The prevalence of Obstructive Sleep Apnea (OSA) is estimated to be between 7% and 17% of the adult population in the U.S., or as many as 52,000,000 people.

The current “gold standard” treatment for OSA is Continuous Positive Airway Pressure (CPAP) machines-the technology for which was developed in 1981. CPAP uses a mask and flow generator to apply air pressure to keep the airway open (splint).

An ongoing problem with CPAP is patient utilization. Of those patients for whom CPAP is prescribed it is estimated that some 30% will not use it or quickly give up on it. Another study estimated that of the patients who do use CPAP machines 34% use it intermittently (approximately 4 nights/week), and/or remove it for part of the night (for this group median nightly usage is 3.1 hours).

If those statistics are correct this means that approximately 1 in 2 of all those diagnosed with OSA either do not use CPAP or use it so infrequently that it has no practical efficacy for them.

Our product, WhisperSom RestBud™, has no oral or nasal interfaces, thus avoiding the issues of claustrophobia, entanglement, skin irritation, and air leakage that contribute to the poor compliance levels for CPAP devices. It does not lead to facial deformities (as Mandibular Advancement Devices and CPAP Masks have been accused of doing), and does not involve surgery. It is easy and comfortable to use and adapt to.

Along with the other electronic components RestBud™ contains a suite of sensors that allow the device to perform respiratory auscultation, assess SpO₂ saturation levels, and determine the sleeping position of the user.

WhisperSom RestBud™ will directly address what many researchers believe are the causative agents in the development of a number of morbidities/chronic diseases(i.e. Stroke, Heart Attacks, other Cardiac problems, as well as Cancer, Diabetes, Hypertension, Cognitive impairment due to the loss of cerebral grey matter, and non-alcoholic fatty liver disease (NAFLD) – the long term cumulative effects of repetitive occurrences of SpO₂ desaturation and large fluctuations of the negative inspiratory intrathoracic pressure.

Most other devices/processes measure their efficacy by a relative improvement in the patient’s Apnea-Hypopnea Index (AHI). It might be more appropriate to measure efficacy by the ability of a device/process to ameliorate the continued accumulation of damage from repetitive Sp0₂ desaturations. Quantifying how much time is spent with Sp0₂ desaturations of <95% (some research has shown that this is the level which leads to heart damage (Naresh M. Punjabi et al. (42) and the depth of those desaturations might be a more useful and enlightening metric.

By using that criteria, the only treatment options that can guarantee to maintain Sp0₂ desaturation of =>95%, and minimize abnormal fluctuations of negative inspiratory intrathoracic pressures during the entire sleeping period, and which is equally efficacious among all levels of severity is CPAP (if used consistently, correctly and appropriately titrated), some surgeries, and the WhisperSom RestBud™.

As of this point in time we have created a Proof of Concept Platform. It has been tested and shown to be efficacious.

Element 1: Detection:

The technology exists to allow the detection of Duty Cycle and Respiration Rate developments that are concurrent with changes to Pharyngeal Patency during the breaths immediately preceding an Obstructive Apnea (55, 56). These changes have been detailed in numerous research papers (1, 2, 3, 4, 8, 35, 44, 57, 59, 62, 73, 82, 89).

This is the results of one study graphically displayed:

Specifically RestBud™will detect the audio signature of respirations and monitor the Sp0₂ levels of the user_. The data streams from the sensors will allow RestBud™ to determine if the user is facing an actual apnea event, a change to the respiratory duty cycle presaging an apnea event, or a hypopnea that would lead to a Sp0₂ level <=95%.

The WhisperSom RestBud™ uses heuristic/self adaptive programming, and pattern matching to detect these respiratory changes. The heuristic/self adaptive programming allows RestBud™ to continuously “learn” which patterns an individual user exhibits that precipitate into an obstructive apnea, and adjusts its actions based upon that information. 

