間施以纖維溶解激酶治療的術前及術後的肺肋膜積水為材料，應用蛋白質體學(proteomics)研究法，應用二維電泳膠片法及質譜儀分析，鑑定出治療前後的蛋白質變化；四、探討利用肋膜間施予纖維溶解激酶藥物來治療肺肋膜積水的病患之後的纖維溶解活性和細胞激素的發炎反應之間的相關性；五、利用肺功能儀器來追蹤兒童膿胸病患的長期肺功能預後。
第一部分的結果顯示，接受肋膜間纖維溶解激酶治療術的這組病患不論在發燒的天數以及需要進一步接受胸腔外科侵入性治療的比率，都比在過去使用傳統胸管引流合併抗生素治療的對照組明顯減少。因此我們初步認為施予膜間纖維溶解激酶治療術的臨床成果有效，而且可以減少外科手術治療的比率。
接著在第二部分的研究，為了探討比較施予肋膜間纖維溶解激酶的頻次，控制每天使用相等同的劑量下，在一組病患每天施予一次，另一組病患每天施予兩次；比較其臨床表徵、以及治療成果。結果顯示無論施予一次、或是施予兩次，纖維溶解酵素治療術的皆可以減少病患需要進一步接受胸腔外科侵入性的比率；兩種方法的臨床成果都有效。
在第三部分的研究顯示在治療前後的二維電泳膠片中，總共觀察到640對蛋白質點，而其中有76對膠片上的點具有統計上的差異；其中63個點在治療後減少，13個點在治療後增加。將這些點來做進一步的蛋白質鑑定時，總共在37個點中鑑定出25個不重覆的蛋白質。增加的蛋白質點主要是纖維蛋白的碎片增加，例如fibrinogen以及相關的蛋白，這足以解釋纖維溶解激酶的理論機制；減少的蛋白質點主要是一些蛋白酵素例如alpha-1-antitrysin及相關的蛋白，以及急性發炎性的蛋白質，例如haptoglobin以及相關的蛋白。總體來說，肋膜間施予纖維溶解激酶治療術不止有纖維溶解的機轉，也可能有調控發炎反應的可能性。
在第四部分的研究結果顯示，接受纖維溶解激酶治療的這一組病患在治療後有較高濃度的urokinase plasminogen activator(u-PA)，但也抑制了plasminogen activator inhibitor (PAI) 的濃度；同時也看到tissue inhibitors of metalloproteinase (TIMP-2)的濃度在治療後的下降，這結果暗示纖維溶解激酶治療可以藉由抑制PAI的活性來促進纖維溶解蛋白的活性，以及抑制TIMP-2可能對肋膜的發炎反應有調控的作用。
在第五部分的研究中，結果呈現接受纖維溶解激酶治療組的病患肺活量(Force vital capacity, FVC)以及第一秒用力呼氣容積(forced expiratory volume in one second, FEV1)比起接受傳統治療組與外科手術治療的兩組病患，都有統計上顯著的進步。這結果顯示纖維溶解激酶治療對於病患的長期肺功能也有改善的作用。
總括來說，我的論文證明了在兒童複雜性副肺炎積水的病患，利用肋膜間施予纖維溶解激酶治療術，在臨床上是一項可靠且有效的治療方法；纖維溶解激酶治療的角色，除了傳統的觀念是增加纖維溶解蛋白的活性，使肋膜積水容易清除外；同時也兼具有調控肋膜間發炎反應的可能性。因此在這種疾病的治療選項上，纖維溶解激酶治療術應該是一個重要的選項。

Parapneumonic effusions challenge clinicians to determine whether they will respond to antibiotics alone, or whether the patient requires pleural drainage to manage an established empyema or prevent an empyema from forming. Although chemical fibrinolysis has been used to manage complicated parapneumonic effusion, less information is available on using intrapleural fibrinolytic therapy in pediatric patients. Accordingly, in this PhD dissertation, I intended to investigate the clinical efficiency and laboratory evidence of intrapleural fibrinolytic therapy in children with complicated parapneumonic effusion.
The specific aims of my project were as follows: (1) to study the clinical effects of intrapleural instillations of streptokinase in the management of parapneumonic effusion in children; (2) to assess the frequency of administration of fibrinolytic treatment in order to provide evidence for clinical use; (3) to investigate the proteomic profiling data of complicated parapneumonic pleural effusion in pediatric patients, as obtained by two-dimensional gel electrophoresis (2D-GE) and protein identification using electrospray ionization tandem mass spectrometry (ESI-MS/MS); (4) to use a cytokine array kit to screen various cytokines in complicated parapneumonic effusion patients receiving or not receiving intrapleural fibrinolytic therapy to compare the differences between these two groups; and (5) to follow up a pulmonary function study in children with parapneumonic effusion.
The results for the first aim showed that the duration of fever after chest tube insertion was also significantly lower in the study group. Fewer patients in the streptokinase group required surgical intervention than in the comparison group. This led to the conclusion that intrapleural fibrinolytic therapy with streptokinase is safe and effective, and can obviate the need for surgery in most cases.
The results for the second aim showed that there were no significant differences between the once- and twice-daily groups. Thus, we found that both once- and twice-daily administration of urokinase were similarly efficacious and resulted in good clinical outcomes.
The results for the third aim showed that a total of 640 pairs of silver-stained protein spots were observed and 76 differences (13 increased, 63 decreased) were detected. Altogether, 37 significant changes to gel spots were selected for protein identification by in-gel digestion, liquid chromatography–tandem mass spectrometry and sequence database search. Among these proteins, those that significantly increased after fibrinolytic therapy reflected the effects of fibrinolytics, such as the fibrinogen gamma chain and fragments of fibrinogen. In those significantly decreased proteins, haptoglobin and related proteins, and alpha-1 antitrypsin and related proteins were observed. Taken together, we suggested that intrapleural fibrinolytic therapy enhanced fibrinolytic activity and decreased inflammatory activity in pleural space.
The results for the fourth aim showed the patients in the fibrinolytic study group had significantly lower plasminogen activator inhibitor (PAI) levels and higher urokinase plasminogen activator (u-PA) levels than before treatment. Moreover, the tissue inhibitors of metalloproteinase-2 (TIMP-2) were also significantly lower in the study group after fibrinolytic therapy. That might indicate that TIMP-2 is implicated in the local inflammatory response in complicated parapneumonic effusion patients.
The results for the fifth aim showed that the fibrinolytic group had significantly higher forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). These results also imply the benefits of intrapleural fibrinolytics.
In conclusion, my dissertation demonstrated the benefits of intrapleural fibrinolytic therapy in children with complicated parapneumonic effusion. The role of intrapleural fibrinolytics not only facilitated pleural effusion drainage by working on the plasminogen activator, but also demonstrated local anti-inflammatory effects in the pleural space. Accordingly, when using interventions to control complicated parapneumonic effusion using intrapleural fibrinolytics, one might consider therapeutic options for these patients.

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