CPAP替代治疗？植入式神经刺激器可降低呼吸暂停严重程度

《新英格兰医学杂志》(New England Journal of Medicine)1月8日在线发表的STAR研究显示，植入式神经刺激器可通过刺激上呼吸道神经和肌肉，进而使阻塞性睡眠呼吸暂停严重程度出现长期的、具有临床意义的降低(N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1308659])。



植入后1年，患者的呼吸暂停-低通气指数(AHI)评分降低68%，氧减饱和度指数(ODI)评分降低70%，并且日间嗜睡和生活质量获得主观改善。这些获益的程度与持续气道正压通气(CPAP)治疗的获益程度相似，并且优于悬雍垂腭咽成形术的获益程度。

该植入式神经刺激器植入右侧中间锁骨下区肋间肌，刺激器的一根导线向上穿入患者的颈部，与3个刺激电极连接。电极可植入到同侧舌下神经的不同结构中，电极在受到刺激时，可将舌头向前推并预防上气道肌肉发生塌陷和引起吸气流阻塞。该神经刺激器还具有第二根传感导线，该导线在同侧的内部和外部肋间肌之间穿过以检测睡眠期间的通气作用力，这样一来舌下神经的刺激就能够与患者的呼吸同步。


Patrick Strollo, Jr.医生

这项研究由匹兹堡大学医学中心耳鼻咽喉科的Patrick J. Strollo Jr.医生及其同事与赞助方Inspire Medical Systems和美国食品药品管理局(FDA)共同设计，共入组126例不能耐受CPAP治疗的患者。患者通过手术方式植入神经刺激器，并被随访1年。手术由22个学术性医学中心和私人医学中心的耳鼻喉科医生进行，中位手术时间为140 min(范围：65~360 min)。

大部分(83%)患者为男性。平均年龄为55岁(范围：31~80岁)，平均体重指数为28.4 kg/m2 (范围：18.4~32.5)。其中22例(17%)患者曾进行悬雍垂腭咽成形术，但该手术未能校正其阻塞性睡眠呼吸暂停。

该研究的主要终点为12个月时通过AHI和ODI评分测定的阻塞性睡眠呼吸暂停严重程度的改变。结果显示，中位AHI评分从29.3起事件/h降至9.0起事件/h，降低了68%。中位ODI评分从25.4起事件/ h降至7.4起事件/h，降低了70%。2/3患者的AHI评分降低至少50%，3/4患者的ODI评分降低至少25%。低氧饱和(＜90%)睡眠时间百分比的中位数从5.4%降至0.9%。

此外，患者的睡眠问卷(此问卷测定疾病特异性生活质量)功能结局评分出现具有临床意义的改善。Epworth嗜睡量表评分恢复正常。

在该研究最后的“激发”期，1年时经植入式神经刺激器治疗有效的首批46例连续患者被随机分成两组，一组继续接受该治疗(晚上开启刺激器)1周，另一组停止该治疗(晚上关掉刺激器)1周。这一激发表明，阻塞性睡眠呼吸暂停的改善事实上得益于这一舌下神经刺激器的使用，因为在停止治疗的患者中观察到睡眠呼吸暂停复发。

未观察到严重手术并发症、再次住院和感染。2例患者发生与刺激器相关的严重不良事件，总发生率＜2%。在这两例患者中，均观察到刺激器导致患者不适，通过进行第二次手术改变刺激器的位置后，不适得以缓解。另有33例严重不良事件被认为与植入术或刺激器无关。

在88%的患者中观察到非严重不良事件，包括术中插管引起的咽痛、切口部位疼痛和肌肉酸痛。与刺激器相关的非严重事件包括电刺激期间的不适(见于40%的患者)和舌头疼痛(21%)。这些事件在患者适应刺激器后或在再次设定刺激器程序调节刺激后得以缓解。

23例患者在术后出现暂时性舌头无力，该事件在所有这些患者中均得以缓解。9例患者使用护齿牙套来缓解舌头疼痛或擦伤。这一方法可能不适用于气道过度塌陷的患者。在该研究中，研究者在药物诱导的睡眠期间使用内镜来筛查潜在的研究参与者，以识别起源于舌后区的功能性上气道塌陷（在舌根部进行神经刺激时，舌后区最易受到影响）。

FDA医疗器械咨询委员会的麻醉和呼吸治疗设备小组将在2月20日就与上市前批准申请相关的资料进行讨论、提建议和投票。

随刊述评：舌下神经刺激似乎有效

加州大学圣地亚哥分校肺和危重病医学部的Atul Malhotra医生表示，上述研究结果为临床医生提供了通过舌下神经刺激来治疗不能耐受CPAP的某些患者的依据。鉴于阻塞性睡眠呼吸暂停的病理生理，将有显著比例的患者可从这一治疗中获益，即使症状只出现减少而不能完全消除。

Malhotra医生声明此前与飞利浦伟康、Apnex和Apnicure公司存在联系(N. Engl. J. Med. 2014 [doi:10.1056/NEJMe1314084])。

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By: MARY ANN MOON, Internal Medicine News Digital Network

An implantable device that stimulates the upper airway nerves and muscles produced long-term, clinically meaningful reductions in the severity of obstructive sleep apnea in an industry-sponsored study reported online Jan. 8 in the New England Journal of Medicine.