Element 2: Intervention techniques:

Numerous investigators have applied external stimulation to change ventilation: electrical stimulation applied directly to the hypoglossal nerve, transcutaneously to the submental region, high-frequency oscillation of the upper airway (UA) mucosa to influence the resolution of obstructive apneas (presumably by stimulating UA dilator muscles), tactile stimulus, and most commonly, audio. Specific experiments have determined that audio stimulus is effective at resolving apneas (5, 14) without always causing an EEG/Cortical arousal. In another experiment (69) tone induced arousals were found to have approximately the same duration as spontaneous arousals (approximately 7 seconds) wherein those produced in conjunction with an apnea had a mean length of 12. 6 seconds (70, 74). D. M. Carlson et al. (72) found that acoustically induced cortical arousal increases phasic pharyngeal muscle and diaphragmatic EMG in NREM sleep.

The audio stimulation that most sleep researches use consists of a 500-4KHz tone applied with initial amplitude of 45dB, which is increased to as much105dB in order to trigger the desired effect. It is not uncommon that even at these extreme amplitudes the volunteer is not aroused or awakened. As a reference: a Vacuum Cleaner is rated at 60dB @ six feet while a Motorcycle is rated at 85dB @ twenty-five feet.

Tones are notoriously poor methods for causing a controlled arousal (Children and Smoke Alarms UL Committee, 6). They are uni-dimensional, which while advantageous in a research environment wherein one attempts to minimize variables, are unsuitable for being adapted to subtly applying the required extraneous stimulus to cause an arousal dependent upper airway opening. Indeed research has shown that stimulus reactions are unique to the individual. The problem of deriving individual specific stimulus patterns that rely only on tones are compounded, according to research (79), that shows that there is sleep-specific dampening peculiar to inspiratory effort-related stimuli for those with OSAS.

For those reasons the WhisperSom RestBud™ takes a radically different approach to the use of acoustic stimuli to achieve an arousal-dependant opening, while minimizing stimulus “overshoot” which may lead to EEG/Cortical arousals (which impair sleep quality). It is our belief that the RestBud™ will be superior in provoking non-Cortical arousals than that of the most effective manual methods (80).

1. RestBud™ uses novel types of acoustic stimulus. The stimulus is chosen from a library of audio files of different content, amplitude, and length. It is delivered to the user via in-ear monitors.
2. By again utilizing heuristic/self adaptive programming RestBud™ will determine which combination of the vast number of controllable parameters afforded by this method of audio stimulus are best suited to meet five goals:
   1. The prevention of a complete loss of airway patency
   2. Promoting the restoration of an open airway
   3. Avoidance of EEG/Cortical arousa5s (14) and awakenings
   4. Assuring that SpO₂ stays =>94%
   5. Avoiding large fluctuations of the negative inspiratory intrathoracic pressure

The benefit of the heuristic/self adaptive programming is that it will allow for the continuous testing and verification of the effectiveness of the stimulus goals. RestBud™ will always adjust its’ stimulus outflow to match the within night variations in the patient’s arousal index (36, 54).

Some studies have determined that approximately 50% of those diagnosed with mild OSA have positional apneas, i.e. they have are apt to have more apneas while sleeping in the supine position. RestBud™ determines if the user has positional apneas and if so will cause them to shift to a non-supine position.

Element 3: Positive aspects of Intervention:

There exists a number of compelling reasons to avoid an apnea (10, 25). Perhaps the most important is not to disrupt the normalization of blood gases.

The importance of normalization of blood gases was supported in two studies by David W. Hudgel et al. (87, 88) in which it was concluded that changes in the amount of inspired CO₂ and O₂ had a dramatic impact on the duration of apneas.

