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Julius H. Comroe memorial lecture |
1 John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, Madison, WI, USA
Abstract
This brief review addresses the characteristics, lability and the mechanisms underlying the hypocapnic-induced apnoeic threshold which is unmasked during NREM sleep. The role of carotid chemoreceptors as fast, sensitive detectors of dynamic changes in CO2 is emphasized and placed in historical context of the long-held debate over central vs. peripheral contributions to CO2 sensing and to apnoea. Finally, evidence is presented which points to a significant role for unstable, central respiratory motor output as a significant contributor to upper airway narrowing and obstruction during sleep.
(Received 14 September 2004;
accepted after revision 22 October 2004; first published online 30 November 2004)
Corresponding author J. A. Dempsey: John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, 1300 University Avenue, Rm. 4245 MSC, Madison, WI, USA. Email: jdempsey{at}wisc.edu
History has shown Julius H. Comroe (1911–84) to be one of the respiratory discipline's most influential physiologists, physicians, teachers and innovators. He conducted groundbreaking, often controversial basic physiological research, especially in the area of chemoreception (see below), and was a master teacher and pedagogist, producing two of the field's first textbooks. He was also a long-time director of San Francisco's Cardiovascular Research Institute, an institution which has contributed immensely to the scientific training of many of the world's best respiratory scientists. In his later years he became a tireless and able advocate in support of basic biomedical research and against micromanagement of research funding priorities by politicians and government officials. His treatise on this subject, entitled ‘Retrospectroscope’ (Comroe, 1977) is a must-read for biomedical scientists. My favourite section of this text, ‘Premature Science and Immature Lungs’, provides fascinating insights into the personalities and discoveries surrounding the history of research into the causes and treatment of newborn respiratory distress syndrome. My mentor at the University of Wisconsin, the late John Rankin, MD (1923–81), while training under Dr Robert Forster at the University of Pennsylvania in the mid-1950s, came to know and admire Dr Comroe, who was a professor and chairman at the graduate school of medicine. Dr Rankin would be pleased that one of his students is delivering the Comroe Memorial Lecture. In turn, I humbly accept this opportunity to represent some of the research efforts of the many pre- and postdoctoral fellows and faculty of the John Rankin Laboratory.
Scope and importance of the sleep apnoea problem
In the past two decades, clinical and basic science research devoted to the causes, consequences, diagnosis and treatment of sleep apnoea has increased exponentially. This effort involves scientists in academia and industry and from a wide variety of disciplines ranging from pharmacology, cardiorespiratory physiology and neurobiology to mathematical modelling. There are many reasons to study the causes and consequences of sleep apnoea and periodic breathing. Physiologically, it is a challenge to understand such mysteries, as to how the sleeping state itself can permit – or even provoke – such abnormal, bizarre behaviour as apnoea and airway closure in an otherwise healthy control system which in wakefulness is precise and mechanically efficient. Equally bizarre is that, once started, alternating periods of apnoea and hyperpnoea are often perpetuated in the sleeping subject. In the past decade correlative analyses of data obtained in cross-sectional and longitudinal epidemiological studies of large, non-clinical community populations have shown prevalences of sleep-disordered breathing which approximate 2–9% of middle-aged adults, 2–3% of children and greater than 10–15% of older adults (Young et al. 2002). Many claim these data point to a major clinical problem. But what is the meaning of these seemingly impressive prevalence numbers unless we can define a ‘biologically significant’ amount of sleep apnoea?
The magnitude of the public health burden attributable to sleep apnoea depends upon the pathophysiological consequences, presumably in the form of daytime sleepiness, cognitive impairment and in chronic hypertension and cardiac failure. However, these proposed cause–effect relationships are not truly revealed by correlational analysis. They can only be determined via long-term interventional trials in humans and tightly controlled prospective experiments using animal models (Brooks et al. 1997; Stradling, 2004). To date, the limited data available from these interventional approaches clearly implicate very severe levels of long-standing sleep apnoea as a significant cause of cardiovascular disease. These effects are likely to be mediated through intermittent hypoxia causing oxidative stress and endothelial dysfunction and increased sympathetic nerve activity, leading eventually to daytime hypertension (Fletcher, 2003; Lavie, 2003). On the other hand, sleep-disordered breathing occurs across a broad continuum of severity in terms of the number of apnoeic or transient hypoventilatory episodes and the magnitude of their effect on systemic haemoglobin O2 saturation and/or sleep-state continuity. We know little of the long-term consequences attending the less severe forms of disordered breathing (apneal hypexia index (AHI) 
10–30 events h–1), with most of the events being hypopnoeas rather than apnoeas. It is these categories which comprise the vast majority of the high-prevalence figures found in the general population to date. Until the appropriate, albeit difficult, long-term interventional experiments are carried out across the continuum of sleep-disordered breathing severity, the disorder of sleep apnoea as a significant clinical entity requiring treatment will remain undefined.
