Obstructive sleep apnea (OSA) is effectively managed by positive airway pressure (PAP) applied to the nose and/or mouth. The principle of PAP is to inflate the critical region of closure in the upper airway, usually at the base of the tongue or the uvula. The effective property of the airway is the elasticity of the tube. This important property permits us to eat, talk, and sing while awake, but a detriment if all you want to do is keep the airway open at night. Those in the sleep laboratory who titrate PAP see the effectiveness of changes of increasing pressure during a titration. The pharyngeal airway during sleep is mechanically acting like a collapsible tube within a rigid box, such that providing a positive internal pressure stabilizes some parts of the collapsible airway.
However, if this is true, then negative pressure surrounding the airway in this rigid box might be useful as an alternative option to open the airway in those who snore or have sleep apnea. The practicality of this approach was demonstrated in two studies. In one study in 1990, vacuum pressure was applied eternally to the neck in spontaneously breathing anesthetized dogs.1 Upper airway resistance was measured using a cuirass applied from the jaw to the chest to provide negative pressure (-2 to -20). This range resulted in a progressive, although not linear, fall in resistance without causing a change in respiratory drive or timing.
Negative Pressure and Collapsibility
The first demonstration in humans using negative external pressure to the submental region was done under anesthesia to record the collapsibility of the passive pharynx and also addressed the potential influence of obesity.2 Submental negative pressure in ten obese and ten nonobese adult women was measured under general anesthesia and induced paralysis. Negative pressure was applied through the use of a silicone collar covering the entire submental region and a vacuum pump. Submental negative pressure decreased observed collapsibility at the retropalatal and retroglossal airway but only in the nonobese group. No such changes were found in obese subjects.
Now that the feasibility of a negative pressure produced in a collar around the human neck could be effective in reducing obstruction, at least in some individuals, attention turned to other examples of where it could be demonstrated. One device currently marketed (aerFree, Sommetrics, Rancho Bernardo CA, DEN140024) lessens respiratory impairment during screening colonoscopy.3 In patients placed on the device -35cmH2O could reduce the decline from baseline of >4 % in oxygen saturation and/or apnea lasting ≥ 20 seconds. During screening colonoscopy, sedation-related respiratory impairment is significantly reduced by continuous negative external pressure (cNEP) (ClinicalTrials.gov NCT01895062).
Sommetrics, who developed the collar for use in moderate anesthesia, subsequently developed a collar for providing cNEP with the intent of testing whether this approach might be effective in treating OSA.4 In a prospective, open-label pilot study in 15 subjects fitted with a first-generation device, 87% were responders to and nine had an excellent response in reducing their apnea-hypopnea index (AHI) <5 per hour, and four had a partial response (AHI <50% baseline and <15 events/h). The range of AHI and BMI was limited, but feasibility was demonstrated for this application. Three minor, self-limited adverse events occurred, which appeared related to contact pressure of the collar on the skin.
cNEP Pilot Study Results
A recently published prospective, open-label pilot study5 included 28 people with moderate OSA AHI15 events/h ≤ AHI ≤30 events/h and each participant tested at least two of six available cNEP devices, which could vary the negative pressure from -10 to -35cmH2O during sleep periods of at least 2 hours (NCT04718142). Approximately 71% responded to therapy, with half of those having an AHI ≤5/h and 21% showing an AHI ≤50% baseline. For the 20 responders, the therapy reduced the portion of total sleep time when peripheral oxygen saturation <90% and improved minimum pulse oximetry oxygen saturation to above 90%. Six patients experienced a minor, self-limited adverse event. Twenty-six participants (93%) stated that they would use cNEP nightly.