During an apnea the SpO₂ levels decline (for instance, for a 26 second apnea the decrease was 9.2% (52, 85)), leading to intermittent hypoxia. Hypoxia by itself has been causally linked to many morbidities. However the role of hypoxia in the characteristic increase in blood pressure and heart rate at the end of an apnea episode remains contested with it being supported as a causative agent in some studies (61, 65, 67, 68, 78, 90). A recently released study by Sarah-Jane C Lusina et al. (27) found, “…that 10 daily exposures to isocapnic hypoxia in humans can increase sympathetic outflow during acute hypoxia and recovery”. The significance of increased sympathetic outflow is that it seems to be directly responsible, at least in part, for the acute blood pressure changes that occur at the end of a self-extinguishing apnea event (28, 29, 91). It is the conclusion from a study by Urs A. Leuenberger et al.(30) that, “…these findings strengthen the rationale that preventing intermittent hypoxia, a goal that is presently best achieved with continuous positive airway pressure therapy, is crucial to prevent the adverse neurocirculatory and cardiovascular consequences of sleep apnea.” Another study that links intermittent hypoxia to increased sympathetic outflow was performed by Urs A. Leuenberger et al. (75).

According to Miliauskas et al. (83), “Hypoxemia depth at night is an important factor for daytime sleepiness …”

It is the conclusion of R. Stoohs et al. (52) that hypoxia is a significant mediating agent in changes to Stroke Volume, and Heart Rate. That view is partially supported by a study by C. P. O’Donnell et al. (66).

Conversely a study (64) concluded, “…that only apnea length and pulse rate changes remained significantly related to [blood pressure changes], while hypoxemia did not”. This conclusion also speaks strongly for the case for termination/prevention of an apnea event.

The magnitude of changes to blood pressure varied significantly between degrees of arousal (15, 16, 17, 23, 50, 64, 85) with non-cortical activations (<3s) having a much lower diastolic than that of an EEG/Cortical arousal (>10s). Other studies show that even with acoustically induced EEG/Cortical arousals the magnitude of blood pressure changes is less than those that occur when an apnea self-extinguishes (17, 77).  It is a conclusion of O’Driscol et al. (26) that the cardiovascular response occurring at the end of an obstructive apnea is almost double that of which happens after a spontaneous arousal.

The magnitude of the change in heart rate (HR) has also been found to be dependent on the type and magnitude of the arousal. In a study by Amy S. Jordan et al. (50, 51, 85) concluded that the HR change to a spontaneous arousal was +12% over baseline, for an induced arousal from sleep it was +20% over baseline, and for the post apnea tachycardia it was +68% (52). Still another study (70) approximately confirmed those HR changes for spontaneous and induced arousals, while this study (71) detected post apnea changes to HR of more than 80%.

While it has been argued that the repetitive arousals related to apnea events is the proximal cause of the elevated blood pressures (non-dipping) associated with long term OSA a study by Melinda J. Carrington et al. (58) questions that theory as does another study by Dina Brooks et al. (84). If valid, then inducing arousals to terminate incipient apneas should have a minimal effect on dipping.

In a similar vein, hypoxia has been implicated as a risk factor in silent cerebral infarct in a study by Kazuo Eguchi et al.(7).

A study by Naresh M. Punjabi et al. (42) concluded that the frequency of hypopneas associated with a 4.0–4.9% oxyhemoglobin desaturation was associated with prevalent cardiovascular disease after adjusting for the frequency of hypopneas with oxyhemoglobin desaturations above 5%.

It is a conclusion of a study that prior sleep apneas increases the arousal threshold to upper airway occlusion on subsequent nights and prolongs the apnea events (45). Decreasing the quantity and duration of apneas may break that positive feedback cycle (76). Indeed, according to W. De Backer et al. (57) that, “…any intervention that stabilizes the breathing pattern will ultimately also lower the tendency to collapse.”

A study by Danny J. Eckert et al. (60) found that acute sustained hypoxia reduced P1 and P2 amplitudes of the RREP and decreased the sensation of respiratory loading.

