臺灣博碩士論文加值系統

目的：阻塞性睡眠呼吸中止症（OSA）造成上呼吸道阻塞和睡眠時間歇性低血氧等症狀，會因呼吸肌肉和口咽肌肉群的效能減弱而加劇疾病的嚴重度。本博士論文研究是雙盲、隨機對照試驗，主要收案對象為中、重度阻塞性睡眠呼吸中止症個案。根據文獻回顧的結果，我們是第一個將這3種介入方式在同一實驗收案的研究，針對新診斷的阻塞性睡眠呼吸中止症個案隨機分派採用三種不同治療介入方式 (1) A組:閾值吸氣肌肉訓練組（TIMT group）、(2) B組:舌頭肌肉訓練組（TMT group）及(3) C組:持續氣道正壓通氣治療組當作控制對照組（CPAP as control group）。所有形式的治療介入都進行3個月。
方法：30名參與個案，經過說明、同意、登記和完成研究評估流程，按照報導試驗統一標準聲明（CONSORT）進行（圖1）。所有阻塞性睡眠呼吸中止症個案皆經耳鼻喉科醫師評估後轉診。在進入研究之前，個案接受正式且結構化訪談、睡眠問卷調查、多頻道睡眠檢查（PSG）和肺功能測試（PFT）檢測。收集參與個案基本數據資料後後，隨即將個案隨機分派進入到A組、B組或C組（圖1）。所有個案在性別、平均年齡和身體質量指數（BMI）進行匹配後收案（表1）。三組個案皆接受醫療、常規照護和所分派組別介入治療照護，A組接受閾值吸氣肌肉訓練、B組接受舌頭肌肉訓練及C組接受持續氣道正壓通氣治療（表2）。多頻道睡眠檢查（PSG）檢測是由睡眠技師完成，他們對於參與個案分組治療和治療前後呼吸暫停指數（AHI）並不知情。所有參與個案和訓練課程均由物理治療師（PT）監督完成，物理治療師每週會利用電話了解患者在該計劃中的治療進展和遵守治療情況做完整治療追縱紀錄。
收案單位：衛生福利部台南醫院耳鼻喉科門診。本研究涉及參與個案的研究所有程序，皆經由國立成功大學人體試驗委員會審查通過後按程序進行收案（IRB No.A-ER-103-168）。（臨床試驗註冊號：NCT02278094）
收案個案：30名參與個案（23名男性，7名女性）完成整個研究治療計畫。研究收案皆經醫師轉診進行評估篩選，有18名因下列因素而未納入收案，原因說明如下：不符合納入標準（6名）、12名受其他因素影響，包含問題如下背痛（4名）、接受手術治療（4名）及交通不方便（4名）。在符合收案條件納入後，有12名參與個案中斷參與或無法繼續到院接受治療，原因如下：(1)A組（2名）：1名因發現工作時間無法配合門診治療而退出，另1名個案出現肺部感染問題須接受其他醫療照護而退出。（2）B組（2名）：1名個案因接受手術而退出，另1名個案因交通不方便而退出。（3）C組（8名）：3名因CPAP適應困難（使用上不便利、無法睡眠和面部水分刺激）、2名個案因接受手術及3名個案失去聯繫而退出本研究(圖1)。全部個案的平均年齡為49.4歲（SD = 8.5，年齡範圍為27至72歲），男性為主（23 / 30,77.0％）。頸圍平均值為38.0公分（頸圍值範圍約29.8至45.0公分），身體質量指數(BMI)呈現為體重過重，平均值為26.6公斤/身高公尺平方（BMI值範圍約19.7至33.2公斤/身高公尺平方）。我們還從病歷中收集有關個案生活習慣危險因子相關數據，包括飲酒習慣（43.3％），習慣性吸煙（13.3％）(表1)。 30個參與個案在3個月內出勤率為71.4％（表4-1及4-2）。
