臺灣博碩士論文加值系統

急性呼吸衰竭一直是重症病患罹病與死亡的重要原因之一，近幾十年來新型呼吸治療技術在新生兒，孩童或成人都有相當大的進步，但仍有少數病患死於極嚴重的呼吸衰竭，或是雖然存活卻因各種併發症產生了慢性肺病。因此如何改善呼吸治療技術以降低併發症與死亡率，是目前重症醫療的一大課題。使用氟碳化合物(Perfluorochemical, PFC)的液體輔助式通氣術(Liquid-assisted ventilation)是一種不同於傳統的呼吸治療技術。此技術的重點在於PFC對於氧氣與二氧化碳有極佳的溶解度，而且已有一些動物實驗發現使用PFC來治療急性肺損傷(Acute lung injury, ALI)之療效。目前部份液態通氣術(Partial liquid ventilation, PLV)是已在進行人體試驗的技術，較被病患和醫療人員接受。然而其相關的機轉，以及在各種不同原因造成的肺損傷的應用上，仍有許多地方須要進一步的研究。本研究的目的是要了解使用PLV治療不同原因引起的ALI時，相關的影響因素、機轉與技術之改良。
本研究方法分為五部份：第一部份吾人藉生理食鹽水灌洗術引發類似早產兒表面張力素缺乏的肺損傷於初生乳豬動物模式上，使用PFC液體(FC-77)來施行PLV，觀察治療效果、補充劑量及病理組織變化，並與正常動物作比較來了解療效極限與相關機轉。第二部份吾人使用相同PLV技術，治療木屑煙吸入性肺損傷所引發嚴重急性呼吸窘迫症候群(Acute respiratory distress syndrome, ARDS) 之初生乳豬動物模式，來了解PLV這種技術治療ALI且合併有全身發炎反應之ARDS時所能達到的療效；同時，也比較加上表面張力素治療與否之影響。在研究第三與第四部份時，吾人分別採用健康與經生理食鹽水灌洗術引發ALI之幼兔動物模式，並採用目前人體試驗所使用的PFC液體(Perflubron)，研究影響其揮發量之相關因素，與肺中存留量對療效的影響。第五部份則採用前人尚未用過的PFC混合配方液體（不同比例的PP2與PP9）來施行PLV，治療經生理食鹽水灌洗術引發ALI之幼兔動物模式，嘗試調配出適用於PLV的理想液體。
本研究結果發現以FC-77施行PLV來治療初生乳豬之肺損傷動物模式可以促進較佳之氣體交換、減輕肺組織病理變化以及改善肺功能，但是相較於正常肺而言，仍有一段差距；而且要維持PLV之療效須間隔一段時間補充FC-77之揮發量。 此外，在治療因木屑煙吸入性肺傷害所引致之ARDS實驗中，發現不論是單獨使用PLV或合併使用表面張力素與PLV均有療效，但兩者合併之組合療法並無進一步加成效果，且不論治療方式為何，所有動物之血壓均呈逐漸變壞現象。另一項發現則是PFC液體之揮發與每分鐘通氣量相關；在固定每分鐘通氣量的情況下，調節呼吸器之呼吸速率與潮氣容積不影響PFC之揮發量。吾人也發現在PFC之初始劑量為2/3至全肺剩餘容積(FRC)量之情況下，若藉由一定間隔的補量在肺中維持1/2 FRC以上之PFC液體量，可以維持ALI之理想氧合狀態以及肺順應性。進而，吾人更發現採用高比例PP9（低蒸氣壓）與低比例PP2（高蒸氣壓）混合的PFC液體，可以在四小時沒有補量的情形下，有效地治療ALI。
以上研究結果顯示：（一）PLV對於治療不同致病原因之ALI確有其療效，但對於ARDS所引起的全身性影響則療效有限；（二）PLV對於治療ALI之機轉主要包括有避免肺塌陷、提供氣體交換的儲存所、避免氣量傷害以及有效的排出氣管與肺泡之廢棄物等；（三）PFC液體之揮發與許多因素相關，且須適當的補量以維持肺中存留量在1/2 FRC量以上方能維持其療效；（四）不同的PFC液體可藉由適當的調配，以使其適用於不同目的的液體輔助式通氣術療法。因此，本研究針對液體輔助式通氣術治療ALI 之相關問題作深入探討，具有將來應用在臨床治療上的潛力。

