臺灣博碩士論文加值系統

體外維生系統 (Extracorporeal life support, ECLS) 是目前醫療上用於重症醫療的一項利器。縱使ECLS目前的成功率已有顯著成長，但其仍有出血、嚴重發炎反應以及肢體缺血等併發症。此外，在ECLS治療期間若使用周邊血管插管，則會造成大量的逆向血流，而增加左心室後負荷。然而，甚少研究探討此現象是否會使動脈波特性惡化，甚至是否會導致心肌氧氣供需失衡。
血管阻抗頻譜 (vascular impedance spectrum) 取決於動脈管的物理特性以及血壓與血流於遠端產生的反射波，由此可知血管阻抗頻譜包含動脈管波傳輸時間 (arterial wave transit time, w)、前進血壓波 (forward pressure wave, Pf) 與反射血壓波 (backward pressure wave, Pb) 等參數。若血管阻抗過分增加，即代表反射波震幅增加，而提高左心室收縮後負荷，進而導致心肌氧氣供需失衡。理論上，要評估血管力學必須同時量測主動脈血壓與血流訊號；然而，實際應用上可以僅利用主動脈血壓波即可評估血管的物理特性。
在本研究中，首先成功建立了大鼠ECLS動物模式，因此可利用此動物模式評估ECLS對動脈管物理特性以及左心室－動脈管交互作用的影響。同時，亦成功利用量測到的主動脈血壓波建構其對應的三角血流波 (assumed triangular flow, Qtri)，進而得到動脈管波傳輸時間、前進血壓波與反射血壓波以描述動脈管物理特性。而此方法最大的好處在於，三角血流波不需校正即可進行後續分析。
根據前述，本研究進一步利用量測的主動脈血壓波與推測而得的三角血流波探討ECLS對正常大鼠的動脈物理特性會造成何種影響。實驗結果顯示，在經過ECLS治療後，雖然主動脈並未出現硬化現象，但大鼠心肌的氧氣供需平衡卻受到破壞，而此現象似乎是受到前進波震幅大幅增加所導致。同時，本研究也利用次世代定序 (next generation sequencing, NGS) 從基因的角度探討ECLS對生物體可能造成的影響。從結果發現，ECLS會造成許多與發炎相關的基因大量表現，透過許多路徑持續誘導發炎反應的維持；此外，ECLS亦會誘導與心臟肥大 (cardiac hypertrophy) 與心臟擴張 (cardiac dilation) 相關的基因表現。
雖然在本研究中，利用動物模式發現ECLS會造成大鼠心肌氧氣供需失衡，但仍難以斷定臨床上ECLS亦會對病人造成相同的結果。但依據本研究建立的方法，未來在臨床上若能於ECLS治療期間以非侵入式方式測得主動脈血壓波，即可建構相對應的三角血流波，並進一步計算得知其動脈物理特性。同時，雖然本研究發現ECLS可能會促使與心臟肥大及心臟擴張相關基因表現，但仍須進一步驗證。

Extracorporeal life support (ECLS) is a life saving device for patients with severe cardiac and/or pulmonary failure. Although the success rates of ECLS have been improved currently, it still causes some severe side effects, such as bleeding, significant inflammation, and limb ischemia. Moreover, the peripheral cannulation may cause massive retrograde aortic ECLS flow to increase the left ventricular (LV) afterload. However, little is known whether it might exert deteriorative effects on arterial wave properties and matching condition between the myocardial oxygen demand and supply.
The vascular impedance spectrum depends on the physical properties of the artery and the reflected pressure and flow waves generated in more distal parts of the arterial tree. The mismatch in vascular impedance causes partial reflections of the forward pressure wave, impairing the systolic loading condition for the LV coupled to the arterial system, then causing a mismatch in the myocardial oxygen supply/demand ratio. Classically, the accurate measurement of vascular mechanics, including arterial wave transit time (w) and the forward (Pf) and backward (Pb) pressure waves, requires simultaneous recording of aortic pressure and flow signals. In practice, it is feasible to estimate the arterial wave properties by using aortic pressure signal alone.
This study used the successfully developed miniature ECLS model in rats to investigate the mechanical alterations in arterial wave properties and the LV-arterial system interaction. Meanwhile, the arterial τw, Pf and Pb were also successfully determined on the basis of the measurement of a single aortic pressure wave and an assumed triangular flow (Qtri). The attractiveness is that calibration of Qtri is not essential in the analysis.
Based on the measured aortic pressure wave and an assumed Qtri, the influences of ECLS on the arterial pulsatility were determined in normal rats. Results from this study provide that the magnitude of the Pf was a predominant factor responsible for the impaired oxygen demand/supply ratio in the rats after ECLS treatment. Moreover, the next generation sequencing (NGS) was used to identify the differences of gene expression profile induced by ECLS. The results found that not only the inflammatory-related genes but also cardiac hypertrophy and cardiac dilation related genes might be induced by ECLS treatment.
Although the mismatch between myocardial oxygen demand and supply in rats after ECLS treatment was demonstrated, there is difficulty in inferring that the ECLS insults on the arterial pulsatility would occur in humans. However, it is believed that evaluating the arterial wave properties in humans receiving ECLS treatment is feasible if the aortic pressure could be obtained non-invasively. Then the construction of the unknown Qtri and the calculation of the arterial τw, Pf and Pb can be automatically achieved. Lastly, there still needs further studies to elucidate whether cardiac hypertrophy and cardiac dilation would be induced after ECLS treatment.

