Mandibular advancement and obstructive sleep apnoea: a method for determining effective mandibular protrusion.

The objectives of the study were to test the hypotheses that it is possible, during routine polysomnography (PSG), to prospectively identify favourable candidates for mandibular repositioning appliance (MRA) therapy in the treatment of obstructive sleep apnoea (OSA) and to accurately estimate an optimal protrusive distance at which to fabricate the MRA. A series of subjects underwent a remotely controlled mandibular positioner (RCMP) test during PSG monitoring. The ability of the RCMP test to eliminate OSA and the target protrusion at which that occurred was compared with the success of a custom oral MRA in the 33 subjects who completed the protocol. The RCMP test was a success in 15 subjects and a failure in 18 subjects. Appliance therapy was initiated in 38 subjects and completed in 33. MRA therapy was successful at target protrusion in 80% of subjects who had a successful RCMP test and failed in 78% of those who failed the RCMP test. In conclusion the remotely controlled mandibular positioner test outcome demonstrated a statistically significant association with mandibular repositioning appliance outcome. The target protrusion determined during the remotely controlled mandibular positioner test was the effective therapeutic protrusion in subjects with a successful remotely controlled mandibular positioner test.

Ventilatory instability during sleep: new insights from the computational model.

We developed a computational model of the human respiratory system and its chemoreflex control during sleep [1] [2] Our model, which is an extension of the model of Grodins et al. [3], combines an accurate description of a plant with a novel controller design. The controller consists of two feedback loops (central and peripheral) each with its own delay and gain. The overall minute ventilation is a sum of central and peripheral components. The model was employed to develop a new graphical method for stability analysis of the respiratory control system similar in concept to the phase plane. The relative chemosensitivities of the peripheral and central loops serve as the plane's coordinates. A region of stability exists with the normal operating point for the system lying well inside its boundaries. Changes to the sensitivities of either loop, caused by known pathologies, displace the operating point toward the border of the stability region. Furthermore, the shape and area of the stability region is significantly influenced by changes in the cerebral blood flow.

Evidence that ventilatory rhythmogenesis in the frog involves two distinct neuronal oscillators.

In Rana catesbeiana the upper airways are used for two distinct yet highly coordinated ventilatory behaviours: buccal ventilation and lung inflation cycles. How these behaviours are generated and coordinated is unknown. The purpose of this study was to identify putative rhythmogenic brainstem loci involved in these ventilatory behaviours. We surveyed the isolated postmetamorphic brainstem to determine sites where local depolarization, produced by microinjecting the non-NMDA glutamate receptor agonist, AMPA, augmented the ventilatory motor patterns. Two sites were identified: a caudal site, at the level of cranial nerve (CN) X, where AMPA injections caused increased buccal burst frequency but abolished lung bursts, and a rostral site, between the levels of CN VIII and IX, where injections increased the frequency of both types of ventilatory bursts. These two sites were further examined using GABA microinjections to locally inhibit cells. GABA injected into the caudal site suppressed the buccal rhythm but the lung rhythm continued, albeit at a different frequency. When GABA was injected into the rostral site the lung bursts were abolished but the buccal rhythm continued. When the two sites were physically separated by transection, both rostral and caudal brainstem sections were capable of rhythmogenesis. The results suggest the respiratory network within the amphibian brainstem is composed of at least two distinct but interacting oscillators, the buccal and lung oscillators. These putative oscillators may provide a promising experimental model for studying coupled oscillators in vertebrates.

Evolution of central respiratory chemoreception: a new twist on an old story.

Evolution of central respiratory chemosensitivity has been linked traditionally to the need for carbon dioxide regulation that accompanied the evolution of air breathing in terresterial animals. We examined the validity of this linkage by investigating the possibility of central chemoreception in air breathing fish that diverged from the amphibian lineage long before the appearance of terrestriality. We showed that the isolated brainstem preparation of the long nose gar (Lepisosteus osseus) produces a putative motor pattern for lung ventilation, which is responsive to CO(2). These findings, together with more inferential evidence, suggest an association between air breathing and central chemosensitivity in aquatic animals that spans the major branches in vertebrate phylogeny. Furthermore, developmental observations in tadpoles suggest that the neural substrates for central chemoreception exist in proximity to that for rhythm generation. We postulate that a primitive ancestral CPG, sensitive to CO(2) is conserved and is evidenced in the intrinsic coupling of respiratory CPG and central chemoreception in modern tetrapods.

Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.

Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.

Brain stem PO(2) and pH of the working heart-brain stem preparation during vascular perfusion with aqueous medium.

The rat working heart-brain stem preparation (WHBP) is an in situ preparation having many of the advantages associated with in vitro preparations while retaining cardiovascular response functionality and an eupnoeic respiratory motor pattern. The preparation is perfused arterially with an aqueous medium having a much lower oxygen-carrying capacity than blood. To evaluate the efficacy of the artificial perfusion in providing adequate gas exchange within the brain stem, we used polarographic PO(2) and pH microelectrodes to determine the tissue PO(2) and pH of the medulla oblongata at various depths. When the perfusate was equilibrated with 5% CO(2) and 95% O(2), average tissue PO(2) was 294 Torr and no hypoxic areas were encountered. Tissue pH was remarkably uniform throughout the tissue, and on average was only 0.04 +/- 0.02 pH units more acidic than that of the perfusate. Increasing the PCO(2) of the perfusate increased tissue PO(2) and decreased arterial resistance. Decreasing perfusate PCO(2) (while keeping pH constant) decreased tissue PO(2) and reduced the respiratory activity. These results suggest that arterial PCO(2), independent of arterial pH, is an essential variable in determining both respiratory drive and cerebrovascular perfusion. We conclude that the medulla of the WHBP is oxygenated and within a physiological pH, which accounts for the eupneic pattern of respiratory motor activity it generates. Furthermore, this preparation may be a useful model for exploring mechanisms of central chemoreception as well as the dynamics of the cerebral vasculature responses following changes in blood gases.

Dynamic ventilatory response to CO(2) in congestive heart failure patients with and without central sleep apnea.

Nonobstructive (i.e., central) sleep apnea is a major cause of sleep-disordered breathing in patients with stable congestive heart failure (CHF). Although central sleep apnea (CSA) is prevalent in this population, occurring in 40-50% of patients, its pathogenesis is poorly understood. Dynamic loop gain and delay of the chemoreflex response to CO(2) was measured during wakefulness in CHF patients with and without CSA by use of a pseudorandom binary CO(2) stimulus method. Use of a hyperoxic background minimized responses derived from peripheral chemoreceptors. The closed-loop and open-loop gain, estimated from the impulse response, was three times greater in patients with nocturnal CSA (n = 9) than in non-CSA patients (n = 9). Loop dynamics, estimated by the 95% response duration time, did not differ between the two groups of patients. We speculate that an increase in dynamic gain of the central chemoreflex response to CO(2) contributes to the genesis of CSA in patients with CHF.

Which came first, the lung or the breath?

Lungs are the characteristic air-filled organs (AO) of the Polypteriformes, lungfish and tetrapods, whereas the swimbladder is ancestral in all other bony fish. Lungs are paired ventral derivatives of the pharynx posterior to the gills. Their respiratory blood supply is the sixth branchial artery and the venous outflow enters the heart separately from systemic and portal blood at the sinus venosus (Polypteriformes) or the atrium (lungfish), or is delivered to a separate left atrium (tetrapods). The swimbladder, on the other hand, is unpaired, and arises dorsally from the posterior pharynx. It is employed in breathing in Ginglymodi (gars), Halecomorphi (bowfin) and in basal teleosts. In most cases, its respiratory blood supply is homologous to that of the lung, but the vein drains to the cardinal veins. Separate intercardiac channels for oxygenated and deoxygenated blood are lacking. The question of the homology of lungs and swimbladders and of breathing mechanisms remains open. On the whole, air ventilatory mechanisms in the actinopterygian lineage are similar among different groups, including Polypteriformes, but are distinct from those of lungfish and tetrapods. However, there is extreme variation within this apparent dichotomy. Furthermore, the possible separate origin of air breathing in actinopterygian and 'sarcopterygian' lines is in conflict with the postulated much more ancient origin of vertebrate air-breathing organs. New studies on the isolated brainstem preparation of the gar (Lepisosteus osseus) show a pattern of efferent activity associated with a glottal opening that is remarkably similar to that seen in the in-vitro brainstem preparation of frogs and tadpoles. Given the complete lack of evidence for AO in chondrichthyans, and the isolated position of placoderms for which buoyancy organs of uncertain homology have been demonstrated, it is likely that homologous pharyngeal AO arose in the ancestors of early bony fish, and was pre-dated by behavioral mechanisms for surface (water) breathing. The primitive AO may have been the posterior gill pouches or even the modified gills themselves, served by the sixth branchial artery. Further development of the dorsal part may have led to the respiratory swimbladder, whereas the paired ventral parts evolved into lungs.