介入治療：A組（n = 12），B組（n = 12）和C組（n = 6）個案，參加3個月的介入性課程。A組，B組和C組的課程，個案剛開始在醫院先接受3-5次的監督訓練，之後則在家完成自主訓練。所有個案必須在他的訓練日誌中記錄訓練的訊息，該記錄在計劃結束時提交給PT。 PT教導所有患者如何進行在醫院及居家自主訓練課程程序。A組使用具有流速獨立、單向閥的吸氣肌肉訓練裝置，進行以30-45分鐘/天、5天/週、12週的醫院及居家自主閾值吸氣肌肉訓練(TIMT)。B組在醫院時使用愛荷華州口腔訓練裝置儀器（IOPI）訓練，在家中則以舌頭肌肉訓練運動(圖2)為主; 進行30-45分鐘/天、5天/週、12週的醫院及居家自主舌頭肌肉訓練(TMT)。這些肌肉訓練模式會請個案每周安排至醫院一次進行及在家自主訓練每周安排四天。對照組則遵循標準的臨床CPAP介入流程程序進行。對於所有三組個案在研究之前和介入治療3個月之後分別進行結構化評估。
結果：所有參與個案基本數據值在平均年齡、身體質量指數或頸圍沒有顯著差異（表1）。 介入3個月治療後效益統整如下(1)在介入治療前後身體質量指數平均值沒有顯著差異變化（表2）、(2)在A和B組舌頭前突和後縮收縮運動的平均值均有顯著增加（p = 0.001），期訓練後成效高於C組、(3)在B組的嗜睡特異性量表（ESS）和打鼾特異性量表（SOS）均呈現顯著改善（p 〈0.05）、(4)三組個案經過12週的介入治療後，在多頻道睡眠檢查在呼吸暫停指數（AHI）平均值變化皆未發現有顯著差異改變、(5)然而A組個案在3個月介入治療後，在多頻道睡眠檢查其他類別睡眠參數發現多項平均值改善，包含仰臥AHI指數 (AHI-supine）、快速眼動睡眠期AHI指數 (AHI-REM）、覺醒指數、睡眠潛伏期、睡眠效率和血氧不飽和指標(ODI)等數據值皆呈現顯著差異; 然而在B組在多頻道睡眠檢查其他類別睡眠參數，發現只有睡眠潛伏期和血氧不飽和指標(ODI)的變化是顯著的（p 〈0.05）。然而我們更發現B組個案在12週的介入治療後其多頻道睡眠檢查中覺醒指數值提升惡化現象（p 〈0.05）。更有趣的是C組在治療3個月後，多頻道睡眠檢查睡眠參數皆沒有顯著變化，僅有睡眠效率有顯著變化。(6) 在A組肺功能數據平均值第一秒鐘用力吐氣肺活量/用力吐氣肺活量（FEV1.0 / FVC）及第六秒鐘用力吐氣肺活量（FEV6.0）和尖峰吸氣流數值峰值（PIF）（p = 0.001）皆呈現治療後平均值改善的顯著效益。A組的介入治療效益明顯高於B組和C組。最後我們的研究亦發現到在A和C組心肺適能(6分鐘步行試驗)改善達到顯著增加效果（p 〈0.05）表現皆優於B組。
重點是在我們研究設計假說是針對不同介入治療措施方法之間做治療效益差異的比較。我們運用單變量線性回歸分析方法，發現頸圍、第六秒鐘用力吐氣肺活量（FEV6.0）和血氧不飽和指標(ODI)是達顯著有意義的變項，鑑定出A組治療效益在快速眼動睡眠期AHI指數(AHI-REM)變化(獨立預測因子)方面上述因子具有顯著之預測力（表5）。
此外，研究中使用線性多元回歸模型發現頸圍治療前後變異量是評估治療結果的重要指標。發現該變量不僅與快速眼動睡眠期AHI指數(AHI-REM)的改善有關，而且還解釋了72.4％的快速眼動睡眠期AHI指數(AHI-REM)變異性。這些研究結果發現表示，正如我們先前研究假設，快速眼動睡眠期AHI指數(AHI-REM)治療成效改善可透過頸圍治療前後變異量改變，當作A組治療有效性與否的早期預測因子(表6及7)。