An important area of new exploration concerns the significance of the interactive effects of sleep apnoea in the presence of chronic disease. For example, the occurrence of sleep apnoea in patients with coronary artery disease impacts significantly on mortality (Mooe et al. 2001). Furthermore, obesity and sleep apnoea, and perhaps even diabetes and sleep apnoea and chronic heart failure and sleep apnoea, may be linked in a positive feedback manner to cardiovascular morbidity and mortality. In these coexisting chronic conditions, the definition of ‘clinically significant’ amounts of sleep-disordered breathing leading to exacerbation of disease is likely to be substantially less than in an otherwise healthy population. Again interventional approaches are important to answering the importance of sleep apnoea in these settings.
My address focuses on only one component of sleep-disordered breathing, namely the neurochemical control of the magnitude and stability of respiratory motor output during sleep. Emphasis is placed on the role of central vs. peripheral chemoreception in causing apnoea and the implications of instabilities in respiratory control for airway narrowing and obstruction. The interested reader is referred to comprehensive reviews on the mechanisms of ventilatory control and causes of ventilatory instability in sleep (Khoo et al. 1982; Khoo, 2000; Younes et al. 2001).
Role of the wakefulness drive
During non-rapid eye movement (NREM) sleep, motor output to both the upper airway and respiratory pump muscles is dramatically reduced, causing mild to moderate sustained hypoventilation in all healthy subjects (+2 to +8 mmHg arterial partial pressure of CO2 (PaCO2)) and increased upper airway muscle hypotonicity and airway collapsibility, leading to an increased upper airway resistance in most otherwise healthy subjects. In sleep, the control of breathing becomes critically dependent upon chemical and mechanical reflex feedback (Skatrud & Dempsey, 1983; Meza et al. 1998). Accordingly, in sleeping humans or dogs if a subject-triggered pressure support mechanical ventilator (PSV) is used to cause progressive increases in tidal volume (VT), apnoea occurs with only small (–2 to –5 mmHg), two- or three-breath transient reductions in PaCO2, approximating the level of the eupnoeic PaCO2 present in wakefulness (see Fig. 1A). Transient hypocapnia is required to cause these apnoeas and small amounts of inspired CO2 will eliminate central apnoeas and periodic breathing in sleep (Berssenbrugge et al. 1983; Xie et al. 1997). The hypocapnic-induced apnoeic threshold is highly state dependant. That is, it is very sensitive and reproducible in NREM sleep, much less sensitive and more variable in rapid eye movement (REM) sleep and highly unpredictable and often absent in the awake human.
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Lability of the apnoeic threshold and the CO2 reserve below eupnoea
The hypocapnic-induced apnoeic threshold is not a constant value. More importantly, the amount of reduction in PaCO2 below eupnoeic PaCO2 and therefore the transient increase in alveolar ventilation required to reach the apnoeic threshold is not constant. Figure 2 shows two ways in which the susceptibility to reaching the apnoeic threshold can be altered.
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PaCO2 /VE, minute ventilation (Khoo, 2000).
That such changes in the CO2 reserve below eupnoea (PaCO2, eupnoea–apnoea) actually do occur solely due to changing (non-hypoxic) background drives to breathe has been shown in sleeping dogs subjected to metabolic acidosis and alkalosis and to specific carotid body pharmacological stimuli (almitrine) and depressants (e.g. dopamine; Nakayama et al. 2002). These primary chemoreceptor-induced conditions of hypo- or hyperventilaton probably involve a change in chemoreceptor PaCO2 threshold. Additional non-chemoreceptor causes of hypo- or hyperventilation which may or may not influence chemoreceptor thresholds would include mechanical influences on lung mechanoreceptors (e.g. increased pulmonary vascular pressures), suprapontine inputs (e.g. behavioural drives), awake-to-sleep transitions, locomotion-linked feedback or feedforward stimuli.
