臺灣博碩士論文加值系統

Baclofen是一種GABAB受體作用劑，可藉由活化GABAB受體來降低迷走神經反射，讓食道括約肌較不會出現陣發性鬆弛，減少逆流事件發生。最近在健康成人的研究發現baclofen會降低氣體灌注食道後引發二度收縮的敏感度，這樣的結果能否套用在胃食道逆流患者身上還有待商榷，因為食道二度收縮的敏感度會因為酸性物質的暴露而提升。為了更進一步了解baclofen對於食道二度收縮的影響，我們在鹽酸灌注食道後的健康受試者身上檢測baclofen對於氣體誘發食道二度收縮的影響。結果顯示，baclofen顯著地降低二度收縮誘發之敏感度以及被誘發成功之頻率，同時也增強受試者對食道酸灌注所引發的胸口灼熱感受度。由於食道本體受到刺激所引發的二度收縮是食道廓清逆流胃液的重要機制，我們的實驗結果可用來解釋為何baclofen用在胃食道逆流症患者身上的療效不如預期。
高解析度食道壓力測定儀能夠統合收縮壓力、收縮時間、收縮長度等三種參數以遠端收縮積分來呈現食道的收縮功能，已成為食道動力學的主流評估工具，只是尚未正式應用於二度收縮的研究。我們透過客製化高解析度食道壓力導管成功地在17位健康受試者身上檢測到以氣體灌注食道後誘發二度收縮的相關參數，並且發現其蠕動模式和一度收縮相類似。高解析度食道壓力測定儀不僅是檢測食道動力學的主流工具，亦可以是影響食道動力學藥物的檢測平台。
胃酸暴露時間是目前診斷胃食道逆流症最重要的指標，但是會受到飲食和作息的影響，存在每日的變異性。為了克服這個問題，食道黏膜阻抗檢測應運而生，以阻抗值來反映食道黏膜受傷的程度。高解析度食道壓力阻抗檢查時於吞嚥引起食道收縮閉合期所擷取新型參數-收縮期阻抗值相較於目前廣為應用在24小時酸鹼阻抗測定檢查取得之平均夜間基礎阻抗值，能夠大幅縮短檢查時間為十五分鐘。我們在逆流性食道炎或是胃酸暴露時間超過4%的診斷標準下，前瞻性地檢測和分析48位具六個月以上典型胃食道逆流症狀患者的收縮期阻抗值後發現，收縮期阻抗值在胃食道逆流症患者顯著低於控制組(837.5 Ω vs. 1220.8 Ω, P <0.001)，對於胃食道逆流症也有良好的鑑別力(AUROC: 0.858)。上述的研究結果顯示高解析度食道壓力阻抗檢查下所測量的收縮期阻抗值是可靠、簡單且低侵入性的胃食道逆流症輔助診斷工具。
胃食道逆流症經常合併食道蠕動不良的問題，由於收縮期阻抗值的測量原理仰賴食道收縮，因此用於診斷合併食道蠕動不良的胃食道逆流症仍有疑慮。我們的研究發現抬腿可增強食道蠕動不良患者食道的收縮力，進而提升收縮期阻抗值的準確度，讓收縮期阻抗值對於胃食道逆流症的鑑別也適用於食道蠕動不良的患者。

The GABAB receptor agonist baclofen is one of the therapeutic agents for gastroesophageal reflex disease (GERD). It is recognized to reduce gastroesophageal reflex events through inhibition of transient lower esophageal sphincter relaxation that is associated with vagovagal reflex. Recent studies on healthy adults revealed that baclofen exerts inhibitory effects on esophageal secondary peristalsis. But it remains unclear whether baclofen affects esophageal secondary peristalsis under esophageal acidification, a situation that occurs in GERD patients. We thus investigated the effect of baclofen on air-induced esophageal secondary peristalsis in healthy adults following esophageal hydrochloric acid (0.1N) infusion. Baclofen reduced the mechaosensitivity and frequency of esophageal secondary peristalsis by esophageal air injection and enhanced heartburn perception subsequent to acid infusion. As the esophageal secondary peristalsis plays an important role in clearance of gastric refluxate, our findings may help explain why therapy with baclofen often does not seem to result in the expected benefit.
High-resolution esophageal manometry (HRM) provides comprehensive and topographic analysis thus has become a mainstream for the evaluation of esophageal motility; however, HRM has not been utilized thus far in the study of esophageal secondary peristalsis. We performed HRM in seventeen healthy adults using a customized catheter and demonstrated that esophageal secondary peristalsis could be induced by rapid air injection. Furthermore, the contraction pattern of esophageal secondary peristalsis in HRM was identical to primary peristalsis. We set up a protocol for the study of esophageal secondary peristalsis with HRM, which might also be a useful testing platform for investigating the effects of agents on esophageal motility.
Acid exposure time (AET) is the current standard for GERD diagnosis. AET could be affected by food intake and lifestyle and subject to change every day. This day-to-day variation could be overcome by measuring the esophageal mucosal impedance, which has been studied as a marker of esophageal mucosal integrity, and therefore reflects the longitudinal reflux burden. In comparison with the most widely used mean nocturnal baseline impedance (MNBI) obtained from 24-h multichannel intraluminal impedance-pH monitoring, a novel impedance-based metric- contractile segment impedance (CSI) calculated through high resolution esophageal impedance manometry (HRIM) during esophageal contraction could significantly shorten the examination time to 15 minutes. We prospectively analyzed CSI of 48 patients with typical reflux symptoms, in which GERD patients were diagnosed based on erosive esophagitis or AET more than 4%. We found that GERD patients exhibited a lower CSI values than controls (837.5 Ω vs. 1220.8 Ω, P <0.001), and CSI had overall excellent diagnostic accuracy for GERD (AUROC 0.858). These results indicate that CSI measured during HRIM appears to be a reliable, time-saving, and less invasive tool for complementing GERD diagnosis.
Ineffective esophageal motility (IEM) as the most common motility disorder of GERD may limit the application of CSI for GERD identification because of possible inadequate mucosa contact. Straight leg raise (SLR) maneuver has been shown to augment esophageal peristaltic vigor in IEM patients. We demonstrated that SLR maneuver enhanced AUROC values of CSI for GERD identification from 0.917 to 0.958. Our results suggest a simple SLR maneuver can improve accuracy of CSI for GERD identification in IEM patients.