結論：本研究結果發現個案經過12週閾值吸氣肌肉訓練(TIMT) (中度負荷設定)後，可以增加下列數值平均值，包含舌頭肌肉力量、主觀睡眠問卷、睡眠參數（仰臥AHI指數(AHI-supine)、快速眼動睡眠AHI指數 (AHI-REM)、覺醒指數、睡眠潛伏期、睡眠效率、血氧不飽和指標(ODI)）、肺功能(第一秒鐘用力吐氣肺活量/用力吐氣肺活量（FEV1.0 / FVC）、第六秒鐘用力吐氣肺活量（FEV6.0）、尖峰吸氣流數值峰值（PIF）)和心肺適能(6分鐘步行試驗)等臨床觀察數值，但似乎沒有對呼吸暫停指數（AHI）的變化造成顯著變化影響。儘管如此，我們的研究結果表明閾值吸氣肌肉訓練(TIMT)訓練可能成為治療阻塞性睡眠呼吸中止症的輔助策略。此外，舌頭肌肉訓練(TMT)顯示舌頭肌肉力量改善，睡眠參數（睡眠潛伏期和血氧不飽和指標(ODI)）和肺功能(尖峰吸氣流數值峰值（PIF）)改善，但同樣不會對呼吸暫停指數（AHI）的變化造成顯著變化影響。在重度阻塞性睡眠呼吸中止症個案吸氣肌肉可能會產生重複且過度吸氣，藉以對抗上呼吸道阻塞，導致對吸氣肌肉產生嚴重有害的影響。在我們之前研究發現對個案不願接受手術或CPAP裝置治療時，多頻道睡眠檢查呼吸暫停指數（AHI）數值≤29.0次/小時或許是一個良好臨床標誌，可作為使用閾值吸氣肌肉訓練(TIMT)阻塞性睡眠呼吸中止症治療成效預測。閾值吸氣肌肉訓練(TIMT)的線性多元回歸模型顯示頸圍治療前後變異值是評估治療結果的重要指標，可以解釋72.4％的快速眼動睡眠AHI指數 (AHI-REM)變異性。此外，我們的研究結果亦顯示心肺適能和肺功能的增加。因此，閾值吸氣肌肉訓練(TIMT)或舌頭肌肉訓練(TMT)皆被認為是阻塞性睡眠呼吸中止症治療的替代方案，因為在肌肉力量、主觀和客觀睡眠質量、肺功能和心肺適能方面發現重要的改善。在未來的臨床研究中，我們不僅可以考慮單獨使用閾值吸氣肌肉訓練(TIMT)或舌頭肌肉訓練(TMT)，還可以考慮與其他類型的訓練相結合，優化收益成效並增強治療的結果。最後，我們建議在不同嚴重程度阻塞性睡眠呼吸中止症個案接受不同介入治療的方式須以更大樣本量做進一步研究、遵循相同嚴謹性的方法、比較不同的訓練強度、並建立生理機制和策略以透過這些機制和運動處方，讓閾值吸氣肌肉訓練(TIMT)或舌頭肌肉訓練(TMT)更能為阻塞性睡眠呼吸中止症個案帶來更大的臨床治療益處。

OBJECTIVES: Obstructive sleep apnea (OSA) (obstructed airway and intermittent hypoxia) negatively affects patients’ oropharyngeal and respiratory muscles. In this dissertation, a double-blind, randomized controlled trial was conducted in participating patients with moderate-to-severe OSA. To our knowledge, this was the first study that investigated the effectiveness of three forms of interventions including threshold inspiratory muscle training (TIMT=Group A), tongue muscle training (TMT=Group B) and standard continuous positive airway pressure intervention (CPAP=Group C). All forms of interventions were conducted for 3 months.