The other means of changing the magnitude of the CO2 reserve below eupnoea is to change the slope of the reduction in ventilation below eupnoea in response to induced hypocapnia (see Fig. 2, bottom). An increased CO2 response slope below eupnoea occurs in hypoxic humans and dogs (see Fig. 3) and in chronic heart failure (CHF) patients who experience periodic breathing in sleep (see Fig. 4). This increased slope of response to reduced PaCO2 results in a reduction of the CO2 reserve and an increased susceptibility to apnoea and periodicity, despite the background hyperventilation and reduced eupnoeic PaCO2. The potential mechanisms, such as changes in cerebral blood flow and therefore in the relative protection of central chemoreceptor PCO2, which might explain these varying sensitivities to CO2 response below eupnoea are discussed in detail in recent publications (Nakayama et al. 2002; Dempsey et al. 2004). This second means of enhancing the susceptibility to apnoea is analogous to the increased ‘controller gain’ concept proposed by Khoo (2000) and Cherniack & Longobardo (1973), the principal difference being that they assessed this sensitivity component by measuring the chemoresponsiveness to added CO2, whereas we have quantified the sensitivity to reduced PCO2 below eupnoea using mechanical ventilation. These CO2 response gains are sometimes, but not always, similar above and below eupnoea. Measurment of the ventilatory response to hypercapnia and extrapolation of this slope below eupnea to zero VE (Cunningham et al. 1986) is a practice which Dr Comroe critically referred to as the construction of ‘pretend’ lines (Comroe, 1965).
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Chemoreceptor mediation of the apnoeic threshold
What are the major sites of CO2 chemoreception responsible for causing apnoea in response to transient ventilatory overshoots in sleep? Are peripheral chemoreceptors sufficient, by themselves, to cause complete cessation of respiratory motor output and apnoea in response to transient reductions in PaCO2? What role if any is played by increased lung stretch during transient hyperventilation? These classic questions concerning the ‘relative contributions’ of varying types of sensory inputs to a physiological response in the intact animal or human have traditionally been very difficult to solve. For example, after more than a century of research, considerable controversy remains concerning the central vs. peripheral contributions to the control of ventilation, cardiac output and sympathetic responses to exercise. A major confounder in addressing these complex integrative problems is that, while we can experimentally identify and isolate individual contributors underlying a given physiological response, each of the contributions almost always changes (increases or decreases), sometimes dramatically, when put together with all of the other influences inherent in the integrated response.
A brief history of peripheral vs. central CO2 responsiveness
More than a half century of classic experiments and controversial evidence relate to this problem of sites of CO2 chemoreception. A significant early contributor to this on-going debate was Julius Comroe. Dr Comroe (Fig. 6) graduated as valedictorian from the University of Pennsylvania Medical School in 1934, at a time when the 1938 Nobel Laureate, the Belgian Corneille Heymans (1892–1968) was producing his landmark observations on the reflex regulation of circulation and respiration. Heymans and colleagues (including his co-investigator father) were great proponents of the carotid chemoreceptors (termed the ‘reflex’ effect) as the dominant receptors for both hypoxia and CO2. They concluded in a 1939 publication (Heymans & Bouckaert, 1939):
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‘The reflex effect is stronger than the central because the reflex hyperpnea is maintained by increasing CO2 in the perfused carotid even though the CO2 tension acting at the center is reduced by concomitant hypocapnia.’
Comroe's research in the 1930s had contributed to the establishment of the carotid chemoreceptor as the locus for O2 sensing, but he had quite strong opposing views to Heymans concerning the relative importance of peripheral vs. central chemoreceptors as CO2 sensors. Comroe and his mentor, Carl Schmidt, concluded in their 1940 Physiological Reviews manuscript on the subject (Schmidt & Comroe, 1940; this was one of two Physiological Reviews manusripts coauthored by Dr Comroe in the 1940s, the other being devoted to mechanisms of exercise hyperpnoea).
