阻塞型睡眠呼吸中止症之骨骼肌失能、神經傳導延遲與代謝異常

Abstract

臨床證據顯示阻塞型睡眠呼吸中止症患者呈現較高發炎指標，而且與心血管疾病的罹病率和致死率有顯著相關。過去許多文獻探討發炎性疾病患者的骨骼肌功能異常，例如慢性阻塞型肺疾病和慢性心衰竭等，然而卻少有探討阻塞型睡眠呼吸中止症患者之骨骼肌功能。本論文分為三部份探討阻塞型睡眠呼吸中止症之骨骼肌失能、神經傳導延遲與代謝異常。所有患者均從台大醫院睡眠中心檢查名單中徵求，邀請年齡在40-65歲之間且肺功能檢查正常的男性參與所有實驗。 第一部分探討不同嚴重程度阻塞型睡眠呼吸中止症患者之呼吸肌功能。首先共有88位患者自願參與本研究，所有患者均接受睡眠檢查、嗜睡量表評估、呼吸肌肌力與耐力檢查、以及疲乏測試。所有呼吸肌測試項目均同步收集表皮肌電圖訊號，分析之參數包括均方根（root mean square）及中位頻譜分析（median power frequency）。此外，在疲乏測試前後以經頸磁場刺激器分別進行5次膈神經刺激，並以表皮肌電圖同步收集橫膈複合肌肉動作電位幅度與傳導時間（compound muscle action potential amplitude and latency）。受測者中有13位診斷為輕度患者、21位中度患者、34位重度患者、另外有20位無阻塞型睡眠呼吸中止症（對照組）。結果顯示重度患者之肌力和肌耐力較對照組顯著下降，而疲乏度顯著增高。輕度和中度患者之肌力與肌耐力則與對照組無顯著差異。此外，重度患者之最大自主收縮或磁場刺激器誘發的疲乏指標均較其他三組顯著；重度患者的橫膈複合肌肉動作電位幅度顯著較另三組低，神經傳導時間則顯著增長。此部分結果顯示重度患者呈現骨骼肌功能顯著異常。再於自願者中徵求15對年齡、身高、體重配對之重度患者與對照組，比較其呼吸肌與下肢肌肉功能的差異。受試者另接受右側膝伸肌肌力、肌耐力與疲乏度測試，並同步收集表皮肌電圖訊號。疲乏測試前後分別進行5次股神經刺激，亦以肌電圖同步收集股外側肌複合肌肉動作電位幅度與傳導時間。結果顯示重度患者之膝伸肌肌力和肌耐力顯著較對照組下降，但最大自主收縮或磁場刺激器誘發的疲乏度則未較對照組增加，神經傳導時間亦未顯著增長。此部分結果顯示重度患者的橫膈疲乏度較膝伸肌顯著。似乎不同部位肌肉因應不同負荷而產生不同適應是導致這些患者骨骼肌功能減退的重要因素之ㄧ。 第二部份探討下肢骨骼肌的代謝功能變化。共有20對年齡、身高、體重配對之重度患者與對照組參與此部份。所有受試者進行核磁共振氫譜掃描檢查股外側肌肌細胞內脂質、肌細胞外脂質、及兩者之比值，以比較兩組受試者的骨骼肌代謝功能是否有差異。另外分析血液中發炎指標、血脂肪參數（lipid profiles）和胰島素阻抗。結果顯示重度患者其肌細胞內脂質和肌細胞外脂質均較對照組顯著為低，其血液發炎指標、血脂肪參數及胰島素阻抗則較對照組高。然而肌細胞內脂質與各項血液參數均無顯著相關，但發炎指標為胰島素阻抗的獨立預測因子。結果顯示重度患者的骨骼肌和系統性代謝功能均受到影響，然而由於兩者之間並無顯著相關，其機制仍有待進一步探討。 第三部份繼續測試前述20對年齡、身高、體重配對之重度患者與對照組之運動耐力，並分析運動耐力受限之原因。所有受試者進行腳踏車最大運動耐力測試，收集氣體進行分析，並在運動過程中同步紀錄橫膈和股外側肌的表皮肌電圖訊號，以了解運動時橫膈和股外側肌的肌電變化。結果顯示重度患者之最大攝氧量較對照組顯著降低，運動耐力受限的主要原因與心跳增加不足及周邊骨骼肌功能不良有關。橫膈和股外側肌隨運動強度增加產生疲乏現象，低限運動時患者股外側肌徵召（recruitment）較橫膈顯著，然而中重度運動強度時患者的橫膈徵召較對照組顯著為高。顯示骨骼肌的確影響整體運動功能表現，但阻塞型睡眠呼吸中止症患者之肌肉參與模式與對照組不同。 最後綜合分析骨骼肌功能表現、神經傳導延遲及代謝異常等參數與阻塞型睡眠呼吸中止症嚴重度之間的相關性。結果顯示在控制年齡與身體質量指數之後，僅膈神經傳導延遲與疾病嚴重度（缺氧次數）呈顯著相關；骨骼肌功能表現和代謝異常參數則與最大運動耐力呈顯著相關。 本研究結論為阻塞型睡眠呼吸中止症患者之骨骼肌功能，包括功能表現、肌電反應、代謝功能，以及神經傳導時間，均與年齡和體型配對之對照組有顯著差異。其骨骼肌功能變化主要與各部位肌肉因使用不同而產生不同適應有關。雖然全身性發炎反應的影響無法排除，但以本研究的結果來看，局部適應的影響較為顯著。未來應以不同之介入研究深入探討其相關變化及可能機轉，以防止或改善患者之失能。