METHODS: Our study on 30 participants who consented, enrolled, and completed the study is highlighted in the consolidated standards of reporting trials (CONSORT) diagram shown in Fig. 1. Potential OSA subjects were first referred by the ear, nose and throat (ENT) physicians. Before the study, participants underwent a structured interview, completed a sleep-related questionnaire, and were evaluated using an overnight polysomnographic (PSG) test and a pulmonary function test (PFT). After the baseline data were collected, patients were randomly assigned to the TIMT, TMT and control groups (Fig. 1). All participants were sex-, age-, and body mass index (BMI)-matched (Table 1). Members in all three groups received routine medical care; however, members in the TIMT and TMT groups were given additional experimental treatments using TIMT and TMT, respectively (Table 2). An experienced technician in the sleep clinic read PSG recordings without knowing the assignment group and the pre-evaluated Apnea-hypopnea index (AHI) level of each participant. All assessment and training sessions were supervised by a physical therapist (PT) who monitored the adherence to the program of each patient by weekly telephone calls.
SETTING: The study was conducted at the Department of Otorhinolaryngology, Tainan Hospital, Ministry of Health and Welfare, Taiwan. The protocols of our study involving human participants were approved by the Institutional Review Board of National Cheng Kung University (IRB No. A-ER-103-168). (Clinical Trials Register Number: NCT02278094)
SUBJECTS: 30 subjects (23 men and 7 women) completed the entire study. Among 48 patients who signed the consent form, 18 patients either did not meet the inclusion criteria (n=6) or had other reasons for early withdrawal (n=12). The 12 withdrawals are further explained as follows: (1) TIMT group (n=2): 1 patient discontinued because of a work-time problem and 1 developed chest infection. (2) TMT group (n=2): 1 patient discontinued because of an surgery and 1 had a transportation issue. (3) Control group (n=8): 3 had ddifficulties with the CPAP (inconvenience, disturbed sleep and facial irritation), 2 discontinued because of surgery, and 3 discontinued due to loss of connection (Fig. 1). The 30 patients who successfully completed the study had a mean age of 49.4 (SD=8.5, age range from 27 to 72), and predominantly male (23/30, 77.0%). The mean neck circumference (NC) was 38.0 cm (ranging from 29.8 to 45.0 cm), and the mean body mass index (BMI) was 26.6 kg/m2 (ranging from 19.7 to 33.2 kg/m2). We also collected data regarding patient characteristics from the clinical chart, including daily alcohol intake (43.3%), habitual smoking (13.3%) (Table 1). Attendance rate for all 30 scheduled follow-ups was 30/42=71.4% in 3 months (Table 4-1＆ Table 4-2).
INTERVENTION: The subjects were enrolled for 3 months of interventional programs in Group A (n=12), Group B (n=12), and Group C (n=6).The programs for Groups A, B and C began with 3-5 supervised sessions after patients finished our home exercise stud. All patients recorded their training information in a diary notes that were submitted to the PT at the end of the program. The PT taught patients in all three groups how to perform both hospital- and home-based training procedures. The home-based TIMT procedure was performed 30-45 min/day, 5 days/week, for 12 weeks utilizing a TIMT training device with a flow-independent one-way valve. The TMT program was conducted both in the hospital and at home at 30-45 min/day, 5 days/week, for 12 weeks, using a Iowa Oral Performance Instrument (IOPI) training device. These sessions were scheduled once per week in the hospital and four days per week at home. The control group followed the standard clinical CPAP interventional program. For patients in all three groups, a structured evaluation was performed before and after the 3-month study.
RESULTS: There were no statistically significant differences in age, BMI, or neck circumference in three groups compared with the baseline (Table 1). The findings of our 3-month study are summarized as follows: (1) The post-interventional change in BMI was not significantly different. (2) In the muscle strength category, both the protrusion and retraction strengths were significantly different (p = 0.001) for both the TIMT and TMT groups, and the values are higher than that of the control group. (3) In the questionnaire category, the Epworth sleepiness scale (ESS) and Snore outcome survey (SOS) were improved significantly in the TIMT group (p 〈 0.05). (4) After the 12-week intervention, the change in the mean AHI score was insignificant among three groups. (5) In the PSG sleep parameter category, we found significant changes in AHI-supine, apnea-hypopnea index during rapid eye movement (REM) sleep (AHI-REM) , arousal index, sleep latency, sleep efficiency, and oxygen desaturation index (ODI) in the TIMT group post 3-month intervention. Among them, in sleep latency and ODI are significant (p 〈 0.05). In contrast, in the TMT group, we found that the arousal index value worsened post-study (p 〈 0.05). Interestingly, the control group showed no significant changes in PSG parameters post 3-month treatment except a significant improvement in sleep latency. (6) In the pulmonary function category, a significantly higher ratio between the forced expiratory volume in one second and the forced vital capacity (FEV1.0/ FVC), an improved forced expiratory volume in six seconds (FEV6.0), and an increase in the peak inspiratory flow(PIF) were observed in TIMT group (p = 0.001). The TIMT group had higher post-intervention scores than the TMT (only PIF, p 〈0.002) and control groups. Finally, (7) a significantly enhanced cardiopulmonary fitness (p 〈0.05) was observed in the TIMT and control groups as measured by the six minutes walking test (p 〈0.05) (Table 2 ＆ Table 3).