Acute respiratory failure continues to be the major etiology of morbidity and mortality in critical patients including neonates, children, and adults. Although there is much advancement in respiratory care, there are still patients who die or survive with chronic lung diseases. Therefore, searching for a better therapeutical strategy to reduce the morbidity and mortality rates is crucial for the critical patients. Liquid-assisted ventilation with oxygenated perfluorochemical (PFC) has been investigated as a respiratory therapeutic method which is much different from conventional mechanical ventilation (CMV). The unique property of PFC makes it a perfect respiratory media to treat acute lung injury (ALI). The technique of partial liquid ventilation (PLV) has now been used for clinical human trials, and accepted easily by clinicians and patients. However, the related mechanisms and the proper applications of PLV in different types of lung injury are still unclear. The purpose of this study is to clarify the related factors, mechanism and refining the technique of PLV in treating different types of ALI.
Five series of animal experiments were conducted in this study: Firstly, repeated saline lavages to induce ALI in newborn piglets were performed to mimic the surfactant-deficient premature lungs, and a PFC liquid (FC-77) was used for PLV. The therapeutic effect, replacing dose, and pathological changes were evaluated. Secondly, we tried to treat the newborn piglets with ALI/ARDS induced by wood smoke inhalation injury by using the same PLV technique. We also compared the effects of single or combined use of exogenous surfactant supplement and PLV. Thirdly, we used the healthy juvenile rabbits to investigate the influence of ventilation strategy on the evaporation rate of perflubron which is the PFC liquid under clinical trial now. Furthermore, we studied the dosing and replacing effects on juvenile rabbits with saline-lavage induced ALI. Finally, we tried a new technique by using combinations of different PFC liquids (PP2 and PP9) for PLV to treat the same ALI animal models.
In study I, we found a better gas exchange, better lung compliance and less pulmonary pathological change in piglets treated with PLV than CMV. However, the oxygenation in the PLV-treated animals was still lower than the normal control groups. In study II, we demonstrated that using PLV alone or exogenous surfactant supplement to treat ARDS induced by smoke inhalation injury had a beneficial effect in gas exchange, but their combination therapy did not have a synergetic effect. Also, the animals with ARDS had progressively deteriorated blood pressures regardless which therapy was used. In study III, we found that the change of minute ventilation influenced the evaporation rate of perflubron, and therefore influenced the redosing strategy. In study IV, we found that using a higher initial perflubron dose [2/3 or full functional residual capacity (FRC) volume], following with as adequate supplemental dose to keep the residual perflubron volume higher than 1/2 FRC amount would keep an ideal oxygenation and lung compliance in animals with ALI. Part V further demonstrated that the mixture with a high proportion of PP9 (low vapor pressure) and a low proportion of PP2 (high vapor pressure) would maintain the treating effects for 4 hours without replacement.
These studies demonstrated the efficacy of PLV to treat different causes of ALI. Also, we found that therapies to improve the pulmonary function might not be enough to effectively treat the systemic dysfunction in ARDS. Preventing atelectasis, reducing lung injury, affording a reservoir of gas exchange, preventing barotraumas, and effectively excreting airway debris explain the major mechanisms of PLV in treating ALI. Furthermore, minute ventilation affects the evaporation rate of PFC liquid and a proper replacement to maintain the PFC residual volume in lungs higher than 1/2 FRC is necessary to maintain the effect of PLV. Additionally, the combination of different PFC liquids was proved to be effective for PLV. All these findings obtained from this research will be important for future clinical application of PLV.

目錄……………………………………………………………………i.
誌謝……………………………………………………………………iv.
中文摘要 ………………………………………………………………vi
英文摘要………………………………………………………………ix
英文縮寫………………………………………………………………xii
第一章 、緒論………………………………………………………1
一、 簡介急性肺損傷與急性呼吸窘迫症候群…………………2
二、 新生兒與早產兒常見之呼吸衰竭原因……………………3
三、 液體輔助式通氣術之概念與理論根據……………………4
四、 以液體輔助式通氣術治療急性肺損傷之研究現況………9
五、 目前治療急性肺損傷的瓶頸及將來液體輔助式通氣術的
使用方向……………………………………………………11
六、 本論文的研究目的…………………………………………12
七、 表與圖………………………………………………………13
第二章 以FC - 77作為液體輔助式通氣術介質治療急性肺損傷
之乳豬動物模式研究………………………………………20
一、 研究緣起及目的……………………………………………21
二、 材料與方法…………………………………………………22
三、 結果…………………………………………………………28
四、 討論…………………………………………………………30
五、 結論…………………………………………………………34
六、 表與圖………………………………………………………35
第三章 液體輔助式通氣術與表面張力素對煙吸入性肺損傷療
效與機轉之探討……………………………………………43
一、 研究緣起及目的……………………………………………44
二、 材料與方法…………………………………………………45
三、 結果…………………………………………………………51
四、 討論…………………………………………………………54
五、 結論…………………………………………………………58
六、 表與圖………………………………………………………58
第四章 呼吸器調節對全氟化合物自肺中揮發角色之探討………66
一、 研究緣起及目的……………………………………………67
二、 材料與方法…………………………………………………67
三、 結果…………………………………………………………71
四、 討論…………………………………………………………73
五、 結論…………………………………………………………77
六、 表與圖………………………………………………………77
第五章 部份液態通氣術之初始劑量與追加方式對治療急性肺
損傷療效之探討……………………………………………88
一、 研究緣起及目的……………………………………………89
二、 材料與方法…………………………………………………90
三、 結果…………………………………………………………96
四、 討論…………………………………………………………99
五、 結論…………………………………………………………103
六、 表與圖………………………………………………………104
第六章 以不同比例之全氟化合物組合治療急性肺損傷療效的
探討：體外與體內之研究…………………………………112
一、 研究緣起及目的……………………………………………113
二、 材料與方法…………………………………………………114
三、 結果…………………………………………………………119
四、 討論…………………………………………………………121
五、 結論…………………………………………………………125
六、 表與圖………………………………………………………125
第七章 總結論………………………………………………………135
參考文獻….……………………………………………………………139
已發表之論文相關著作..………………………………………………153

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