Pathophysiology of sleep apnea

Abstract

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae.

Fig. 1.

A: periodic (Cheyne-Stokes) breathing in chronic heart failure in non-REM sleep. Note the gradual crescendo and decrescendo of tidal volume (V_t) and esophageal pressure (P_es), the intermittent hypoxemia (SaO₂), and the subtle changes in EEG amplitude attending the termination of each periodic breathing cycle. Periodic cycles of apnea plus hyperpnea are fairly uniform and are each 50–60 s in duration. [From Tkacova et al. (681).] B: periodic “cluster-type” breathing in non-REM sleep in a healthy sea-level native during the initial night at 4,300 m altitude. Tidal volume is estimated from expansion of the ribcage (RC) and abdomen (Abd) using inductance plethysmography. Note the abrupt increase in V_t (to 1.5–2.5 times control, steady-state values) at the end of each apneic period. Each periodic cycle is 20–25 s in length. Also note the mild levels of arterial hypocapnia and alkaline pH determined from blood sampling over several periodic cycles. [From Berssenbrugge et al. (53).] C: cyclical “mixed,” i.e., central followed by obstructed apneas, causing intermittent hypoxemia during non-REM sleep. The cessation of airflow denotes the onset of apnea. The absence of cyclical changes in esophageal pressure over the initial 8–10 s of the apnea demonstrates 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 and 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.

Fig. 2.

Road map for the discussion of pathogenesis of cyclical obstructive sleep apnea.

Fig. 3.

A: midsagittal magnetic resonance image (MRI) in a normal subject (left) and in a patient with severe OSA (right). Highlighted are the four upper airway regions (nasopharynx, retropalatal region, retroglossal region, hypopharynx) and upper airway soft tissue (soft palate, tongue, fat) and craniofacial structures (mandible). Fat deposits are shown in white on the MRI. Note that in the apneic patient: a) the upper airway is smaller, in both the retropalatal and retroglossal region; b) the soft palate is longer and tongue size is larger; and c) the quantity of subcutaneous fat is greater. [From Schwab et al. (597).] B: state dependence of upper airway size in a normal subject as assessed via three-dimensional reconstructions of MRI images. Images represent averages taken over several respiratory cycles during eupneic breathing in sleep and wakefulness. Airway volume during NREM sleep is smaller in the retropalatal (RP) region, not in the retroglossal (RG) region. Such images show the marked effect of sleep, per se, on the loss of upper airway muscle dilator tone and also show that the upper airway does not narrow as a homogeneous tube during sleep. [From Trudo et al. (687).]

Fig. 4.

Starling resistor model of obstructive sleep apnea. In the Starling resistor model, the collapsible segment of the tube is bound by an upstream and downstream segment with corresponding upstream pressure (P_us), downstream pressure (P_ds), and upstream resistance and downstream resistance. Airway occlusion occurs when the surrounding tissue pressure (P_out), (comprised of pharyngeal muscles and pharyngeal and submucosal fat, mucosal edema, etc.; see sect. iiiC), becomes greater than the intraluminal pressure (P_in), resulting in a transmural pressure of zero. In this model of the upper airway, P_us is atmospheric at the airway opening, and P_ds is the tracheal pressure. The critical closing pressure of the collapsible airway (P_crit) is represented by P_in. When the P_crit is significantly lower than P_us and P_ds, flow through the tube occurs. When P_ds falls during inspiration below P_crit, inspiratory airflow limitation occurs and is independent of further decreases in P_ds. Under this condition, the pharynx is in a state of partial collapse, and maximal inspiratory airflow varies linearly as a function of the difference between P_us and P_crit. Finally, when P_us falls below P_crit, the upper airway is completely occluded. [Adapted from Gold and Schwartz (195).]

Fig. 5.

Effects of spontaneous central apnea on upper airway patency during NREM sleep. Fiber optic nasopharyngoscopy was used to determine airway dimensions at the level of the velo- or oropharynx. The initiation of central apnea is identified by the open inverted arrow, with the cessation of both airflow and oscillation of esophageal pressure (P_es). Complete airway occlusion occurred ∼10 s following the onset of central apnea and before an inspiratory effort occurred, as noted by the constant P_es. Central 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 an accompanying ventilatory overshoot. [From Badr et al. (25).]

Fig. 6.