‘The mere fact that the response of the whole animal to CO2 is not altered by inactivation of the chemoreceptors is irrefutable evidence that they do not play a prominent role in the hyperpnea of CO2.’
Comroe and Schmidt also determined that the ventilatory response threshold to increasing CO2 required four to seven times greater increases in PCO2 at the carotid body vs. the ‘center’, the latter terminology referring to ‘respiratory centers’ some 15–20 years before the discovery of specific ‘central’ hydrogen ion-sensitive chemoreceptors. Comroe and Schmidt felt strongly that their straightforward experimental approach (carotid body denervation) offered the best approach to this problem of relative strengths of CO2 chemoreception over the isolated carotid body perfusion protocols used in cross-circulation experiments by Heymans and coworkers. They stated that the ‘lessons to be learned’ from this peripheral vs. central CO2 response controversy were as follows.
‘When the results of technically sound simple experiments conflict with those of comparably sound complicated ones, the burden of proof is on the latter! In this particular field, there has been a notable tendency to glorify the complicated experiment.’
Dr Comroe was careful to qualify these early findings in anaesthetized animals by also cautioning that the dominance of the center over the reflex effect may not be ‘. . . applicable to the intact, unanaesthetized animal or man’, and also updated some of his earlier studies with their newer findings showing the carotid chemoreceptors to be quite responsive to metabolically induced changes in arterial pH.
About 25 years later Dr Comroe predicted in his classic textbook Respiratory Physiology (Comroe, 1965) that there are probably some special circumstances under which the carotid chemoreceptors might serve as an important CO2 sensor. These included the presence of interactive stimuli (hypoxia and hypercapnia) acting at the carotid chemoreceptors or during sudden rapid changes in PaCO2. However, for these latter dynamic responses at the carotid chemoreceptors he still required that PaCO2 increase more than 20 mmHg. As outlined below, most (but not all) investigations over the past 40 years share this concept that the chemoreception of CO2 is almost exclusively or at least largely the domain of the medullary chemoreceptors.
Following Leusen's (Leusen, 1954) and then Loeschke and Mitchell's clear demonstration of pH-sensitive chemoreceptors near the ventral lateral surface of the medulla in the 1950s through mid-1960s (Mitchell et al. 1966), Pappenheimer and Fencl used ventricular-cisternal perfusion of artificial cerebral spinal fluid of varying bicarbonate concentrations in the unanaesthetized goat to demonstrate the high sensitivity of these ‘central chemoreceptors’ in a physiological preparation. These latter authors (Fencl et al. 1966), concluded that ventilation during CO2 inhalation was a ‘single function of brain interstitial fluid hydrogen ion’. Other studies using carotid body denervation in unanaesthetized animals showed that the slope of the steady-state ventilatory response to inhaled CO2 was determined by a 60–80% contribution from central chemoreception and 20–40% from peripheral chemoreception. Our own recent work confirmed that even the hyperoxic CO2 ventilatory response (PaO2 > 500 mmHg) was depressed by 40% following carotid body denervation in the awake dog (Rodman et al. 2001).
In the past decade [H+]-sensitive chemoreceptors participating at least to some extent in ventilatory control have been identified at multiple loci throughout the brainstem (Nattie, 2000). Furthermore, it has recently been suggested that these medullary chemoreceptors have a ‘perivascular’ location and may therefore be at least theoretically capable of quickly sensing alterations in arterial blood gases and pH (Bradley et al. 2002; Okada et al. 2002). In summary, the central chemoreceptors appear to be well equipped as CO2 sensors both in terms of the magnitude and perhaps even the rapidity of their response, but these characteristics do not rule out a significant contribution from carotid chemoreception to apnoea and breathing periodicity in sleep.
