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Topical Review |
1 The John Rankin Laboratory of Pulmonary Medicine, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, 53726-2368, USA
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(Received 21 July 2004;
accepted after revision 22 July 2004;
first published online 29 July 2004)
Corresponding author J. A. Dempsey: The John Rankin Laboratory of Pulmonary Medicine, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, 53726-2368, USA. Email: jdempsey{at}wisc.edu
Sleep effects on ventilatory control stability
Sleep presents major challenges to the stability of ventilatory control and to the homeostatic regulation of O2 and CO2 transport. All healthy humans hypoventilate to a significant degree at sleep onset and throughout the night (PaCO2, 2–8 mmHg > awake). Furthermore, resistance to flow through the upper airway is increased variably but significantly in a very large percentage of healthy subjects, and cyclical overshoots and undershoots of ventilation occur in a significant segment of the population who do not experience ventilatory instability in wakefulness.
Several factors contribute to these effects of sleep. First, the loss of supra-pontine neural input to the medullary respiratory pattern generator (‘wakefulness drive’) results in reduced rhythmic and tonic activation of both phrenic and hypoglossal motor neurones (Orem et al. 1985). (The magnitude of the respiratory motor output attributable to ‘wakefulness’ drives has been included in theoretical models of respiratory control (Longobardo et al. 2002). However, this wakefulness input has no fixed magnitude. Rather, its most important characteristic is its marked variability, as opposed to the highly reproducible responses obtained in NREM sleep, in response to such perturbations as changes in airway resistance or hypocapnia (Skatrud & Dempsey, 1983; Wilson et al. 1984).) Second, sleep state is not constant, which greatly enhances the opportunity for changing respiratory drives and airway resistance. Third, the supine position and the associated reduction in functional residual capacity occurring in sleep will reduce caudal traction on and therefore narrow the upper airway, and will also cause greater arterial O2 desaturation and CO2 retention for any given apnoeic length.
There are multiple, complex causes of sleep-induced periodic breathing. The propensity for unstable, periodic breathing in a given subject or condition has been assessed using the concept of ‘loop gain’ (GL), the combination of three types of gain, namely controller (Gc), plant (Gp), and mixing (Gm) gains (Khoo, 2000; Younes et al. 2001). The higher the GL, the greater the probability of periodic breathing. This quantitative approach to predicting ventilatory instability and periodicity has provided a valuable tool for understanding the complex, multifaceted determinants of periodic breathing. However it is a concept that was developed to characterize the dynamic behaviour of linear systems (Khoo, 2000). Thus the usefulness of the GL index as a predictor of instability only applies over the range of linear changes in the ventilatory stimulus–response slope and does not consider the mechanisms and/or conditions which predispose to apnoea. (Loop gain (GL) is determined by: (a) plant gain (
pulmonary capillary PCO2/ 
A) as determined by the position of A versus PaCO2 on the iso-metabolic line (see Fig. 2 below), and also by A: 
distribution and the prevailing functional residual capacity (FRC) (b) controller gain (E/PACO2) as determined by chemosensitivity (above eupnoea), lung and airway mechanics and respiratory muscle power output; and (c) mixing gain ( chemoreceptor PCO2/ pulmonary capillary PCO2), as determined by circulatory delay time, thoracic blood volume and brain extracellular fluid volume (Younes et al. 2001).) Accordingly, when PaCO2 falls below eupnoea and apnoea ensues, controller gain, and therefore loop gain would actually be reduced (i.e. the CO2 ventilatory response slope is zero), thereby predicting a stable breathing pattern even in the face of apnoea.