Loop gain (LG) depicts the ratio of ventilatory response to disturbance ratio. A: example of a LG of 0.72. The ventilatory control system is disturbed with a transient reduction in ventilation (a). This produces a response (b) in the opposite direction that is 72% as large as the disturbance. The next response (c) will also be 72% as large as b, etc. Thus a LG of 0.72 produces transient fluctuations in ventilation, but ventilation eventually returns to baseline. B: a LG ≥1 will produce a response that is equal or greater in magnitude to the disturbance. Ventilation, therefore, oscillates without returning to baseline. The system in B is highly unstable. The closer LG is to zero, the smaller the fluctuations in ventilation, and thus the more stable the system (Fig. 7 illustrates how the magnitude of ventilatory overshoots and undershoots, i.e., stability, are determined by two key components of loop gain, namely, controller and plant gains). [From Wellman et al. (715).]

Fig. 7.

Diagrammatic representation of the relationship between alveolar ventilation (V_A) and alveolar Pco₂ (Pa_CO2) at a fixed resting CO₂ production (of 250 ml/min); Pa_CO2 = V̇co₂/ V̇_A × K. The schematic figure shows how changing plant gain (A, top) or controller gain (B, bottom) will influence the “CO₂ reserve” or ΔPa_CO2 between eupnea and apnea. A: changing the background drive to breathe without changing the slope of the ΔV_A vs. ΔPa_CO2 relationship above or below eupnea. For example, background hyperventilation raises V_A and lowers Pa_CO2 along the isometabolic hyperbola. This means that a greater transient increase in V_A and reduction in Pa_CO2 is required to reach the apneic threshold than it would be under control, normocapnic conditions. The reverse is true for conditions which reduce the background drive to breathe and cause hypoventilation. B: at any given level of background Pa_CO2, changing the slope (or responsiveness) of the ΔV_A-ΔPa_CO2 relationship below eupnea would alter the CO₂ reserve or the amount of reduction in Pa_CO2 required to cause apnea. Changing the slope of the ventilatory response to CO₂ above eupnea would alter the susceptibility for transient ventilatory overshoots. See text for a discussion of conditions which change controller and plant gain and therefore the susceptibility to transient ventilatory overshoots to apnea and ventilatory instability in sleep. [Adapted from Dempsey (127).]

Fig. 8.

Determinants of how imposed airway obstruction may lead to cyclical obstruction in OSA patients. The figure starts with the OSA patient on sufficient CPAP to ensure a patent airway, optimum airflow and ventilation, blood gases, and stable EEG in NREM sleep. The CPAP level is then quickly removed causing an obstructive apnea with subsequent O₂ desaturation and CO₂ accumulation. At the termination of the airway obstruction, a transient arousal occurs (A), accompanied by a transient ventilatory overshoot, with subsequent return to sleep and another airway obstruction, thereby beginning the cascade of cyclical ventilatory over- and undershoots and obstructions (see text for explanation of factors which determine the resolution of an airway obstruction and therefore the cyclical nature of OSA). [From Younes (753).]

Fig. 9.

Determinants of how imposed oscillations in respiratory motor output and ventilation (via hypoxia) might lead to cyclical airway obstruction in a subject with an upper airway anatomy susceptible to closure during sleep. Mean values are shown for upper airway resistance during wakefulness and NREM sleep at the left. Breath by breath peak upper airway resistance (R_ua) is then shown before, during, and after hypoxic exposure. A subject with a fivefold increase in R_ua from awake to sleep but with stable breathing and mild CO₂ retention is shown. During early hypoxic exposure, oscillations in respiratory muscle output (EMG_di) but without central apnea occurred, leading to periodic airway obstruction coincident with the nadir of EMG_di. However, with continued hypoxia and fully developed periodic breathing with apneas and profound O₂ desaturation and CO₂ accumulation, R_ua remained very low (even approximating waking levels) during breaths with high levels of respiratory motor output following each central apnea. Then, upon return to normoxia, cyclical airway obstructions returned again at the nadir of EMG_di. [From Warner et al. (708).]

Fig. 10.

The upper airway in obstructive sleep apnea: a reliance on upper airway dilator muscles for patency. Magnetic resonance images sagittal (left) and coronal (right) of a subject with obstructive sleep apnea. The airway is narrowed but remains patent in wakefulness, in large part because of key dilator muscles, labeled in the center diagram with cranial nerve innervations in parentheses. Arrows indicate overall force vector and are shown on both the diagram and images. Upward directed arrows (red) signify force vectors for levator palatini and tensor veli palatini muscles in raising the soft palate (uvula) and lateral walls. Because the pharynx is collapsible at all tangents, multiple muscle groups must act in concert to prevent collapse of the pharynx.