The role of hypercapnia is OSA is ambiguous, however in a study by Ayappa et al. (12) “Pa_CO2 was directly related to apnea/interapnea duration ratio such that with increasing chronic hypercapnia the interapnea duration shortens relative to the apnea duration”.

RestBud™ can help avert intermittent hypoxia and hypercapnia.

Intervention will minimize changes to intrathoracic pressure. Continued respiratory effort after an obstruction leads to increases in negative intrathoracic pressure. Negative intrathoracic pressure encourages venous return to the right ventricle, increases after load on the left ventricle, which causes ventricular hypertrophy and results in congestive heart failure (34).

Studies have shown that there is always a degree of ventilatory overshoot (hyperpnea), be it from a spontaneous, induced arousal, or an apnea related arousal. However the magnitude of the overshoot was found to be significantly larger for an self-extinguishing apnea: In a study by Amy S. Jordan et al. (50, 51) it was determined that the inspiratory minute ventilation change from a spontaneous arousal was +10% over baseline, for an induced arousal from sleep (non apnea) it was +15% over baseline, and from an self-terminating apnea it was 60% (53). If loop gain is the controlling mechanism in the occurrence of repetitive apneas and the amount of Pa_CO2 is the mediating agent then controlling the degree of hyperpnea should affect the amount of loop gain.

This view is supported in studies that find that hyperventilation is a causal agent for further respiratory disturbances, with the arousal intensity and duration linked to the degree of ventilatory overshoot (35, 46, 86).

In a similar vein some researchers (38, 43, 46) have theorized that the termination of an apnea event by an arousal will invariably lead to periods of repetitive cycling (post hyperventilation apnea). However, other experimental data argues against that conclusion (32, 41, 51, 81, 86).

On the other hand hypoxia is a well-known cause of increased carotid chemoreceptor gain and CNS neurotransmitter turnover which, in turn, appears to lead to apnea promotion (30, 31, 47, 48). Preventing apnea inspired intermittent hypoxia would logically lead to decreased overall loop gain.

Dilation of the airway may be inhibited by the surface tension between the apposing

mucosal surfaces, indeed there exists experimental evidence that an application of a topical lubricant consistently reduced the severity of OSA (39, 40).

RestBud™ will act to restore airway patency before the effect of mucosal surface tension occurs, which if allowed to happen, would require a higher amount of stimulus to overcome.

Element 4: Sleep architecture

While it is generally accepted that any arousal leads to changes in sleep architecture (although the linkage between the AHI and the degree of patient fatigue is not well understood) there exists experimental data that indicates an auditory stimulation which causes a lower level of arousal (CNS) is not as disruptive as that which causes an EEG/Cortical arousal (determined by MSLT and PVT testing) (18).

Stimulation has been found to decrease the frequency of apneas, apnea duration, and changes to sleep architecture with decreased sleep stages I and II, and increased stages III and IV (11). Another study conformed aspects of that study and furthermore found that the improvements reduced the frequency and duration continued for two days. In addition there was an improvement in MSLT scores (13).

In a similar vein another rationale to initiate a controlled arousal through a CNS activation is that the impact upon sleep continuity is

Most patients with OSA develop periods of stable breathing and sleep (36). Younes et al. (38) found that 78% of patients with OSA develop periods of stable breathing and sleep even though there were incidents of complete obstructions (37). Indeed studies have shown that the number of respiratory related arousals (as defined by the AHI) are much lower is Stage 3, Stage 4 (Slow Wave Sleep), and REM (36). Thus most patients currently diagnosed with OSA are capable of dilating their airway without the need of arousal and are receiving restorative sleep.

It was the conclusion of a study by Anne Berssenbrugge et al (62) that, “…attribute(s) the observed pattern of stabilization of breathing with acute restoration of normoxia in hypoxia to the following: the initial transient prolongation of apneic duration results from the increase in the C02-apneic threshold; as Pa_O2, rises further, the relative ‘gain’ of the peripheral chemoreceptors decreases (reducing the ventilatory overshoot) and PE falls (allowing a rise in Pa_CO2) both of which act to eliminate apneas and lead to the subsequent stabilization of breathing pattern”.