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Our view of the multiple factors affecting transient ventilatory overshoots (hyperventilation) and undershoots (hypoventilation) in NREM sleep are shown in Fig. 1 and are based on the observation that significant transient overshoots in ventilation and blood pressure precede and terminate most apnoeic and/or hypopnoeic events. An increased drive to breathe, depending on its magnitude and duration, also causes a persistent, centrally mediated excitatory ‘memory’ effect or short-term potentiation (STP) which would normally prevent a sudden ventilatory undershoot and maintain ventilatory stability (Eldridge & Millhorn, 1986). There are several factors which oppose this stabilizing effect of STP during this post-hyperpnoeic period (see Fig. 1). However, as outlined below, during NREM sleep it is the transient hypocapnia initiated during the ventilatory overshoot which is the dominant inhibitory influence required to cause the apnoea.
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The ‘unmasking’ of a highly sensitive apnoeic threshold in NREM sleep, some 2–5 mmHg PaCO2 below (sleeping) eupnoeic PaCO2 and within 1–2 mmHg of the normal waking eupnoeic PaCO2 has been documented in healthy sleeping subjects in several ways. First, positive-pressure mechanical ventilation through a nasal mask was used to progressively reduce PaCO2 below eupnoea, which caused progressive, linear reductions in the amplitude of diaphragm EMG until apnoea occurred (Skatrud & Dempsey, 1983). Mechanical ventilation also elicits a non-chemical, neuro-mechanical inhibitory effect on the amplitude of respiratory motor output (Henke et al. 1988), but this can be minimized by using a subject-triggered pressure support form of mechanical ventilation and a background of continuous positive airway pressure (CPAP) to minimize upper airway resistance (Meza et al. 1998). Second, mechanical ventilation was used to control airway and chest wall mechanics in normal subjects during NREM sleep and wakefulness, to demonstrate a sleep-induced increase of 2–4 mmHg in the set-point for PaCO2 which was independent of any sleep-induced changes in airway resistance (Simon et al. 1993). Third, periodic breathing caused by chronic heart failure, hypoxia, or idiopathic central apnoea was alleviated by small increments in PaCO2 (via increased inspired CO2 fraction (FIO2); Berssenbrugge et al. 1983; Xie et al. 1997). Finally, Semple et al. (Semple et al. 1999) recently used mechanical ventilation to control tidal volume at waking, eupnoeic levels in order to prevent the hypoventilation and increase in PaCO2 normally experienced upon transition from awake to light sleep. At sleep onset, apnoeas of up to 15 s ensued. These observations demonstrate the marked CO2 dependence of ventilatory control at sleep onset and the critical importance of the normal sleep-induced hypoventilation as a deterrent to apnoea and instability.
Apnoea really has two PCO2 ‘thresholds’, namely the apnoeic initiation threshold (as outlined above) and the higher PaCO2 at which apnoea is terminated and respiratory rhythm re-initiated. In real life when apnoeas are initiated by transient reductions in alveolar PCO2 (PACO2), some of the delay in resumption of breathing rhythm is likely to be due to a persistent alkalinity in the environment of the brain chemoreceptors at a time when arterial PCO2 (PaCO2) is restored to eupnoeic levels. However, even when apnoeas are caused experimentally by purely mechanical feedback at normocapnic PaCO2 (using controlled mechanical ventilation or upper airway negative pressure) the PaCO2 will rise 3–5 mmHg or so above spontaneous eupnoea before breathing is re-initiated (Leevers et al. 1994; Satoh et al. 2001). What causes this persistent, prolongation of apnoea to occur in the face of rising chemoreceptor stimuli, i.e. a so-called ‘inertial’ or short-term inhibition effect, following the cessation of rhythmic respiratory motor output? Expiratory muscle EMG consistently shows tonic activity throughout the apnoea (Satoh et al. 2001), suggesting that inspiratory neuronal activity is actively and reciprocally inhibited (Sears et al. 1982). Recordings from medullary respiratory neurones during apnoeas may (Remmers et al. 1986) or may not (Orem & Vidruk, 1998) also show tonic activity of expiratory or post-inspiratory neurones and may even show persistent rhythmic activity of some bulbar inspiratory neurones (Batsel, 1967). So, apnoeas are clearly not quiet, passive events but are alive with a variety of tonic and even rhythmic neural activities. Together, these two PCO2 thresholds in sleep mean that even small transient reductions in PaCO2 will initiate apnoea and that prolongation of apnoea will exacerbate hypercapnia and hypoxaemia leading to transient arousals and ventilatory overshoots upon apnoea termination.