Fig. 11.

Neurochemical control of the upper airway motoneurons. Presynaptic and postsynaptic excitatory and inhibitory neurochemicals influence the activity of upper airway motoneurons. Numerous excitatory (green) and inhibitory (red) receptor subtypes have been identified using molecular, protein, and physiological studies. Precise roles in motor functions (e.g., respiratory, speech, swallowing, etc.) have not been delineated for any of the receptors. While reductions in noradrenergic tone may contribute to reduced dilator muscle activity in non-REM sleep, the source of reduced motor tone in REM sleep has not been elucidated. Many of the identified receptor subtypes could be targeted pharmacologically, yet none of these is specific to pharyngeal dilator muscles and thus significant side effects including wakefulness are anticipated upon activation of the excitatory targets. M₂, muscarinic; α, adrenergic; 5HT, serotonin; P₂X₂, purinergic; GLY, glycinergic; HCRT, hypocretinergic/orexinergic; GLU, glutamatergic; A, adenosinergic; GABA, γ-aminobutyric acid.

Fig. 12.

Mixed (central and obstructive) sleep apneas produce marked sympathoexcitation and transient blood pressure elevations in a patient with sleep apnea syndrome. P_eso, esophageal pressure; Sat, saturation. [From Skatrud et al. (620).]

Fig. 13.

Mean arterial pressures in patients with OSA before and after effective CPAP (A) and subtherapeutic CPAP (B). [From Becker et al. (41).]

Fig. 14.

In healthy humans, brief (20-min) exposure to intermittent asphyxia causes sympathetic activation that persists after normalization of blood gases, not only during the interasphyxia phases, but also in the room air recovery period. [From Xie et al. (736).]

Fig. 15.

Putative mechanisms by which OSA activates the sympathetic nervous system, initiating a cascade of events that results in cardiovascular disease. CNS, central nervous system; RAAS, renin-angiotensin-aldosterone system. *Inflammation; ^†oxidant stress.

Fig. 16.

Hyperinsulinemic euglycemic clamps performed in healthy humans and mice during exposure to hypoxia. A: 30 min of sustained hypoxia (vertical gray bar; arterial oxyhemoglobin saturation to 75%) reduced whole body glucose uptake (solid circles) compared with the same healthy human subjects under normoxic conditions (open circles) with plasma glucose clamped at ∼80–100 mg/dl (463). B: 9 h of exposure to intermittent hypoxia (Fi_O2 reduced to 0.050–0.060 over 30 s and returned to 0.209 in the subsequent 30 s resulting in 60 hypoxic episodes/h) reduced whole body glucose uptake (solid squares) compared with a comparable group of lean healthy C57BL/6J mice under control conditions (open squares) with plasma glucose clamped at ∼100 mg/dl (263).

Fig. 17.

Putative pathways for the physiological disturbances of intermittent hypoxia and sleep fragmentation to cause insulin resistance through activation of “classical” (white) or “lipotoxic” (grey) pathways.

Fig. 18.

Proposed model of NADPH oxidase injury from hypoxia reoxygenation. Hypoxia/reoxygenation events increase the production of angiotensin II peripherally or in astrocytes, resulting in activation of angiotensin 1A receptors on catecholaminergic neurons. AT receptor activation upregulates NADPH oxidase activity, resulting in oxidative injury. Sleep apnea and intermittent hypoxia are associated with marked inflammation in the brain including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and tumor necrosis factor-α (TNF-α). Whether this proinflammatory response occurs in neurons or adjacent microglial cells should now be advanced.

Fig. 19.

Activation of caspase-3 in motoneurons following exposure to intermittent hypoxia. Top left: DAB stained (brown) hypoglossal motoneurons with minimal cleaved caspase-3 (black). In contrast, even after 3 days of IH exposure, caspase is evident in the nucleus (bottom left). Cleaved caspase-3 is persistently elevated across intermittent hypoxia at 4 wk (top right) and 6 mo (bottom right), but little enters the nucleus, suggesting that the observed loss of neurons occurs largely through nonapoptotic means.