RestBud™ will promote these periods of natural sleep by ameliorating some of the causes of respiratory instability.

A provocative and confounding issue is the information gathered by studies that seek to measure the impact on sleep by the use of non-invasive ambulatory blood pressure monitoring (APBM). Some conclusions are that, “Sleep is often disturbed by blood pressure monitoring but, irrespective of whether recording provokes arousal, monitored blood pressure is the same.” (19) which was confirmed by (22, 24), another found that, “…86.4% of subjects did not perceive an appreciable sleep deprivation during overnight ABP monitoring despite a frequency of measurements set to 1 every 15 minutes over the entire 24-hour period” (20). The results of that study closely mirrored those reported by Parati G, et al. (21). Both studies relied on questionnaires about the perceived quality of sleep. These studies raise an interesting issue: If ambulatory blood pressure monitoring (with its’ attendant tactile and audio stimulus – cuff inflation/deflation) does lead to arousals then why do those machines not cause changes to blood pressure and perceived sleep deprivation, although a partial explanation is offered in a study (63) that concluded that, “Ambulatory monitoring for 48 consecutive hours reveals a statistically significant pressor response that could reflect a novelty effect in the use of the monitoring device for the first time.” This is all interesting in light of the fact that in many ways the APBM mirrors the stimulus that will be provided by RestBud™.

Element 5: Excessive Daytime Sleepiness (EDS)

While it is our contention that those who refuse conventional treatment options have implicitly decided to live with a degree of excessive daytime sleepiness (EDS), fatigue, and cognitive impairment, and while we are sure that our device resolves the issue of accumulating damage from repetitive SpO₂ desaturations, it may not improve sleep architecture (research papers are not definitive). We are pleased to see that there exists some reason to believe that EDS is not as quite as large an issue as many believe (95). It is the conclusion of this study, “…that in this community-based cohort, subjective sleepiness is absent in many individuals…with moderate to severe sleep-disordered breathing.” Vishesh K. Kapur, MD, et al. (93). Another report found that “…a recent review of the Sleep Heart Health Study showed that EDS – considered as a score greater than 10 on the Epworth Sleepiness Scale – was experienced by up to 21% of individuals who did not have sleep apnea, whereas in patients with an apnea hypopnea index (AHI) greater than 30, only 40% of cases experienced sleepiness.” Hernández García (94).

Excerpts from a review by a judge from a SBIR funding application-

Significance: The proposed project is significant in that it provides a simpler therapy for obstructive sleep apnea (OSA) than current treatments such as continuous positive airway pressure (CPAP). If successful, it would be potentially adopted by 12 million patients and commercially profitable.

Approach: The approach may be a good one in that it may be more tolerated than the currently used continuous positive airway pressure (CPAP), which requires the wearing of a pressurized mask and is not acceptable by many patients.

Protection of Human Subjects: There are no significant health risks from use of chest and abdomen belts, or microphone.

Innovation: The project is innovative in that it proposes to replace continuous positive airway pressure (CPAP), the usual treatment for obstructive sleep apnea (OSA), with a simpler system. They propose to detect onset of apnea with sensors, which might include belts around the chest and abdomen to measure ventilation, and a microphone to measure sound. When it detects onset of apnea it would slightly arouse the patient with a vibrator or loudspeaker, thus improving muscle tone in the throat.

Potential Benefits of the Proposed Research to Subjects and Others: If successful, there are potential benefits to subjects.

Importance of Knowledge to be Gained: If successful, there are potential benefits to apnea sufferers.

In Conclusion:

The WhisperSom RestBud™ is potentially a treatment modality that is efficacious, and should be readily accepted by its’ target population.

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