目錄.................................................................................................i
縮寫名詞對照表...............................................................................vi
摘要................................................................................................ix
Abstract.........................................................................................xi
圖目錄...........................................................................................xiv
表目錄..........................................................................................xvii
Chapter 1........................................................................................1
1-1. Historical of extracorporeal life support..................................2
1-2. Configurations and cannulation strategies..............................3
1-3. Complications induced by extracorporeal life support............4
1-4. Arterial impedance as ventricular afterload............................7
1-5. Qualification of the pulsatile nature of the arterial system......9
1-6. Quantification the arterial pulsitility using only the measured aortic pressure pulse.....................................................................11
1-7. Ventricular/vascular coupling.................................................13
1-8. Purpose of the thesis............................................................14
Chapter 2......................................................................................17
2-1. Introduction...........................................................................18
2-2. Materials and methods..........................................................19
2-2-1. Animals..............................................................................19
2-2-2. Anesthesia and surgical preparation.................................20
2-2-3. Cardiac arrest and extracorporeal life support..................21
2-2-4. Discontinuation of extracorporeal life support and intensive care unit phase.............................................................................22
2-2-5. Estimation of inflammatory response................................23
2-2-6. Statistical analysis............................................................23
2-3. Results..................................................................................24
2-4. Discussion............................................................................26
2-5. Conclusions..........................................................................30
Chapter 3.....................................................................................40
3-1. Introduction...........................................................................41
3-2. Materials and methods.........................................................43
3-2-1. Animals and catheterization..............................................43
3-2-3. Mathematic consideration for the aortic input impedance analysis........................................................................................45
3-2-4. Impulse response function curve and Dolph-Chebyshev weighting function........................................................................47
3-2-5. Arterial wave separation analysis......................................49
3-2-6. Statistics...........................................................................50
3-3. Results..................................................................................51
3-4. Discussion............................................................................54
3-5. Conclusions..........................................................................59
Chapter 4.....................................................................................67
4-1. Introduction..........................................................................68
4-2. Materials and methods.........................................................70
4-2-1. Animals and surgical procedure........................................70
4-2-2. Initiation and discontinuation of extracorporeal life support and intensive care unit phase.......................................................72
4-2-3. Construction of the unknown flow wave by using a triangle .....................................................................................................73
4-2-4. Impulse response function curve......................................74
4-2-5. Arterial wave separation analysis......................................75
4-2-6. Statistical analysis............................................................75
4-3. Results..................................................................................76
4-4. Discussion............................................................................78
4-5. Conclusions..........................................................................83
Chapter 5.....................................................................................94
5-1. Introduction...........................................................................95
5-2. Materials and methods.........................................................95
5-2-1. Animals and surgical procedure........................................95
5-2-2. Initiation and discontinuation of extracorporeal life support and intensive care unit phase.......................................................97
5-2-3. Next-generation sequencing and analysis of the changes of gene expression before and after extracorporeal life support .....................................................................................................98
5-2-4. Functional analysis...........................................................99
5-3. Results................................................................................100
5-4. Discussion...........................................................................101
4-5. Conclusions........................................................................103
Chapter 6....................................................................................109
References..................................................................................114

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