In a univariate linear regression analysis, we found that the NC, FEV6.0, and ODI were dependent variables in the identification of AHI-REM changes in response to treatments (Table 5).
Further, our linear multiple regression modeling found that the NC was an important measurement for evaluating treatment outcome. This variable was found to be not only related to the improvement of the AHI-REM, but also explained 72.4% of AHI-REM variability. These findings indicate that, as we hypothesized previously, the AHI-REM as measured by the NC can be used as an early predictor for the effectiveness of the TIMT treatment (Table 7).
CONCLUSIONS: Our 12 weeks of moderate load of the TIMT resulted in improved tongue and respiratory muscle strength, better subjective sleep quality, improved sleep parameters (AHI-supine, AHI-REM, arousal index, sleep latency, sleep efficiency, and ODI), and improved pulmonary function and cardiopulmonary function. Despite these statistically significant findings, TIMT did not suggest a significant overall AHI change. Nevertheless, our results indicated that TIMT could emerge as an adjunct strategy for treating OSA. Additionally, the TMT training showed improved tongue muscle strength, sleep parameters (sleep latency and ODI), and PIF, but again did not lead to a significant AHI change. It is possible that repetitive inspiratory effort against an obstructed airway may also induce deleterious effects on the inspiratory muscles in severe OSA patients. A baseline AHI ≤ 29.0 events/hr. may serve as a good clinical marker to predict the outcome of the OSA treatment using TIMT for patients who are unwilling to accept surgery or the CPAP device. A linear multiple regression models indicate that the NC is a powerful and significant variable to explain 72.4% of the AHI-REM variability. Additionally, our results show an increase in cardiopulmonary fitness and pulmonary function. Thus, the TIMT or TMT can be considered as an alternative for OSA management, since important improvements were found in muscle strength, subjective and objective sleep quality, pulmonary function and cardiopulmonary fitness. In future clinical study, we may consider not only the sole use of TIMT or TMT, but also a combination with other types of training, optimizing the gains and enhancing the results. Finally, we recommend further studies with a larger sample size, in different groups of patients in different OSA severity, following the same methodological rigor in comparing different training intensities and establishing the physiological mechanisms and strategy through which TIMT or TMT would bring greater benefits to OSA patients.