第一章、文獻回顧 1
第一節、胃食道逆流症保護機制：食道動力學觀點-食道本體運動功能及食道胃接合部屏障 1
1.1概述 1
1.2食道一度收縮和胃食道逆流症之關係 4
1.2.1食道一度收縮的神經迴路及神經傳導物質 4
1.2.2食道一度收縮標準評估工具-食道壓力測量儀 5
1.2.3食道一度收縮在胃食道逆流症上的臨床意義 8
1.3食道二度收縮當前之文獻回顧 9
1.3.1食道二度收縮在胃食道逆流症上的臨床價值 9
1.3.2食道二度收縮在食道壓力測量儀上的特徵 10
1.3.3食道二度收縮誘發之神經迴路 11
1.3.4影響食道二度收縮功能之因素 13
1.4食道胃接合部屏障結構及運動功能完整性 14
1.4.1橫膈膜裂孔疝氣和食道胃接合部低壓 14
1.4.2陣發性下食道括約肌鬆弛之機轉及臨床意義 16
1.4.3 GABAB受體對陣發性下食道括約肌鬆弛之影響 16
1.4.4 GABAB受體活化劑- baclofen對食道動力學的影響 19
1.4.5 GABAB受體活化劑- baclofen在胃食道逆流症上的應用 19
第二節、胃食道逆流症診斷：食道黏膜阻抗值的應用 20
2.1概述 20
2.2當前胃食道逆流症之診斷標準 20
2.2.1內視鏡診斷：逆流性食道炎及巴瑞特氏食道 20
2.2.2酸鹼阻抗測定檢查：測定胃酸暴露時間以及偵測逆流事件 21
2.2.3胃食道逆流症之分型及其處置 22
2.3食道黏膜阻抗值-食道黏膜完整性評估 24
2.3.1食道黏膜阻抗值基本概念 24
2.3.2食道黏膜阻抗值測量現有工具及其在胃食道逆流症之臨床應用 25
2.3.3新型食道黏膜阻抗值測量工具-收縮期阻抗值之原理及初步報告 25
2.3.4新型食道黏膜阻抗值測量工具-收縮期阻抗值之原理及初步報告 28
第三節、食道動力學之吞嚥誘發測試在胃食道逆流症的應用 31
3.1現有吞嚥誘發測試之概念及其胃食道逆流症應用 31
3.2新型吞嚥誘發測試-抬腿誘發測試之原理及臨床應用 33
第二章、本研究假說及目標 35
第一節、以食道酸灌注模擬逆流事件發生時GABAB受體活化劑–baclofen對食道二度收縮及食道敏感性的影響 35
1.1在食道酸灌注下GABAB受體活化劑 – baclofen抑制二度收縮誘發敏感度及頻率 36
1.2在食道酸灌注下GABAB受體活化劑 – baclofen增加食道對酸灌注之症狀敏感度 36
第二節、以高解析度食道壓力測定儀進行氣體灌注誘發食道二度收縮之可行性 36
2.1以氣體灌注於具側孔之客製化高解析度食道壓力測定導管能夠成功誘發出食道二度收縮 36
2.2在高解析度食道壓力測定導管所見二度收縮運動模式和一度收縮相似 36
第三節、以高解析度食道壓力阻抗測定儀量測之收縮期阻抗值診斷胃食道逆流症 37
3.1收縮期阻抗值和靜止基礎阻抗值、平均夜間基礎阻抗值以及胃酸暴露時間的相關性 37
3.2收縮期阻抗值可以鑑別具典型逆流症狀患者是否診斷為胃食道逆流症 38
3.3在抬腿誘發測試下能夠改善收縮期阻抗值對胃食道逆流症之鑑別力 38
第三章、在食道酸灌注模擬胃食道逆流事件發生時GABAB 受體活化劑- baclofen對食道二度收縮的影響 38
第一節、研究方法 38
第二節、研究結果 42
第三節、研究討論 48
第四章、以高解析度食道壓力測定儀進行氣體灌注誘發食道二度收縮之可行性研究 51
第一節、研究方法 51
第二節、研究結果 54
第三節、研究討論 60
第五章、以高解析度食道壓力阻抗測定儀量測之收縮期阻抗值診斷胃食道逆流症的可靠性 62
第一節、研究方法 62
第二節、研究結果 67
第三節、研究討論 76
第六章、結語及未來展望 79
參考文獻 82
附錄 博士研究期間相關第一作者SCI期刊發表 98

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