Lability of the apnoeic threshold and the CO2 reserve
The apnoeic threshold and the CO2 reserve are not fixed quantities. They will change inversely with both the sensitivity of the ventilatory response to CO2 below eupnoea and the plant gain. Thus, increasing the drive to breathe and lowering the prevailing steady-state PaCO2 does not mean that one is at greater risk of inducing apnoea and/or ventilatory instability. Similarly, simply increasing the background PaCO2 via sustained hypoventilation does not protect against crossing the apnoeic threshold. In fact quite the opposite occurs. For example, unstable, periodic ventilatory patterns during sleep in short-term hypoxia or chronic heart failure (CHF) are stabilized when further hyperventilation and hypocapnia are induced by increasing background drive by pharmacological means (Sutton et al. 1979; Javaheri et al. 1996) or by sojourning for longer periods at high altitude (Berssenbrugge et al. 1984).
Influence of background drive
There appear to be two reasons for the increased protection against apnoea and instability afforded by increased ventilatory drive, as illustrated in Fig. 2. First, hyper- or hypoventilation means relocation along the isometabolic A:PaCO2 hyperbola. Accordingly, with increased background drive and therefore high A and low PaCO2, plant gain is reduced, i.e. the increase in A required for a given reduction in PaCO2 is increased. Second, the slope of the decrease in A with a reduction in end-tidal CO2 pressure (PETCO2) below eupnoea showed no significant change from control in the background of hyper- or hypoventilation attending these metabolic acid–base derangements. Thus, the CO2 reserve (i.e. PETCO2 required between eupnoea and the apnoeic threshold) changed inversely with the change in plant gain, as PETCO2 averaged 1.8 times higher in metabolic acidosis (6.7 ± 0.8 mmHg) than in metabolic alkalosis 3.7 ± 1.0 mmHg) (Nakayama et al. 2002).
These changes in plant gain accompanied by no change in the ventilatory sensitivity to reductions in CO2 below eupnoea markedly enhance the likelihood that the apnoeic threshold is crossed (with further transient ventilatory perturbations) in metabolic alkalosis and greatly reduces this likelihood in metabolic acidosis. For example, as shown by contrasting Fig. 3A and B, the enhanced susceptibility to apnoea and to periodic breathing during the hypoventilation of metabolic alkalosis was manifested: (a) consistently in response to small transient reductions in PETCO2 accompanying the transient increases in tidal volume (VT) at even the lowest levels of pressure support ventilation (PSV); and (b) occasionally during spontaneous eupnoea (i.e. with no PSV applied) – periodic breathing occurs over several minutes sometimes triggered by a single augmented breath but other times with no apparent triggering other than the background hypoventilation.
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In hypoxia, the accompanying hyperventilation and reduced plant gain – by itself – protects against apnoea and instability, just as occurred with increased non-hypoxic stimuli to breathe (e.g. pharmacological carotid chemoreceptor stimulation and metabolic acidosis – see Figs 2 and 3A). However, in hypoxia the stabilizing factor of reduced plant gain is counteracted by an increase in the slope of the ventilatory response to reduced PaCO2 below eupnoea, thereby greatly reducing the magnitude of the CO2 reserve between eupnoea and apnoea (see Fig. 2; bottom panel and Fig. 3C) (Xie et al. 2001; Nakayama et al. 2002). The effect of even relatively mild hypoxia (PETO2 54–64 mmHg) was especially evident in the sleeping human in whom the average CO2 reserve between eupnoea and apnoea was reduced by two-thirds from 3.4 to 1.1 mmHg PETCO2. In the presence of hypoxia, the ventilatory response to CO2 above eupnoea is also increased in slope (Cunningham et al. 1986) and this would cause greater ventilatory overshoots in response to transient chemical stimuli, thereby further enhancing opportunities to reach the apnoeic threshold.