Sites of respiratory rhythmogenesis during development in the tadpole.

During ontogeny, amphibian larvae experience a dramatic alteration in the motor act of breathing as the premetamorphic gill breather develops into the postmetamorphic lung ventilator. We tested the hypothesis that the site of lung rhythmogenesis relocates during metamorphosis by recording fictive lung ventilation before and after transecting the in vitro brain stem of pre- and postmetamorphic Rana catesbeiana into four segments. In premetamorphic tadpoles, the two caudalmost brain stem segments combined proved to be the minimum brain stem configuration necessary and sufficient for lung burst generation. In the postmetamorphic counterpart, this function was supplied by the combination of the two rostralmost brain stem segments. In the postmetamorphic brain stem, a 500-microm segment lying just rostral to cranial nerve IX conveys rhythmogenic capability to neighboring rostral or caudal segments. We conclude that lung rhythmogenic capability translocates rostrally during development as the tadpole shifts from gill to lung ventilation.

Location of central respiratory chemoreceptors in the developing tadpole.

The location of central respiratory chemoreceptors in amphibian larvae may change as the central chemoreceptive function shifts from driving gill to driving lung ventilation during metamorphosis. We examined this possibility in the in vitro brain stem of the pre- and postmetamorphic Rana catesbeiana tadpole by microinjecting hypercapnic artificial cerebrospinal fluid (aCSF) while recording fictive lung ventilation. The rostral and caudal brain stem were separately explored systematically using injections of 11 nl of aCSF equilibrated with 100% CO2 that transiently acidified a 500-microm region, producing a maximum reduction in pH of 0.23 +/- 0.06 at the site of injection. In postmetamorphic tadpoles, chemoreceptive sites were concentrated in the rostral compared with the caudal brain stem. No such segregation was observed in the premetamorphic tadpole. We conclude that, as in lung rhythmogenic function, respiratory chemosensitivity emerges rostrally in the amphibian brain stem during development.

Braking of expiratory airflow in obese pigs during wakefulness and sleep.

Braking of expiratory airflow is a phenomenon prominently seen in neonates where it is thought to defend end-expiratory lung volume. This paper describes pronounced expiratory braking in an adult animal, the obese Vietnamese pot-bellied pig. Three obese pigs were chronically instrumented for recording of intrapleural pressure and bioelectric signals related to sleep. Airflow was measured by a pneumotachograph attached to a facemask. Expiratory airflow resistance was calculated for 10 consecutive expirations during wakefulness, NREM, and REM sleep. All animals demonstrated a biphasic expiratory flow pattern characterized by an initial plateau in flow at a low value followed by a rapid increase later in expiration. Airflow resistance during early expiration was on average four-fold higher than during late expiration. A striking observation was the maintenance of pronounced expiratory braking during NREM and REM sleep. Expiratory braking in these animals is likely due to laryngeal mechanisms and may serve to preserve end-expiratory lung volume or improve hemodynamics.

Oxygen sensitive chemoreceptors in the first gill arch of the tadpole, Rana catesbeiana.

Spike frequency was recorded in the nerve of the isolated superfused first gill arch of the bullfrog larva, Rana catesbeiana and the response to different superfusate PO2 was evaluated. In the metamorphic tadpole, spike frequency increased significantly when the superfusate PO2 was decreased (mean +/- SEM): 8.5 +/- 1.6 Hz at 650 Torr, 11.7 +/- 1.9 Hz at 140 Torr, 13.3 +/- 1.8 Hz at 65 Torr, 14.8 +/- 2.4 Hz at 0 Torr (ANOVA, p = 0.0002). The O2 sensitive chemoreceptor stimulants NaCN and almitrine also increased the spike frequency. This study demonstrates the presence of O2 sensitive chemoreceptors in the first gill arch of the tadpole.

Developmental disinhibition: turning off inhibition turns on breathing in vertebrates.