Carotid chemoreceptors and the dynamic response to CO2
We would now like to make the case for the carotid chemoreceptors as important CO2 sensors, especially under dynamic conditions of: (i) a rapidly changing PaCO2; and (b) when this change in PaCO2 occurs simultaneously with other changing sensory inputs which are also determinants of respiratory motor output, in particular enhanced lung stretch. Thus, in anaesthetized cats, Lahiri and others have amply documented the sensitive response of carotid sinus nerve activity to PaCO2 changes and the interactive effect between PaCO2 and many other carotid chemoreceptor stimuli in their effect on phrenic nerve output (Lahiri et al. 1989). Bajic et al. (1994) demonstrated a significant effect of lung stretch on medullary respiratory neuronal responsiveness to carotid body stimulation. Bowes et al. (1983) showed, by using carotid body denervation and passive transient hyperpnoea in the awake, vagally blocked dogs, that the carotid chemoreceptors per se were capable of small but significant within-breath modulation of expiratory time in response to transient reductions in PaCO2. Our data in the sleeping intact dog or human using pressure support ventilation showed that apnoeas normally occurred within 10–15 s (or within two breaths) following a transient ventilatory overshoot (Nakayama et al. 2003; see Fig. 1). Denervation of the carotid bodies in the dog prevented the normal appearance of these apnoeas, i.e. expiration time was prolonged, but not until the hypocapnia had been present for more than 30 s. So in the awake or sleeping unanaesthetized animal the carotid chemoreceptors are sensitive, fast-responding CO2 sensors. Furthermore, they are required for the normal occurrence of apnoeas immediately following a transient hyperventilation (see Fig. 7).
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Finally, the reduction in PaCO2 required to cause apnoea of equal lengths was almost two times greater (–5 vs. –10 mmHg PaCO2) in the carotid body-denervated vs. the intact animal (Nakayama et al. 2003). These data suggest that the sensitivity to dynamic reductions in PaCO2 is substantially greater at the peripheral vs. the central chemoreceptors. Our recent preliminary studies in the intact, carotid body-perfused sleeping dog also show that brain hypocapnia per se (i.e. caused by using pressure support ventilation to increase VT and reduce PaCO2 in the presence of a normal tonic input from an isolated and perfused normocapnic, normoxic intact carotid chemoreceptor) must be reduced 10 mmHg or more below control values to cause apnoea.
Are the mendullary chemoreceptors, by themselves, really this insensitive to dynamic reductions in PCO2? While our data do point to this possibility, we caution that other experimental approaches using physiological preparations are required to test this hypothesis further. These surprising data do not specify whether this apparent insensitivity to hypocapnia at the medullary (vs. carotid) chemoreceptors is attributable to the absence of an interaction between brain hypocapnia and lung stretch (see below).
Hypocapnia is required but is not the sole cause of apnoea
Although carotid chemoreceptors are required to cause the initiation of the ventilatory undershoot and for the periodic breathing which may follow, carotid chemoreceptor hypocapnia, by itself, may not be sufficient to cause apnoea. For example, when the blood perfusing the isolated carotid chemoreceptor in the sleeping dog was made progressively hypocapnic, VT and the amplitude of diaphragm electromyogram (EMGdi) were also reduced in a stepwise fashion, but the prolongation in duration of expiration was minimal (<2 times > control; see Fig. 8). Also, progressive reductions in VT with no change in breathing stability occurred in the anaesthetized cat with stepwise reductions in PaCO2 imposed in a perfusate isolated to the pontomedullary region; breathing instability and apnoea occurred only in extreme hypocapnia (to <10 mmHg PaCO2; Berkenbosch et al. 1984). While these data oppose the concept of an alinear flattening (or ‘hockey stick’ shape) to the CO2 ventilatory response immediately below eupnoea (Cunningham et al. 1986), they also suggest that hypocapnia, sufficient to cause apnoea when it occurs because of a ventilatory overshoot, would not cause apnoea by itself when it occurs at the carotid or central chemoreceptors. Even extreme hyperoxia (PaO2 > 500 mmHg) administered via extracorpeal perfusion to the isolated carotid body was insufficient to cause apnoea (Smith et al. 1995).