Many congestive heart failure (CHF) patients experience highly unstable and periodic ‘Cheyne-Stokes’ respiration in sleep and this often coincides with chronic hyperventilation and hypocapnia. As explained above, by itself, this hyperventilation in CHF will decrease plant gain and stabilize breathing pattern. However, several influences apparently override this protection. Many investigators have reported that severe CHF is accompanied by increased peripheral chemo-responsiveness (Sun et al. 1999) and prolonged circulation times, both of which would contribute to ventilatory overshoot and periodicity. In addition the CO2 reserve below eupnoea is markedly reduced to less than one-half normal in these patients, for two reasons (Xie et al. 2002). First, as is the case with hypoxia, the ventilatory response slope to CO2 below eupnoea is significantly increased in CHF patients (see Fig. 2). Second, these patients experience little or no significant hypoventilation and therefore no increase in PaCO2 in the transition from awake to NREM sleep (also see below).
Influence of REM sleep
In (phasic) REM sleep the CO2 reserve is widened and much more variable than in NREM sleep (Xi et al. 1993). Accordingly, central apnoeas and periodic breathing following a ventilatory overshoot are rare in REM sleep, just as are augmented ventilatory responses to chemoreceptor stimuli (Phillipson & Bowes, 1986). Thus, while tachypnea and a variable VT are common in REM sleep, apnoea and periodic breathing occur very rarely, even in CHF or hypoxia or central sleep apnoea syndrome (Berssenbrugge et al. 1983; Hanly et al. 1989). In REM sleep, ponto-medullary inspiratory neurones are markedly excited (Orem, 1994) and apparently (like behavioural inputs in wakefulness) cause dissociation of the respiratory pattern generator from the usual excitatory or inhibitory inputs from chemo- and mechano-receptors (Phillipson & Bowes, 1986; Smith et al. 1997).
Causes of changes in ventilatory responsiveness below eupnoea and reductions in the CO2 reserve
Why do conditions of sustained hyperventilation elicited by hypoxia and CHF cause an increased slope of the ventilatory response to CO2 below eupnoea and a reduced CO2 reserve in sleep? A popular concept suggests that a dominance of peripheral over central chemoreceptor contributions to the total ventilatory drive creates instability (Cherniack & Longobordo, 1994; Khoo, 2000). This opinion is based on evidence of ventilatory instability in conditions such as hypoxia, medullary chemoreceptor ablation and carotid chemoreceptor sensitization (via dopamine receptor blockade). However, this hypothesis was not supported by more direct tests in the sleeping animal. First, as shown in Fig. 2, non-hypoxic pharmacological stimulation of carotid chemoreceptors and ventilation using almitrine (which, like hypoxia increases carotid body and ventilatory sensitivity to CO2; Nishino & Lahiri, 1981), did not mimic the effects of hypoxia by increasing the slope of the ventilatory response below eupnoea and narrowing the CO2 reserve (see Fig. 2). Rather, with almitrine-induced hyperventilation, the slope of the CO2 response below eupnoea remained unchanged from control and the CO2 reserve was widened in proportion to the decrease in plant gain – just as occurred with (normoxic) metabolic acidosis.
