Physiology in medicine: obstructive sleep apnea pathogenesis and treatment--considerations beyond airway anatomy

Abstract

We review evidence in support of significant contributions to the pathogenesis of obstructive sleep apnea (OSA) from pathophysiological factors beyond the well-accepted importance of airway anatomy. Emphasis is placed on contributions from neurochemical control of central respiratory motor output through its effects on output stability, upper airway dilator muscle activation, and arousability. In turn, we consider the evidence demonstrating effective treatment of OSA via approaches that address each of these pathophysiologic risk factors. Finally, a case is made for combining treatments aimed at both anatomical and ventilatory control system deficiencies and for individualizing treatment to address a patient's own specific risk factors.

Keywords: chemosensitivity; collapsible airway; sleep apnea.

Figures

Fig. 1.

A: polysomnographic tracings of obstructive sleep apnea from a detailed experimental study of a patient with severe disease (apnea-hypopnea index = 56 events/h). Note the repeated oxygen desaturations as a result of severely impaired (hypopnea) or absent (apnea) airflow despite continual breathing efforts (Pepi) and the cyclical breathing pattern that ensues as the patient oscillates between sleep and arousal (downward pointing arrows). B: one obstructed apneic event (between the dotted vertical lines in A) to illustrate the compensatory events occurring during and following the obstruction. The cessation and resumption of flow defines the apneic event. Note the progressive increase in inspiratory effort (Pepi) and dilator muscle EMG (EMGgg) during the apnea, the transient arousal coincident with airway opening, and ventilatory overshoot at apnea termination. As the patient returns to sleep, note the gradual reduction in breathing frequency and flow rate, and increased pharyngeal pressure (signifying increased airway resistance) leading to the next obstruction. Evidence of snoring is shown on the flow tracing. Progressive increases in EMGgg activity occurred throughout the obstructive event, although in this instance they were not sufficient to restore flow, which occurred only upon arousal. Pharyngeal pressure serves as a measure of the inspiratory effort made against the obstructed airway, thereby reflecting the magnitude of central respiratory motor output in response to chemoreceptor stimuli accumulated during the obstructed apnea. Arousal threshold is determined by the pharyngeal pressure achieved through respiratory pump muscle contractions during an airway obstruction at the point of EEG arousal. EMGgg, electromyogram of the genioglossus muscle (intramuscular); EMGsub, EMG of the submental muscle (surface); EEG, electroencephalogram (C3-A2); Pepi, pressure at the level of the epiglottis; Flow, airflow measured via nasal mask and pneumotachograph; SaO2, arterial blood oxygen saturation measured via pulse oximetry at the finger. Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Eckert DJ and Malhotra A. 2008. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 5: 144–153. Official Journal of the American Thoracic Society.

Fig. 2.

Central apnea preceding obstructive apnea in subjects with a combination of unstable central respiratory motor output plus a collapsible airway. A: effects of a spontaneous central apnea on upper airway patency during non-rapid eye movement sleep. Fiber optic nasopharyngoscopy was used to determine airway dimensions at the level of the velopharynx or oropharynx. Initiation of central apnea is identified by the open inverted arrow, with the cessation of both airflow and oscillation of esophageal pressure (Pes). Complete airway occlusion occurred about 15–20 s following the onset of central apnea and before an inspiratory effort occurred, as noted by the constant Pes. Apnea continued and the airway remained closed for 35 s, showing partial return of airflow with resumption of inspiratory effort and then complete airway patency on arousal from sleep with accompanying ventilatory overshoot. [From Badr et al. (3).] B: cyclical, mixed (i.e., central followed by obstructed) apneas causing intermittent hypoxemia during non-rapid eye movement sleep. The cessation of airflow denotes the onset of apnea. The absence of cyclical changes in esophageal pressure over the initial 8 to 10 s of the apnea demonstrate that this initial phase of the apnea is due to the absence of central respiratory motor output and inspiratory muscle contractions. Over the latter half of the apnea, flow is still absent but progressive, cyclical increments occur in the negativity of esophageal pressure, indicating increasing inspiratory efforts against a closed airway in response to rising asphyxic chemoreceptor stimuli. The arrows shown at the termination of each apneic period indicate periods of transient cortical arousal accompanied by ventilatory overshoot. [From Dempsey et al. (11).]

Fig. 3.

A: polysomnographic recording from a patient with severe OSA [apnea-hypopnea index(AHI) ∼60/h] during air breathing. Cyclical obstructive apneas were indicated by the absence of flow despite continued respiratory efforts and the paradoxical motions of rib cage and abdomen. B: most of the obstructed apneas were prevented in this patient when a selective rebreathe mask-reservoir system was used to raise FiCO2 only during the hyperpneic phase of an event, thereby preventing the transient hypocapnia and holding PetCO2 at levels experienced equal to those during stable eupneic air breathing (not shown). The 4-min periods shown for both control (A) and isocapnic treatment (B) conditions were representative of the breathing pattern, PetCO2, and AHI experienced during the total 90- to 95-min periods of control and treatment conditions studied in this patient. A reduction in AHI of 30 to 90% with this isocapnic treatment was observed in 14 of 26 patients with moderate to severe OSA and Pcrit of −2 to +5 cmH2O. AB, abdominal movement; RC, rib cage movement. [From Xie et al. (92).]

Fig. 4.

Schematic illustrating the interaction of airway anatomy with neurochemical control on the magnitude and stability of central respiratory motor output, airway muscle dilator recruitment, and arousability in the pathogenesis of cyclical OSA. Patients with an anatomical predisposition to pharyngeal collapse may experience two types of overlapping scenarios leading to cyclical OSA in sleep. Right: progression initiated by an airway obstruction at sleep onset in a patient with a severely collapsible upper airway; left: progression to airway obstruction (at the nadir of the respiratory cycle) initiated by an unstable central respiratory motor output in a patient with elevated loop gain and a mildly collapsible airway. Bottom: factors that determine the consequences of airway obstruction and accumulating chemoreceptor stimuli on subsequent, postapneic ventilation, airway patency and EEG arousal. These control system characteristics include the responsiveness of both the upper airway and chest wall pump muscles and of central nervous system (CNS) arousability to the rising chemoreceptor stimuli (also see the text and the apneic event shown in Fig. 1B). UAW, upper airway; FRC, functional residual capacity.

Fig. 5.

Effect of mild hypercapnia in a patient with OSA. Repetitive obstructive apneas with associated transient arousals were noted during air breathing as indicated by the repeated absence of flow despite respiratory efforts. Almost all of these obstructions and arousals were eliminated by raising PetCO2 an average of 2 mmHg (left arrow) above stable, nonobstructed breathing levels in sleep (stable control breathing is not shown in the figure). Abrupt removal of the added FiCO2 (right arrow) resulted in the immediate return of the cyclical obstructive apneas. Respiratory effort was estimated by respiratory inductance plethysmography. Data are from the author's laboratory. On the basis of these types of findings we raised PetCO2 2–5 mmHg via dead-space rebreathing during 90–120 min of sleep in a group of patients with moderate to severe OSA and observed an average 85% reduction in AHI below air-breathing control in 17 of 21 patients (92). PetCO2, end tidal Pco2.