Development requires age-dependent changes in essential behaviors. While the mechanisms determining the developmental expression of such behavior in vertebrates remain largely unknown, a few studies have identified permissive mechanisms in which the appearance of promoting signals activates pre-established networks. Here we report a different developmental process. Specifically, we show that the neuronal substrate that produces putative lung breathing in tadpoles is formed early in development, but remains more or less inactive until metamorphosis because of suppression mediated by a GABA(B) receptor-dependent mechanism. Blocking this suppression using 2-hydroxy-saclofen, a GABA(B) receptor antagonist, results in the precocious production of the putative lung breathing motor pattern. This blocker failed to augment putative lung breaths after metamorphosis. Thus, our results suggest that loss of an inhibitory signal during development (i.e., developmental disinhibition) is responsible for the developmental expression of air breathing.

Evolution of air-breathing and central CO(2)/H(+) respiratory chemosensitivity: new insights from an old fish?

While little is known of the origin of air-breathing in vertebrates, primitive air breathers can be found among extant lobe-finned (Sarcopterygii) and ray-finned (Actinopterygii) fish. The descendents of Sarcopterygii, the tetrapods, generate lung ventilation using a central pattern generator, the activity of which is modulated by central and peripheral CO(2)/H(+) chemoreception. Air-breathing in Actinopterygii, in contrast, has been considered a 'reflexive' behaviour with little evidence for central CO(2)/H(+) respiratory chemoreceptors. Here, we describe experiments using an in vitro brainstem preparation of a primitive air-breathing actinopterygian, the longnose gar Lepisosteus osseus. Our data suggest (i) that gill and air-breathing motor patterns can be produced autonomously by the isolated brainstem, and (ii) that the frequency of the air-breathing motor pattern is increased by hypercarbia. These results are the first evidence consistent with the presence of an air-breathing central pattern generator with central CO(2)/H(+) respiratory chemosensitivity in any primitive actinopterygian fish. We speculate that the origin of the central neuronal controller for air-breathing preceded the divergence of the sarcopterygian and actinopterygian lineages and dates back to a common air-breathing ancestor.

Baclofen eliminates cluster lung breathing of the tadpole brainstem, in vitro.

Intermittent lung ventilation is a respiratory pattern wherein breaths occur in clusters. Intermittent lung ventilation is common in amphibians and can occur in mammals. Isolated brainstems from postmetamorphic tadpoles exhibiting episodic lung ventilatory bursts were superfused with baclofen, a potent gamma-aminobutyric acid (GABA)(B) receptor agonist. At moderate concentrations (0.125 to 0.5 microM), the number of lung bursts per episode decreased but their overall frequency was unchanged. At 0.5 microM, only 1.22+/-0.24 lung bursts occurred per episode, indicating virtually no clustering. Only at higher concentrations was overall breathing frequency decreased. Therefore, at moderate concentrations of baclofen continuous ventilation replaced episodic ventilation, suggesting that a GABA(B) receptor-dependent pathway may regulate the clustering of lung breaths.

Treatment, airway and compliance effects of a titratable oral appliance.

STUDY OBJECTIVES: To measure the effects of a titratable anterior mandibular repositioner on airway size and Obstructive Sleep Apnea (OSA) and to evaluate its compliance. DESIGN: Before and after insertion sleep studies were obtained in a total of 38 OSA patients of varying severity from three different sites. Covert compliance was measured by means of a newly-developed, miniaturized, temperature-sensitive, imbedded monitor. Validity testing was completed in six adult volunteers who wore monitors imbedded into small acrylic appliances. MEASUREMENTS AND RESULTS: The mean RDI before treatment was 32.6 (SEM 2.1) and after the insertion of the appliance, the RDI was reduced to 12.1 (SEM 1.7, p<0.001). RDI was reduced to less than 15/hour in 80% of a group of moderate OSA patients (RDI 15 to 30) and in 61% of a group of severe OSA patients (RDI > 30) with respect to baseline RDI. Fiber optic video endoscopy was performed on 9 OSA patients with and without the appliance. No significant differences in hypopharynx or oropharynx cross sectional areas were found, but at the level of the velopharynx, the airway size was significantly increased (p<0.05). The index of agreement was 0.99 between the monitor clock time and the subject's log sheets. Compliance data from eight OSA subjects instructed to wear the appliance during sleep indicated that it was worn for a mean of 6.8 hours with a range of 5.6 to 7.5 hours per night. CONCLUSION: The titratable adjustable mandibular advancement appliance, made from thermoelastic acrylic, significantly reduces RDI in moderate to severe OSA patients, has a direct effect on airway size and is well worn throughout the night.