The same rationale led us to try the reverse experiment. We recently used low-dose dopamine infusion to cause hypoventilation (i.e. increased Gp) and to reduce the CO2 responsiveness of the carotid chemoreceptors (Lahiri et al. 1980, 1989; Nishino & Lahiri, 1981; Sabol & Ward, 1987). Like metabolic alkalosis (see above) the slope of the CO2 response below eupnoea remained unchanged from control (see Fig. 2); thus the CO2 reserve was narrowed in proportion to the increase in plant gain. During dopamine infusion, brief apnoeas and periodic breathing occurred occasionally during spontaneous breathing in sleep and consistently with small transient perturbations in VT and PCO2 provided by low levels of pressure support ventilation. This instability in ventilatory control during dopamine infusion contrasted with the marked resistance to apnoea and periodic breathing found during PSV-induced transient hypocapnia following carotid body denervation (CBX) (Nakayama et al. 2003). Perhaps this difference between dopamine and CBX reflects the importance to hypocapnic-induced apnoea and periodicity of at least some level of carotid body CO2 responsiveness – even if markedly subnormal – in the face of a high plant gain and reduced CO2 reserve.
So, contrary to predictions based on the peripheral–central chemoreceptor imbalance concept (Khoo, 2000), non-hypoxic stimulation of the carotid chemoreceptors combined with hypocapnic inhibition of the central chemoreceptors, widened the CO2 reserve and enhanced ventilatory stability. Furthermore, non-hypoxic inhibition of the peripheral chemoreceptors combined with hypercapnoeic stimulation of the central chemoreceptors narrowed the CO2 reserve and made the control system more susceptible to apnoea and periodicity.
Through what other mechanisms might hypoxia increase the slope of the ventilatory response to reduced PCO2 below eupnoea and move the eupnoeic PaCO2 so close to the apnoeic threshold? First, perhaps a unique sensory output from the carotid chemoreceptors is elicited by hypoxia which is quite different from pharmacological stimuli. Certainly different stimuli such as hypoxia, PCO2 and pH have been shown to activate quite different types of receptors within the carotid chemoreceptor (Summers et al. 2002).
A second potential mediator of these effects might be found in the central inhibitory effects of hypoxia on ventilatory control, as has been well documented in anaesthetized animals (Neubauer & Bisgard, 1994), but at present the findings on this question in unanaesthetized preparations are contradictory. On the one hand, the well-known cerebral vasodilatory effects of hypoxia would be expected to inhibit breathing by reducing medullary PCO2 for any given arterial PCO2. For example, 30–40% swings in middle cerebral artery blood flow were recently found to accompany periodic breathing in NREM sleep (mostly Stage II) in hypoxic humans (see Fig. 4). The observed increases in cerebral blood flow correspond to large reductions of 6–8 mmHg in the PCO2 difference between arterial and jugular venous blood (Chapman et al. 1979). In awake humans we reduced the slope of the cerebral blood flow response to hypercapnia by about 65% via indomethicin administration, and this caused an average 50% increase in the steady-state ventilatory response to inhaled CO2 (Xie et al. 2003). This study and other earlier studies using fixed reductions in cerebral blood flow in awake goats (Chapman et al. 1979) show that changes in cerebral blood flow clearly influence the chemical control of breathing, presumably acting via changes in brain chemoreceptor PCO2. On the other hand, in sleeping unanaesthetized dogs in which the isolated and extra-corporally perfused carotid chemoreceptors were maintained normocapnic and normoxic (Curran et al. 2000), cerebral hypoxia per se was found to stimulate – not depress – eupnoeic ventilation. A similar intact, isolated carotid chemoreceptor preparation used in the awake goat showed that short-term potentiation of ventilatory output immediately following carotid chemoreceptor stimulation was not affected by CNS hypoxia (Engwall et al. 1994). This fundamental question concerning the influence of CNS hypoxia and cerebral blood flow on ventilatory control needs to be further addresed in physiological preparations – both awake and asleep.
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The reduced CO2 reserve observed with CHF patients cannot be attributed to arterial hypoxaemia which usually is absent in CHF. Correlative evidence suggests that elevated pulmonary capillary wedge pressures may stimulate a vagally mediated hyperventilation in these patients (Solin et al. 1999). Whether this specific stimulus would, like hypoxia, sensitize the slope of the CO2 response below eupnoea and reduce the CO2 reserve remains unknown.
