乙酰唑胺加CPAP可改善OSA患者高原反应

《美国医学会杂志》(JAMA)发表的一项研究显示，对于到高海拔地区旅行的阻塞性睡眠呼吸暂停(OSA)患者，联合使用乙酰唑胺和自动连续气道正压通气(CPAP)的疗效优于单用CPAP (2012 [doi:10.1001/jama.2012.94847])。

这项随机、安慰剂对照、双盲交叉研究由瑞士苏黎世大学医院的Tsogyal Latshang博士及其同事进行，共纳入51例通常在800米海拔居住且定期使用CPAP的OSA患者。所有患者在2009年夏天接受睡眠检查，第1次检查在海拔490米的苏黎世大学医院进行，之后在2个瑞士山区度假胜地(一处海拔1630米，另一处海拔2590米)旅游3天，2周后再旅游1次。

患者在海拔1630米处停留2天和在海拔2590米处停留1天期间接受乙酰唑胺或安慰剂治疗。乙酰唑胺用法用量为每天早上250 mg×1，每晚饭前250 mg×2；安慰剂用法用量相同。患者回到800米以下海拔处居住2周，然后再次前往上述2个高海拔度假胜地居住3天，接受另一种治疗(乙酰唑胺或安慰剂)。在睡眠检查期间，患者不使用自己的CPAP设备，而是使用同一类型的自动调节CPAP设备，但使用患者自己的面罩。

结果显示，在海拔1630米处，乙酰唑胺/CPAP联合治疗组的中位夜间氧饱和度为94%，比安慰剂组的93%高1%。在海拔2590米处，联合治疗组的中位夜间氧饱和度为91%，比安慰剂组的89%高2%。在海拔2590米处，联合治疗组患者在13%(中位数)的夜间睡眠期间氧饱和度低于90%，而安慰剂组患者在57%(中位数)的夜间睡眠期间氧饱和度低于90%(P＜0.001)。

在2个高海拔处，联合治疗组的呼吸暂停/低通气指数评分均低于安慰剂组。基线时，在海拔490米医院单纯接受CPAP治疗的情况下，患者的中位呼吸暂停/低通气指数为6.6起事件/h。在海拔1630米处，安慰剂组的中位呼吸暂停/低通气指数为10.7起事件/h，而乙酰唑胺组为5.8起事件/h。在海拔2590米处，安慰剂组的中位呼吸暂停/低通气指数为19.3起事件/h，而乙酰唑胺组为6.8起事件/h(所有P值＜0.001)。研究者表示，呼吸暂停/低通气指数的降低主要与中枢呼吸暂停/低通气例数较少相关，特别是在非快速眼动睡眠期间，但阻塞性呼吸暂停/低通气也略有减轻(海拔2590米处)。

次要终点包括睡眠时间、运动能力、警觉症状和不良反应。联合治疗组在海拔1630米和2590米处的中位睡眠时间分别比安慰剂组多24分钟(451 vs. 427)和34分钟(446 vs. 412)(P＜0.001)。联合治疗组的睡眠效率和非快速眼动睡眠也高于安慰剂组，但患者自报的日间嗜睡与安慰剂组相比无显著差异。

联合治疗组在海拔1630米(59次/分 vs. 60次/分)和2590米(61次/分 vs. 64次/分)处的心率均稍低于安慰剂组，并且联合治疗组在海拔1630米(96 mmHg vs. 101 mmHg)和2590米(99 mmHg vs. 104 mmHg)处的血压均低于安慰剂组(P＜0.05)。

乙酰唑胺最常见的不良反应是口腔气味难闻和轻至中度感觉异常，但无患者停止治疗。该研究的局限性在于患者在高海拔区居住的时间较短且研究人群主要为中度肥胖且仅患有稳定合并症的中年男性，因此研究结果不具有普遍意义。

该研究获瑞士国家科学基金会等机构资助。一位研究者声明与IMT Medical等公司存在联系。

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By: TARA HAELLE, Internal Medicine News Digital Network

Using a combination treatment of acetazolamide and auto-CPAP therapy in patients with obstructive sleep apnea traveling to high altitudes was more effective than CPAP use alone, according to a study published in JAMA.

