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Crossing the Threshold

Implications for Central Sleep Apnea

Center for Sleep and Chronobiology University of Toronto Toronto, Canada

The pathophysiology of central sleep apnea (CSA) syndromes is fraught with paradoxes that have perplexed clinicians and physiologists alike. Central apneas during sleep arise when the summation of respiratory stimuli fall below a threshold level required to generate ventilation (1). Accordingly, all forms of CSA have the same "phenotypical" appearance: cessation of airflow in the absence of respiratory efforts. However, they may arise from diametrically opposite "genotypes," which has been a source of confusion.

Some forms of CSA develop secondary to alveolar hypoventilation syndromes in which there is a reduction in respiratory drive due to insensitivity of the chemoreceptors. Pa_CO2 is elevated (1). At the onset of sleep, there is a further depression of chemosensitivity, accompanied by an increase in Pa_CO2 and the Pa_CO2 threshold for apnea. As a result, respiratory drive is suppressed and central apnea ensues. This type of CSA constitutes the hypercapnic "genotype".

Nonhypercapnic forms of CSA represent a second "genotype" in which Pa_CO2 is normal or low. In contrast to hypercapnic CSA, chemosensitivity is elevated (1). Nonhypercapnic CSA can occur secondary to medical disorders in which respiratory drive is increased, such as congestive heart failure (2) or in association with a primary increase in chemosensitivity, so-called idiopathic CSA (3). The central paradox of nonhypercapnic CSA is that the withdrawal of respiratory drive that causes apnea is a consequence of an abrupt increase in respiratory drive that forces Pa_CO2 below the threshold. This observation suggests that when ambient Pa_CO2 is close to the apneic threshold, it destabilizes the respiratory control system by making it more susceptible to the development of central apneas following relatively small increases in ventilation (1). However, there is a paucity of experimental data on factors that could influence the difference between eupneic Pa_CO2 and the apneic threshold and on whether this difference is narrowed in patients with nonhypercapnic forms of CSA. Two articles in this issue of the Journal shed light on these issues.

In this issue of AJRCCM (pp. 1251–1259), Nakayama and coworkers (4) investigated conditions that alter the difference in end tidal PCO₂ (PET_CO2) between spontaneous breathing and the apneic threshold (PET_CO2) in dogs on pressure support during nonrapid eye movement sleep. Apneas were induced by increments in pressure support and ventilation. The apneic threshold was defined as the PET_CO2 on the breath just before the onset of at least three cycles of apnea-hyperventilation. Two conditions narrowed PET_CO2 from 5 mm Hg during control conditions to approximately 4 mm Hg and reduced the pressure support required to induce central apneas. The first was a primary metabolic alkalosis induced by bicarbonate that reduced ventilatory drive. This increased PET_CO2. The second was a primary hypoxia-induced increase in respiratory drive with respiratory alkalosis. This reduced PET_CO2. These findings confirm that a narrower PET_CO2 increases the susceptibility to central apnea. They also establish that alkalosis is a factor that narrows PET_CO2 and strongly suggest that changes in hydrogen ion or pH are the intermediaries through which Pa_CO2 influences ventilation under these experimental conditions.

During metabolic alkalosis, Pa_CO2 rises in compensation for alkalosis, but as this compensation is never complete (pH was 0.129 above control), Pa_CO2 and hydrogen ion will remain close to the apneic threshold. Therefore, the magnitude of the fall in Pa_CO2 required to lower ventilation to zero is reduced. Similarly, in the case of respiratory alkalosis, metabolic compensation by retaining hydrogen ion is incomplete so that the change in Pa_CO2 or hydrogen ion required to induce apnea is reduced. Why then did the peripheral chemoreceptor stimulant almitrine have the opposite effect to hypoxia and widen the PET_CO2? The most likely explanation is that hypoxia is an inconstant and nonlinear respiratory stimulant. The definition of the apneic threshold in this study was the PET_CO2 that precipitated three consecutive cycles of apnea hyperventilation. During hypoxic exposure, Pa_O2 was low and on the steep portion of the oxyhemoglobin dissociation curve. Therefore, during apnea, Pa_O2 would fall further, providing an increase in respiratory drive that could provoke postapneic ventilatory overshoot. This would tend to drive Pa_CO2 below threshold, facilitating periodic breathing. However, the degree of reduction in Pa_O2 during apneas was not reported. In contrast, almitrine probably provides a more constant ventilatory stimulation that is linear. Accordingly, almitrine-induced increases in ventilation would have raised Pa_O2 to supranormal levels on the flat portion of the oxyhemoglobin dissociation curve. When the first apnea was triggered, hypoxia would not have developed and would not have provided an additional stimulus for postapneic ventilatory overshoot. This would dampen oscillations in Pa_CO2 and stabilize breathing. Similarly, acetazolamide induced-metabolic acidosis, which also widened PET_CO2, would provide a relatively constant central stimulus to breathe, with more complete respiratory compensation (pH was only 0.037 below control), and would thereby tend to stabilize breathing.

How well do these experimental findings in dogs fit with observations in humans with nonhypercapnic CSA? As it turns out, rather well. In a study by Xie and coworkers (5) in this issue (pp. 1245–1250), patients with congestive heart failure who had CSA had a narrowed PET_CO2 on pressure support compared with control subjects without CSA, even though their PET_CO2 during spontaneous breathing was not significantly different. However, neither their pH nor Pa_O2 was reported. Patients with congestive heart failure frequently have combined respiratory and metabolic alkalosis owing to the hyperventilation from pulmonary congestion and increased chemosensitivity and to the effects of diuretics that cause bicarbonate retention (6, 7). Therefore, patients with CSA may have been more alkalotic than those without CSA. Xie and colleagues (5) also found that unlike patients without CSA, in those with CSA, PET_CO2 did not increase at sleep onset, which maintained PET_CO2 closer to the apneic threshold as previously reported (8). However, although this study is the first to demonstrate a narrowed PET_CO2 in patients with congestive heart failure who have CSA, the results must be interpreted with caution. They used continuous positive airway pressures of 2 to 6 cm H₂O to "stabilize the upper airway" in their patients. This intervention can raise Pa_CO2 and augment cardiac output (9, 10). In addition, they used CO₂ to stabilize breathing in the patients with CSA and sedatives to maintain sleep. These interventions may therefore have introduced artifacts into their results.

Other observations in humans are consistent with those of Nakayama and colleagues (4). High-altitude periodic breathing is caused by hypoxia and is reversed by acetazolamide. Similarly, acetazolamide attenuates idiopathic CSA (1). Theophylline and CO₂, central respiratory stimulants, alleviate CSA in patients with congestive heart failure (11, 12), as does oxygen (13). The general principle arising from these studies is that factors that narrow PET_CO2, or provide inconstant respiratory drive, interact with other factors such as augmented chemosensitivity, pulmonary congestion, and arousals from sleep (1, 6) to destabilize respiratory control and predispose to CSA. Conversely, factors that widen PET_CO2 and provide a more constant respiratory drive stabilize respiration.

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