ABSTRACT I
中文摘要 VI
ABBREVIATIONS IX
ACKNOWLEDGEMENT XI
TABLE OF CONTENTS XII
LIST OF TABLES XV
LIST OF FIGURES XVI
CHAPTER 1 INTRODUCTION 1
1.1 BACKGROUND 1
1.2 PURPOSES 6
1.3 HYPOTHESES 6
CHAPTER 2 LITERATURE REVIEW 8
2.1 REVIEW OF OBSTRUCTIVE SLEEP APNEA (OSA) 8
2.2 EPIDEMIOLOGY OF OSA 9
2.3 RISK FACTORS FOR OSA 10
2.4 DIAGNOSIS OF OSA 11
2.5 MANAGEMENT OF OSA 12
2.6 MYOFUNCTIONAL THERAPY (MT) FOR OSA 13
2.6.1 THRESHOLD INSPIRATORY MUSCLE TRAINING (TIMT) 13
2.6.2 TONGUE MUSCLE EXERCISES (TMT) 13
2.7 SUMMARY 14
CHAPTER 3 MATERIALS AND METHODS 16
3.1 STUDY DESIGN 16
3.1.1 STUDY SETTING 16
3.1.2 STUDY SUBJECTS 16
3.1.3 INSTRUMENT 17
3.1.3.1 POLYSOMNOGRAPHY (PSG) 17
3.1.3.2 EPWORTH SLEEPINESS SCALE (ESS) 18
3.1.3.3 PITTSBURG SLEEP QUALITY INDEX (PSQI) 19
3.1.3.4 SNORE OUTCOME SURVEY (SOS) 19
3.1.3.5 DEMOGRAPHIC DATA 19
3.1.3.6 SIX-MINUTE WALKING TEST DISTANCE (6MWD) 20
3.1.3.7 PULMONARY FUNCTION TEST 21
3.1.3.8 TONGUE MUSCLE STRENGTH TEST 21
3.2 PROCEDURE OF THE STUDY 22
3.2.1 PROCEDURE OF RCT 22
3.2.2 THE STRATEGY OF INTERVENTION AT THRESHOLD INSPIRATORY MUSCLE TRAINING (TIMT) 23
3.2.3 THE STRATEGY OF INTERVENTION AT TONGUE MUSCLE TRAINING (TMT) 24
3.2.4 THE STRATEGY OF INTERVENTION AT CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) 24
3.3 DATA ANALYSIS 24
CHAPTER 4 RESULTS 26
4.1 DEMOGRAPHIC AND ANTHROPOMETRIC CHARACTERISTICS OF SUBJECTS 26
4.2 COMPARISONS OF TREATMENT EFFECTS BETWEEN BASELINE AND POST 3 MONTHS, ACCORDING TO DIFFERENT INTERVENTIONS 26
4.3 COMPARISONS OF TREATMENT DIFFERENCE AMONG DIFFERENT INTERVENTIONS 27
4.4 ASSESSMENTS OF　MUSCLE TRAINING PARAMETERS 28
4.5 UNIVARIATE LINEAR REGRESSION ANALYSIS OF AHI-REM AND AHI-SUPINE CHANGE IN THE TIMT GROUP 28
4.6 MULTIPLE REGRESSION ANALYSIS MODEL OF AHI-REM CHANGE IN THE TIMT GROUP 29
CHAPTER 5 DISCUSSION 30
5.1 EFFECTS OF INTERVENTION ON DEMOGRAPHIC VARIABLES 31
5.1.1 EFFECTS OF TIMT TRAINING ON DEMOGRAPHIC CHANGE 32
5.1.2 EFFECTS OF TMT TRAINING ON DEMOGRAPHIC CHANGE 32
5.2 EFFECTS OF THE TREATMENT INTERVENTION ON MUSCLE STRENGTH 34
5.2.1 EFFECTS OF TREATMENT INTERVENTION ON THRESHOLD INSPIRATORY MUSCLE STRENGTH 34
5.2.2 EFFECTS OF THE TREATMENT INTERVENTION ON TONGUE MUSCLE STRENGTH 37
5.3 EFFECTS OF THE THREE TREATMENT INTERVENTION ON SLEEP QUESTIONNAIRES 38
5.4 EFFECTS OF THE THREE TREATMENT INTERVENTION ON PSG PARAMETERS 40
5.4.1 EFFECTS OF THE TIMT TREATMENT INTERVENTION ON PSG PARAMETERS 40
5.4.2 EFFECTS OF TMT TREATMENT INTERVENTION ON PSG PARAMETERS 42
5.5 EFFECTS OF THE THREE TREATMENT INTERVENTION ON PULMONARY FUNCTION 44
5.5.1 EFFECTS OF THE TIMT TREATMENT INTERVENTION ON PULMONSRY FUNCTION 44
5.5.2 EFFECTS OF THE TMT TREATMENT INTERVENTION ON PULMONSRY FUNCTION 45
5.6 EFFECTS OF THE THREE TREATMENT INTERVENTION ON CARDIOPULMONSRY FITNESS 46
5.7 LIMITATIONS AND FUTURE RESEARCH 47
5.8 CONCLUSIONS 48
APPENDIX 70

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