Based upon the results of a number of peripheral studies including those by our competitor we believe that the WhisperSom RestBud™ has no negative impact upon the users’ Sleep Architecture, indeed it could very well be beneficial.

Before exploring this issue I would like to reiterate that we see WhisperSom RestBud™ as an alternative primary treatment for those who snore and those who are diagnosed with OSA that are unable or unwilling to use continuous positive airway pressure (CPAP) therapy, or as a conjunctive treatment option for those patients who snore or use CPAP intermittently.

WhisperSom RestBud™ is designed to deal with the effects of loud snoring and repeated hypoxias; which various studies have linked to the development of a number of life threatening morbidities but not limited to heart attack, stroke, cancer, and diabetes.

It is the nature of research that studies often seem to contradict one another. That which was determined once to be valid are constantly, after further study, is found not to be.

Examples abound: Fish oil, multivitamins, alcoholic intake, and chocolate have all been declared to be “good” or “bad” and then subsequently determined not to be so.

In a similar vein there are concepts pertaining to OSA that, for many years, were widely believed to be facts:

One of these was that an apnea episode was terminated by a micro arousal. The micro arousal led to a restoration of tracheal patency and the restoration of respiration.

This “fact” was upended by the publication of a paper (Role of Arousals in the Pathogenesis of Obstructive Sleep Apnea) by Magdy Younes in 2004.

In the same theme it may be that causing a controlled arousal may very well lead to diminishment of the overt symptoms of OSA, i.e. excessive daytime sleepiness, cognitive impairment, and fatigue.

Based upon the following studies it is our belief that controlled arousals (non EEG/Central Nervous System (CNS) activations that are less than 3 seconds) should lead to an improvement in Sleep Architecture because-

• Maintenance of a Blood Oxygen level that is >94% (elimination of hypoxia)
• Fewer apneas
• Elimination of large fluctuations of negative inspiratory intrathoracic pressure

A number of studies have indicated that the number of sleep disturbances, the depths of hypoxias, and the length of arousals all affect the degree of the overt symptoms.

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

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 apneic 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 Respiratory-Related Evoked Potential (RREP) and decreased the sensation of respiratory loading.

The role of hypercapnia inn 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”.

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.

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 confirmed aspects of that study and furthermore found that the improvements reduced the frequency and duration, and 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

This is important in the light of a study by Daniel J. Schwartz, M.D et al. (92) that claims that cortical arousals, many of which are greater than 15 seconds in duration,….constituted 18.4% of all arousals and accounted for 37.5% of the total arousal time.

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”.

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 press or 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 APB mirrors the stimulus that will be provided by Morpheus.

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, we are none –the-less 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 a study by Vishesh K. Kapur, MD, et al. (93). this study: “that in this community-based cohort, subjective sleepiness is absent in many individuals…with moderate to severe sleep-disordered breathing” 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). 

Extracts

“The presence of transient electrocortical arousal in the current study appears to be able to influence respiration consistent with termination, or early resolution, of obstructive apneas in patients with OSA. Furthermore, such nonrespiratory afferent stimulation appears to be able to influence apnea resolution without involving ascending arousal systems. Resolution of the apnea after stimulation was generally associated with qualitatively increased submental EMG compared with the EMG during the apnea whether electrocortical arousal occurred, suggesting a similar mechanism of response to tones irrespective of cortical involvement.

The current findings suggest that strategies of induced arousal, at an intensity level stimulating respiration while avoiding recruitment of the ascending arousal system and its potential effects of sleep disruption, could have potential application as a therapeutic modality in patients with OSA.”

Induced Arousal in Obstructive Apnea

Robert C. Basner, Ergun Oanl, David W. Carley, Edward J. Stepanaski, and Melvin Lopata.Department of Medicine, Section of Respiratory and Critical Care Medicine, University of Illinois at Chicago College of Medicine, and the Department of Veterans Affairs West Side Medical Center and University of Illinois Hospital, Chicago, Illinois 60612

0161-7567/95 Copyright © 1995 the American Physiological Society

“…Tones delivered relatively early and late in the apnea were equally likely to be associated with resolution of the apnea. These data indicate that transient arousal, induced by non-respiratory stimulation, influences the resolution of obstructive apneas during sleep…the tendency for the stimulus to resolve the apnea within 2 s of the tone.…the current study appears to be able to influence respiration consistent with termination, or early resolution, of obstructive apneas in patients with OSA. Furthermore, such non-respiratory afferent stimulation appears to be able to influence apnea resolution without involving ascending arousal systems.”

Respiratory and Arousal Responses to Acoustic Stimulation

Robert C. Basner; ErgünÖnal; Melvin Lopata; Robert Applebaum; and David W. Carley

DOI 10.1378/chest.112.6.1567 Chest 1997;112;1567-1571

“…The apnea index, the number of times per hour that SaO2 dropped below 85% (SaO₂< 85%/hour), and the total apnea duration expressed as a percentage of total sleep time during stimulation nights decreased to approximately 50% of the corresponding values on the control night.”

Effect of induced transient arousal on obstructive apnea duration

1. C. Basner, E. Onal, D. W. Carley, E. J. Stepanski and M. Lopata

Department of Medicine, Section of Respiratory and Critical Care Medicine, University of Illinois at Chicago College of Medicine, and the Department of Veterans Affairs West Side Medical Center and University of Illinois Hospital, Chicago, Illinois 60612

0161-7567/95 Copyright © 1995 the American Physiological Society

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