Another promising explanation for the reduced CO2 reserve in CHF might be found in a blunted cerebrovascular endothelial response to CO2. The effects of CO2 on cerebral blood flow provide an important counter-regulatory mechanism which serves to minimize changes in brain [H+], thereby stabilizing the breathing pattern in the face of perturbations in PaCO2. For example, hypocapnia normally causes marked cerebral vasoconstriction and reduced cerebral blood flow which attenuates the fall in brain PCO2 relative to that in arterial blood. Accordingly, ventilatory inhibition in response to reduced PCO2 will be lessened because of the attenuated decrease in central chemoreceptor [H+]. Patients with CHF (Georgiadis et al. 2000) and an animal model of CHF (Caparas et al. 2000) show reduced cerebral blood flow responses to CO2. More specifically, our recent data showed that CHF patients with periodic breathing in sleep demonstrate a significantly attenuated reduction in cerebral blood flow response to hypocapnia relative to CHF patients without periodicity (Xie et al. 2003).
Again, an important potential role for cerebral blood flow in the regulation of breathing and breathing stability is implicated. Its true contributions will depend upon the relative importance of central chemoreceptor PCO2 in causing apnoea. In this regard, the elegantly documented increase in carotid chemoreceptor responsiveness in an animal model of CHF (Sun et al. 1999) points to sensitization of peripheral chemoreceptor inputs as a potentially important determinant of a sensitized apnoeic threshold and reduced CO2 reserve.
To summarize the findings of changing susceptibilities to apnoea and periodic breathing, we believe there is no easily determined, single index such as loop gain, at least as presently conceived, which predicts ventilatory instability in sleep. Rather, at a minimum it is important to consider plant gain together with several elements of controller gain in response to PCO2 both above eupnoea (i.e. the gain of the response to increased ventilatory stimuli – both chemical and state-related) and below eupnoea. The change in the spontaneous, eupnoeic PaCO2 in the transition from wakefulness to sleep may also have an important bearing on the magnitude of the CO2 reserve and ventilatory stability during sleep. All of these variables are significant determinants of the propensity for both ventilatory overshoot and undershoot.
Ventilatory control instability and obstructive sleep apnoea
How might the occurrence of instability in central respiratory motor output during sleep relate to the major clinical problem of repetitive airway obstruction and high resistance hypopnoeas in the ‘obstructive sleep apnoea syndrome’ (OSA)? Conventional opinion would cite the highly significant risk factors of obesity and the volume of upper airway soft tissue structures and cranio-facial abnormalities in OSA (Dempsey et al. 2002; Schwab, 2003) to support the idea that the inherent passive collapsibility of upper airway is the dominant determinant of OSA and that sleep promotes the obstruction by removing the abnormally augmented activation of upper airway dilator muscles present during wakefulness in OSA patients (White, 2002). However, there is accumulating evidence to demonstrate that neuro-mechanical control of the stability and coordination of motor output to both the respiratory pump muscles and the resistance muscles of the upper airway during sleep is also likely to be a significant player in many types of repetitive sleep apnoeas. For example, many OSA patients display an enhanced controller (and therefore loop) gain during sleep, which would predispose to periodic breathing (Younes et al. 2001). When these types of patients were tracheostomized in order to bypass the upper airway, marked periodic breathing during sleep was revealed (Onal & Lopata, 1982). Furthermore, the severe OSA patient's ability to effectively compensate (via effective neural control of the respiratory muscles of both the upper airway and the pump, without EEG arousal) for airway narrowing and increased mechanical load was shown by correlational analysis to be a more important determinant of the degree of cycling behaviour of airway patency and ventilation than was the inherent passive collapsibility of the airway (Younes, 2003).