There is currently an ongoing pivotal trial on the use of a second-generation collar called Study Using Negative Pressure to Reduce Apnea (SUPRA). For this trial, Sommetrics designed an improved collar in three sizes to deploy a standardized protocol developed in collaboration with the United States Food and Drug Administration (FDA) (NCT04861038). It is designed to rigorously test the safety, efficacy, and durability of an aerSleep II system in subjects who had a prior diagnosis of OSA and would not or did not tolerate CPAP. Other requirements are a BMI <42, age >18 years, and AHI at baseline of 15-50/hr. as measured over two nights of home sleep testing (NoxT3s, Nox Medical). This is the first OSA therapy study to address the unpredictability of the pandemic era by trying to minimize person-to-person contact by limiting in-person visits to collar demonstration, fit and download of use, as well as internet deployment of virtual visits, staff coaching, and electronic patient-reported outcome measurements (ePRO). Two-night home sleep testing was performed to document effectiveness and durability of the response. One to two weeks after collar fitting, and then at 12 and 24 weeks. The primary endpoint is AHI, with a change from baseline to <5 or at least 50% to a value less than 20/hr.
Subjects will be enrolled at up to fifteen study sites in the United States to ensure that approximately 79 subjects who are termed initial responders can be evaluated after 24 weeks of home use with the aerSleep II device. After a 1–2 week period of acclimation, subjects will have a second HST (HST #2). Initial responders with a ≥50% reduction in AHI from baseline with an AHI <20/hour will be continued on home treatment. Non-responders will be discontinued from the study.
The primary endpoints are a sustained response in a majority of those on aerSleep II therapy at 24 weeks, as defined as a change of at least 50% of their baseline AHI with an AHI rate less than 20 per hour at the final home sleep test at 24 weeks. Primary safety items related to adverse device effects. Secondary endpoints are the change in ODI, the AHI change from baseline for all subjects that acclimate to the aerSleep II device, the proportion of subjects that acclimate to the device that exhibit a change in AHI after 24 weeks of home use with the aerSleep II device, the change in self-reported sleep disturbance from baseline as measured by Patient-Reported Outcomes Measurement Information System (PROMISTM) Sleep Disturbance and Sleep Disturbance 8b questionnaires, and perceived change from baseline as measured by the Patient Global Impression Scale questionnaire.
Evolving OSA Treatment Options
Alternatives in the treatment of OSA continue to evolve from the first use of PAP as an alternative to tracheostomy and then uvulopalatopharyngoplasty. New technologies such as hypoglossal nerve stimulation and improvements on oral appliance therapy have a place in the therapeutic regimen.
The recognition that OSA is a common, serious and chronic condition is becoming more accepted. It is so common as to justify investment in improved therapy and patient management. The “care that fits” model will continue to evolve and reach clinical use through such pathways of identifying the underlying physiology and improved understanding of the mechanisms of therapy. OSA is more complicated than we think, and no one approach will work or be acceptable for treating this chronic disorder.
Kingman Strohl, MD, is a pulmonary/sleep physician and Professor of Medicine at University Hospitals Cleveland Medical Center and the Director of the Case Sleep Fellowship at Case Western Reserve University.
This article originally appeared in Sleep Lab Magazine Jul/Aug 2023.
References
- Wolin AD, Strohl KP, Acree BN, Fouke JM. Responses to negative pressure surrounding the neck in anesthetized animals. Journal of applied physiology (Bethesda, Md : 1985). 1990;68(1):154-160.
- Kato S, Isono S, Amemiya M, et al. Submental negative pressure application decreases collapsibility of the passive pharyngeal airway in nonobese women. Journal of applied physiology (Bethesda, Md : 1985). 2015;118(7):912-920.
- Kais SS, Klein KB, Rose RM, Endemann S, Coyle WJ. Continuous negative external pressure (cNEP) reduces respiratory impairment during screening colonoscopy: a pilot study. Endoscopy. 2016;48(6):584-587.
- Kram JA, Woidtke RV, Klein KB, Rose RM. Evaluation of Continuous Negative External Pressure (cNEP) for the Treatment of Obstructive Sleep Apnea: A Pilot Study. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2017;13(8):1009-1012.
- Kram JA, Pelayo R. Variable negative external pressure-an alternative to continuous positive airway pressure for the treatment of obstructive sleep apnea: a pilot study. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2022;18(1):305-314.
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