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Consequences of an unstable central respiratory motor output to airway obstruction
There is growing evidence that periodic oscillations in central respiratory motor output to both the upper airway and the respiratory pump muscles may, under certain circumstances, cause airway obstruction. In obstructive sleep apnoea (OSA) patients, airway obstruction has been shown to occur at the nadir of inspiratory drive and tracheostomies commonly resulted in periodic breathing with central apnoeas, at least for a significant time period following the surgery (Onal & Lopata, 1982). Recently, severe OSA patients have been shown to have a high ‘loop gain’ in their ventilatory control system, which is a strong predictor of ventilatory instability (Younes et al. 2001). Furthermore, bronchoscopic examination of the upper airway showed that spontaneous central apnoeas during sleep caused upper airway closure and induced central apnoea (using transient hyperventilation) in otherwise healthy subjects caused marked airway narrowing (Badr et al. 1995). These apnoeic effects on airway patency occurred within 8–10 s after the central apnoea was initiated and did not require an inspiratory effort. All central apnoeas appear to include an airway narrowing component, but the degree to which the central instability–obstructive link occurs also depends critically upon the inherent anatomy and compliance of the subject's upper airway. In turn, this inherent airway collapsibility is determined principally by fat and soft tissue deposition encroaching on the pharyngeal lumen and/or by inherent craniofacial dimensions of the upper airway. Both of these anatomical parameters have been identified as major risk factors for sleep-disordered breathing in cross-sectional and longitudinal population studies (Peppard et al. 2000; Dempsey et al. 2002; Schwab, 2003).
These central neural control–airway obstruction links can be demonstrated experimentally by creating central output instabilities using transient periods of hypoxia in sleeping human subjects with a wide variety of inherent airway collapsibilities during sleep, as indicated by the interindividual differences in the awake-to-sleep changes in airway resistance (see Fig. 9A). In sleeping subjects with anatomically stable airways, superimposition of transient or steady-state instability of central respiratory motor output with hypoxia did not increase airway resistance (Warner et al. 1987). However, in the snorer with patent airways but very high airway resistance during steady-state sleep, transitional periods of oscillating high and low ventilatory drive imposed upon induction of or recovery from hypoxia caused airway obstruction at the nadir of respiratory drive (see Fig. 9B). However, when hypoxia was continued, causing periodic breathing cycles, airway resistance was greatly reduced upon reinitiation of breathing rhythm following each period of apnoea. Diaphragmatic EMG activity was also very high at the termination of these apnoeas and apparently the steep crescendo of chemoreceptor-driven inspiratory motor output also included marked and near-simultaneous activation of pharyngeal dilator muscles. Thus, increased controller gain resulting from hypoxaemia has a paradoxical dual role in simultaneously promoting and protecting against upper airway obstructions. The usual EEG measures of transient arousal from sleep did not show any consistent changes in these studies; however, it is to be expected that arousals would occur at the end of many apnoeic periods and this would, of course, also promote airway patency.
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Conclusion
The study of sleep apnoea is likely to be important clinically because of the high prevalence of episodes of sleep-disordered breathing in the general population. However, the burden to public health remains undefined in the absence of sufficient interventional and prospective studies to determine true cause–effect, pathophysiological consequences of mild to moderate levels of sleep-disordered breathing both in health and in coexisting disease states. The sleeping state predisposes to unstable breathing by means of decreased activation of both upper airway and respiratory pump musculature and by it unmasking a highly sensitive and labile hypocapnia-induced apnoeic threshold. The apnoea that normally occurs following a transient hyperventilation in sleep requires the interactive, inhibitory inputs from both hypocapnia acting at the level of the carotid body and lung stretch. Surprisingly, based on the ventilatory depression obtained from carotid chemoreceptor-intact vs. -denervated animals, central chemoreceptors appear to be much less responsive than do carotid chemoreceptors to hyperventilation and to hypocapnia, although their apnoeic threshold has not yet been adequately quantified in the intact, sleeping animal or human. Finally, accumulating evidence points to a strong link between unstable central respiratory motor output and airway obstruction during sleep, although the extent of this relationship and its importance to the diagnosis and treatment of the obstructive sleep apnoea syndrome remains undefined.
Footnotes
Experimental Biology, Washington, DC, USA, April 2004.
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Acknowledgements
We dedicate this publication to the memory of Dr John Rankin (1923–81), leader, mentor and friend. The original research cited from the author's laboratory was funded by NHLBI and the American Heart Association. The author is especially indebted to his long-time collaborators on the causes of sleep apnoea, Curtis Smith, James Skatrud and Ailiang Xie, and to Bert Forster and Gerald Bisgard whose early collaborations formed the Wisconsin perspective on chemoreceptor integrative function. He also thanks Anthony Jacques and Ben Dempsey for their assistance with the manuscript preparation.
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