An implication of these clinical data is that an inherently collapsible airway may allow for significant airway narrowing and even obstruction in sleep, but any subsequent repetitive cycling behaviour in airway patency and ventilation is critically dependent upon neuro-chemical control mechanisms. What is not known from these reports in long-standing OSA patients is the extent to which their predisposition towards instability in neural control is inborn and/or is exacerbated by chronic intermittent hypoxia – a well-known cause of increased carotid chemoreceptor gain and CNS neuro-transmitter turnover (Ling et al. 2001; Peng et al. 2001).
In addition to these clinical examples outlined above, there are many experimentally documented links between respiratory neural control and airway patency. First, unstable oscillations in respiratory motor output produced in sleep during the transition from normoxia to hypoxia (and from steady-state hypoxia to normoxia) will cause airway obstruction which occurs at the nadir of the cycling respiratory motor output (Warner et al. 1987). Likewise, in OSA patients the nadir of upper airway muscle EMG activity coincides with the onset of airway obstruction (Suratt et al. 1985). We emphasize that an oscillating respiratory motor output precipitated by transient hypoxia caused airway obstruction during periods of low respiratory motor output only in those subjects who had upper airways that were highly compliant and already narrowed prior to the induction of an oscillating respiratory drive (e.g. a snorer with an airway resistance (Rua) of 20–50 cmH2O l–1 s–1 during sleep). However, even in these subjects, if the hypoxia was continued for several minutes leading to full-blown, cluster-type periodic breathing, airway obstruction did not persist. On the contrary, upon re-initiation of breathing rhythm at the termination of each apnoea, inspiratory motor output and flow rate were very high and Rua was reduced to near waking levels (Warner et al. 1987). Apparently the steep crescendo in chemoreceptor (plus arousal)-driven inspiratory motor output upon apnoea cessation must include marked and near-simultaneous activation of both pharyngeal dilator and inspiratory pump muscles.
Second, bronchoscopy performed during induced or naturally occurring central apnoeas, revealed that upper airway obstruction occurs early (< 10 s) during the central apnoeic period and even in the absence of inspiratory efforts (Badr et al. 1995). Apparently, all so-called ‘central’ apnoeas have an ‘obstructive’ airway component, but this is usually not detectable in the absence of inspiratory effort.
Third, obstructive apnoeas will precipitate central apnoeas and oscillatory ventilation. For example, with airway obstruction, accumulation of chemoreceptor stimuli will cause ventilatory overshoots and hypocapnia, followed by central apnoea or hypopnoea (Iber et al. 1986). Transient arousals at apnoea termination are likely to enhance the magnitude of the overshoot and subsequent cycling. In addition, the mechanical events occurring in a narrowed or obstructed airway, such as negative pressure, pharyngeal tissue deformation and/or palatal tissue vibration at high frequency (simulating snoring) are excitatory to pharyngeal muscle activity but inhibitory to respiratory pump muscles (Eastwood et al. 1999). These dual reflex responses to airway pressures serve to preserve or restore airway patency (Brouillette & Thach, 1979) but also act to reduce respiratory motor output to the pump muscles and will even cause central apnoea if the airway pressure changes occur during the expiratory phase (Harms et al. 1996).
These many links between the stability of respiratory motor output and airway resistance have implications for both the diagnosis and treatment of OSA. For example, routine non-invasive polysomnography does not include independent, sensitive, measures of respiratory motor output or effort; nor does it provide accurate assessment of airway calibre during an apnoea in the absence of inspiratory effort (Kryger, 1994; Morrell et al. 1995). Accordingly, reductions in central respiratory drive preceding an obstruction or the prevalence of truly ‘mixed’ (central plus obstructive) apnoeas are likely to be underestimated. Future treatment of OSA may need to focus on both optimizing neural drive to the upper airway muscles and on preventing subsequent apnoeas and cycling by stabilizing respiratory motor output (Strohl, 2003).
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1 h of hypoxia (PaO2 = 47 mmHg, PaCO2 = 31 mmHg). Despite a similar level of background hyperventilation as with metabolic acidosis (see 