Obstructive sleep apnea (OSA) is associated with higher inflammatory markers. It has been reported that skeletal muscle dysfunction is common in systemic inflammatory diseases. However, whether skeletal muscle dysfunction developed in OSA is still unknown. The present study was designed to investigate the skeletal muscle dysfunction, nerve conduction delay, and metabolic abnormalities in patients with OSA. The men whose ages ranged 40-65 years and with normal pulmonary function were recruited. The purpose of the first part was to investigate the inspiratory muscle function in patients with different severity of OSA. Eighty-eight participants firstly underwent polysomnography assessments were recruited. The measurements included Epworth sleepiness scale, strength and endurance of inspiratory muscles, and fatigue test during either maximal voluntary efforts or in response to cervical magnetic stimulation (CMS) with simultaneously sEMG recordings. The parameters of sEMG included root mean square, median power frequency, compound muscle action potential (CMAP) amplitude and latency, which represented phrenic nerve conduction time (PNCT). The results showed there were 20 subjects without OSA, 13 mild OSA, 21 moderate OSA, and 34 severe OSA. Patients with severe OSA had significantly lower levels of muscle strength and endurance, and higher fatigability than the subjects in the other three groups. Furthermore, the performance and sEMG parameters of inspiratory muscles and knee extensors were compared in a subgroup consisted of 15 pairs of patients with severe OSA and without OSA matched for age-, and body mass index (BMI). The participants received performance tests for vastus lateralis (VL) with simultaneous sEMG recording. It was shown that patients in OSA group had significantly lower strength and endurance of knee extensors, but no significant difference in fatigability than those of the controls. CMAP amplitude and latency for VL in OSA group were not significantly different from those in the control group. It indicated that different adaptations might play an important role on skeletal muscle dysfunction in severe OSA. The second part was designed to examine the metabolic characteristics of lower extremity in patients with OSA. Twenty pairs of patients with severe OSA and non-OSA controls matched with age and BMI volunteered to this part of study. Blood samples were drawn and proton magnetic resonance spectroscopy was used to detect intramyocellular and extramyocellular lipid contents (IMCL and EMCL). It was shown significantly lower values of IMCL and EMCL, higher inflammatory markers and insulin resistance, and worse lipid profiles in severe OSA group than the control group after controlling for age and BMI. There was no significant correlation between the biochemistrical variables and IMCL or EMCL. It seemed that metabolic properties changed in OSA patients; however, the mechanisms were needed to be further studied. The third part determined the exercise capacity with simultaneous sEMG recordings for diaphragm and VL during the exercise testing. Twenty patients with severe OSA and 20 matched controls participated in this study. The results showed that significantly lower values of oxygen consumption at peak exercise and at anaerobic threshold in OSA group. The major limiting factors were abnormal heart rate response to exercise and peripheral muscle fatigue. The sEMG results showed that knee extensors fatigued at the relatively lower exercise intensity in patients with OSA, but their inspiratory muscles fatigued only at the peak phase of exercise. Interrelationships among skeletal muscle dysfunction, nerve conduction delay, and metabolic properties in OSA showed that only PNCT correlated significantly with apnea-hypopnea index. Skeletal muscles performance, electromyographic properties, and metabolic properties were correlated significantly with exercise capacity. In summary, skeletal muscle dysfunction, nerve conduction delay, and metabolic abnormalities were observed in patients with severe OSA than their age-, and BMI-matched controls. Muscle adaptation to chronic increased activation might play an obvious role than the systemic oxidative stress in the effect of OSA on skeletal muscles. Future studies are needed to investigate the effect of intervention on skeletal muscle function in OSA populations, and to explore the possible mechanisms.