Patients with obstructive sleep apnea (OSA) who took acetazolamide and used CPAP at two different altitudes higher than baseline had lower apnea/hypopnea index scores and higher nighttime oxygen saturation percentages than patients who took a placebo and used CPAP.

Dr. Tsogyal Latshang and associates at the University Hospital Zurich reported the results of their randomized, placebo-controlled, double-blind crossover study with 51 OSA patients in JAMA Dec. 12 (2012 [doi:10.1001/jama.2012.94847]).

All the patients, who normally live below 800 meters altitude and use CPAP regularly, underwent sleep studies during the summer of 2009, first at the University Hospital Zurich (490 m) and then at two Swiss mountain resorts, one at 1,630 m and one at 2,590 m, during two 3-day trips.

The patients took either acetazolamide or a placebo while spending 2 days at 1,630 m and 1 day at 2,590 m. The acetazolamide was dispensed as one 250-mg dose each morning and two 250-mg doses each evening before meals; the placebo looked identical.

After 2 weeks spent below 800 m following the first 3-day trip, the patients then spent another 3 days at the high-altitude resorts to take the other intervention (acetazolamide or placebo). During the sleep studies, instead of using their own CPAP devices, the patients all used the same type of autoadjusting CPAP machine with their own masks.

The combination therapy of acetazolamide and CPAP increased the patients’ median nighttime oxygen saturation at 1,630 meters by 1%, from 93% with placebo to 94% with combination therapy. At 2,590 meters, the increase was 2%, from 89% with placebo to 91% with combination therapy. At the higher altitude, patients receiving combination therapy spent a median 13% of nighttime sleep with oxygen saturation below 90%, compared to a median of 57% (P less than .001) below 90% oxygen saturation with placebo.

Patients receiving combination therapy also had lower apnea/hypopnea index scores at both altitudes, compared with placebo. The median at baseline, in the hospital at 490 meters with CPAP only, was 6.6 events/hour. At 1,630 meters, patients with placebo had a median 10.7 events/h, compared with 5.8 when taking acetazolamide. At 2,590 m, patients’ median apnea/hypopnea index improved from 19.3 events/h with placebo to 6.8 with acetazolamide. (All P values under .001)

"The reduction in the apnea/hypopnea index was mainly related to a lower number of central apneas/hypopneas, particularly during nonrapid eye movement sleep, but obstructive apneas/hypopneas were slightly reduced as well (at 2,590 m)," the researchers reported.

Secondary outcomes measured included sleep time, exercise performance, vigilance symptoms, and adverse effects. Patients taking acetazolamide slept a median 24 minutes more (451 minutes, compared with 427) at 1,630 m and 34 minutes more (446 minutes, compared with 412) at 2,590 m (P less than .001). Sleep efficiency and nonrapid eye movement sleep were also higher with combination therapy than placebo, although self-reported daytime sleepiness was not significantly different.

Patients’ heart rate was slightly lower with combination therapy (59 beats per minute, compared with 60 at 1,630 m; and 61 bmp, compared with 64 at 2,590 m), and patients taking acetazolamide had lower blood pressure at altitude than with placebo (96 mm HG, compared with 101 mm HG at 1,630 m; and 99 mm HG, compared with 104 mm HG at 2,590 m; P < .05)

The most common adverse effects reported with acetazolamide were an unpleasant taste in the mouth and mild to moderate paresthesias, but no patients discontinued therapy. Primary study limitations include the limited ability to generalize beyond short high-altitude duration and beyond the predominantly middle-aged male cohort, who were moderately obese and had only stable comorbidities.

The study was funded by grants from the Swiss National Science Foundation, Lung Leagues of Zurich and Schaffhausen, Center for Clinical Research, University of Zurich, University Hospital Zurich, and Philips Respironics (unconditional grant) in Switzerland. The only disclosure reported was Dr. Bloch’s consultancy for IMT Medical and his receipt of unconditional institutional grants from Philips Respironics and ResMed.