One year after implantation, patients showed a 68% reduction in scores on the Apnea-Hypopnea Index (AHI) and a 70% reduction in scores on the Oxygen Desaturation Index (ODI), as well as subjective improvements in daytime sleepiness and quality of life. The magnitude of these benefits was similar to that reported for continuous positive airway pressure (CPAP) therapy and superior to that reported for uvulopalatopharyngoplasty, said Dr. Patrick J. Strollo Jr. of the department of otolaryngology, University of Pittsburgh Medical Center and his associates in the STAR (Stimulation Therapy for Apnea Reduction) trial group.
 
Upper-airway stimulation using implanted electrodes to stimulate the hypoglossal nerve on one side of the neck "has been developed as a possible treatment option" for moderate to severe obstructive sleep apnea "and has shown promise in feasibility trials," the investigators noted.

For their study, designed in collaboration with the sponsor (Inspire Medical Systems) and the Food and Drug Administration, 126 patients who couldn’t tolerate CPAP therapy underwent surgical implantation of the device and were followed for 1 year. Otolaryngologists at 22 academic and private medical centers performed the surgery, which took a median of 140 minutes (range, 65-360 minutes).

Most (83%) of the participants were men. The mean age was 55 years (range, 31-80 years), and the mean body mass index was 28.4 kg/m2 (range, 18.4-32.5). Twenty-two of these patients (17%) had undergone uvulopalatopharyngoplasty, which had not corrected their obstructive sleep apnea.

The device includes a neurostimulator implanted in the intercostal muscles in the right mid-infraclavicular region, with one lead threaded upward inside the patient’s neck that is attached to three stimulation electrodes. The electrodes can be placed in a variety of configurations on the ipsilateral hypoglossal nerve, which, when stimulated, pushes the tongue forward and prevents the upper-airway muscles from collapsing and causing inspiratory flow obstruction.

The device also has a second, sensing lead tunneled between the internal and external intercostal muscles on the ipsilateral side to detect ventilatory effort during sleep, so that the stimulation of the hypoglossal nerve can be synchronized with the patient’s breathing.

The primary outcome of the study was the change in severity of obstructive sleep apnea, as measured by scores on the AHI and the ODI, at 12 months. The median AHI score decreased 68%, from 29.3 events per hour to 9.0 events per hour. The median ODI score dropped 70%, from 25.4 events per hour to 7.4 events per hour, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1308659]).

Two-thirds of the participants showed a reduction of at least 50% in AHI score, and three-quarters showed a reduction of at least 25% in ODI score. And the median percentage of sleep time spent with poor oxygen saturation (less than 90%) declined from 5.4% to 0.9%.

In addition, patients’ scores on the Functional Outcomes of Sleep Questionnaire, which measures disease-specific quality of life, showed clinically meaningful improvement. And scores on the Epworth Sleepiness Scale normalized.

In the final, "challenge," phase of this study, the first 46 consecutive patients who had responded to this treatment at 1 year were randomly assigned to either continue it (turn the devices on at night) or to discontinue it (turn the devices off at night) for 1 more week. This challenge demonstrated that the improvements in obstructive sleep apnea were in fact from the use of the hypoglossal-stimulation device, as sleep apnea relapsed in the patients who discontinued treatment.
 
There were no serious procedural complications, no rehospitalizations, and no infections. Two patients developed serious device-related adverse events, for an overall rate of less than 2%. In both cases, the device caused discomfort that was resolved by a second surgery to reposition it. Another 33 serious adverse events were considered to be unrelated to the implantation procedure or the device.

Nonserious adverse events – including sore throat from intubation during the procedure, pain at the incision sites, and muscle soreness – occurred in 88% of the study subjects. Nonserious events related to the device included discomfort during electrostimulation, reported by 40% of patients, and tongue soreness, reported by 21%. These resolved as the patients became acclimated to the device or after the device was reprogrammed to adjust the stimulation.

Twenty-three patients experienced temporary tongue weakness after the surgery, which resolved in all of them. Nine patients began using a tooth guard to resolve tongue soreness or abrasion.

"This approach may not be appropriate for persons with excessive airway collapsibility," Dr. Strollo and his associates cautioned. They screened potential study participants using endoscopy during drug-induced sleep, to identify functional upper-airway collapse originating in the retrolingual region, which would be the most amenable to neurostimulation at the base of the tongue.

The FDA’s Anesthesiology and Respiratory Therapy Devices Panel of the Medical Devices Advisory Committee will discuss, make recommendations, and vote on information related to the premarket approval application on Feb. 20.

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Hypoglossal nerve stimulation appears effective

The findings by Strollo et al. give clinicians the rationale to consider hypoglossal nerve stimulation for selected patients who have trouble with CPAP therapy, said Dr. Atul Malhotra.

Given the pathophysiology of obstructive sleep apnea, a substantial proportion of patients would probably benefit from this treatment, even though symptoms were only reduced rather than completely eradicated. "Although the elimination of apnea would clearly be desirable, the observed reductions are probably similar to the benefits observed with CPAP, particularly when one considers the variability of adherence to CPAP therapy," he said.

Dr. Atul Malhotra is in the division of pulmonary and critical care medicine at the University of California, San Diego. He reported previous ties to Philips Respironics, Apnex, and Apnicure. These remarks were taken from his editorial accompanying Dr. Strollo’s report (N. Engl. J. Med. 2014 [doi:10.1056/NEJMe1314084]).