The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in...

J Physiol 560.1 (2004) pp 1–11 1

Top i ca l Rev iew

The ventilatory responsiveness to CO2 below eupnoeaas a determinant of ventilatory stability in sleep

Jerome A. Dempsey, Curtis A. Smith, Tadeuez Przybylowski, Bruno Chenuel, Ailiang Xie,Hideaki Nakayama and James B. Skatrud

The John Rankin Laboratory of Pulmonary Medicine, Department of Population Health Sciences, University of Wisconsin-Madison,Madison, WI, 53726-2368, USA

Sleep unmasks a highly sensitive hypocapnia-induced apnoeic threshold, whereby apnoeais initiated by small transient reductions in arterial CO2 pressure (P aCO2 ) below eupnoeaand respiratory rhythm is not restored until P aCO2 has risen significantly above eupnoeiclevels. We propose that the ‘CO2 reserve’ (i.e. the difference in P aCO2 between eupnoea andthe apnoeic threshold (AT)), when combined with ‘plant gain’ (or the ventilatory increaserequired for a given reduction in P aCO2 ) and ‘controller gain’ (ventilatory responsivenessto CO2 above eupnoea) are the key determinants of breathing instability in sleep. The CO2

reserve varies inversely with both plant gain and the slope of the ventilatory response toreduced CO2 below eupnoea; it is highly labile in non-random eye movement (NREM)sleep. With many types of increases or decreases in background ventilatory drive and P aCO2 ,the slope of the ventilatory response to reduced P aCO2 below eupnoea remains unchangedfrom control. Thus, the CO2 reserve varies inversely with plant gain, i.e. it is widened withhyperventilation and narrowed with hypoventilation, regardless of the stimulus and whetherit acts primarily at the peripheral or central chemoreceptors. However, there are notableexceptions, such as hypoxia, heart failure, or increased pulmonary vascular pressures, whichall increase the slope of the CO2 response below eupnoea and narrow the CO2 reservedespite an accompanying hyperventilation and reduced plant gain. Finally, we review growingevidence that chemoreceptor-induced instability in respiratory motor output during sleepcontributes significantly to the major clinical problem of cyclical obstructive sleep apnoea.

(Resubmitted 21 July 2004; accepted 22 July 2004; first published online 29 July 2004)Corresponding author J. A. Dempsey: The John Rankin Laboratory of Pulmonary Medicine, Department of PopulationHealth Sciences, University of Wisconsin-Madison, Madison, WI, 53726-2368, USA. Email: [email protected]

Sleep effects on ventilatory control stability

Sleep presents major challenges to the stability ofventilatory control and to the homeostatic regulation ofO2 and CO2 transport. All healthy humans hypoventilateto a significant degree at sleep onset and throughoutthe night (PaCO2 , 2–8 mmHg > awake). Furthermore,resistance to flow through the upper airway is increasedvariably but significantly in a very large percentage ofhealthy subjects, and cyclical overshoots and undershootsof ventilation occur in a significant segment of thepopulation who do not experience ventilatory instability inwakefulness.

Several factors contribute to these effects of sleep. First,the loss of supra-pontine neural input to the medullaryrespiratory pattern generator (‘wakefulness drive’) resultsin reduced rhythmic and tonic activation of both phrenic

and hypoglossal motor neurones (Orem et al. 1985).(The magnitude of the respiratory motor outputattributable to ‘wakefulness’ drives has been included intheoretical models of respiratory control (Longobardoet al. 2002). However, this wakefulness input has no fixedmagnitude. Rather, its most important characteristic is itsmarked variability, as opposed to the highly reproducibleresponses obtained in NREM sleep, in response to suchperturbations as changes in airway resistance or hypo-capnia (Skatrud & Dempsey, 1983; Wilson et al. 1984).)Second, sleep state is not constant, which greatly enhancesthe opportunity for changing respiratory drives and airwayresistance. Third, the supine position and the associatedreduction in functional residual capacity occurring insleep will reduce caudal traction on and therefore narrowthe upper airway, and will also cause greater arterial O2

C© The Physiological Society 2004 DOI: 10.1113/jphysiol.2004.072371

2 J. A. Dempsey and others J Physiol 560.1

desaturation and CO2 retention for any given apnoeiclength.

There are multiple, complex causes of sleep-inducedperiodic breathing. The propensity for unstable, periodicbreathing in a given subject or condition has been assessedusing the concept of ‘loop gain’ (GL), the combination ofthree types of gain, namely controller (Gc), plant (Gp),

Figure 1. Schematic representation of the factors influencingsleep-induced breathing instabilitiesA, Cheyne-Stokes respiration in heart failure; B, periodic breathingclusters in hypoxia. C and D isolated ventilatory overshoots followedby hypopnea (C) or apnoea (D). The ventilatory overshoot isdetermined by: (a) increased magnitude of chemoreceptor stimuli,which in turn are dependent upon the duration of any precedingapnoea or hypopnoea, the functional residual capacity and themetabolic rate; (b) the gain of the chemoreceptor response, which inpart depends upon state of consciousness; and (c) the translation ofrespiratory drive to ventilation which is dependent upon the prevailingupper airway resistance. Following the ventilatory overshoot acontinued excitatory short-term potentiation (STP) of respiratory motoroutput favours stabilization of breathing pattern. The effectiveness ofSTP as a stabilizer will depend upon the magnitude and duration ofthe preceding stimulus. Inhibitory effects opposing STP (and causingapnoea) include: lung stretch at high VT which will have a carry-overinhibitory effect, baroreceptor stimulation coincident with the risingsystemic pressure during the overshoot phase which also contributesto a reduced respiratory motor output to both the pump and upperairway musculature, and transient hypocapnia. ‘Inertia’ refers to thecontinued short-term inhibition of inspiratory drive, prolongation ofapnoea and delayed resumption of rhythmic respiration in the face ofa P aCO2 which increases to above eupnoeic levels.

and mixing (Gm) gains (Khoo, 2000; Younes et al. 2001).The higher the GL, the greater the probability of periodicbreathing. This quantitative approach to predictingventilatory instability and periodicity has provided avaluable tool for understanding the complex, multifaceteddeterminants of periodic breathing. However it is aconcept that was developed to characterize the dynamicbehaviour of linear systems (Khoo, 2000). Thus theusefulness of the GL index as a predictor of instabilityonly applies over the range of linear changes in theventilatory stimulus–response slope and does not considerthe mechanisms and/or conditions which predispose toapnoea. (Loop gain (GL) is determined by: (a) plant gain(� pulmonary capillary PCO2/�V̇A) as determined by theposition of V̇A versus PaCO2 on the iso-metabolic line (seeFig. 2 below), and also by V̇A : Q̇ distribution and theprevailing functional residual capacity (FRC) (b)controller gain (V̇E/PACO2 ) as determined by chemo-sensitivity (above eupnoea), lung and airway mechanicsand respiratory muscle power output; and (c) mixinggain (� chemoreceptor PCO2 /� pulmonary capillaryPCO2 ), as determined by circulatory delay time, thoracicblood volume and brain extracellular fluid volume (Youneset al. 2001).) Accordingly, when PaCO2 falls below eupnoeaand apnoea ensues, controller gain, and therefore loopgain would actually be reduced (i.e. the CO2 ventilatoryresponse slope is zero), thereby predicting a stablebreathing pattern even in the face of apnoea.

We believe a neglected but important element to‘controller’ gain is the CO2 responsiveness below eupnoea,i.e. over the range between eupnoea and apnoea. Certainly,understanding how apnoeas occur is an important partof understanding periodic breathing, for several reasons:(a) apnoeas are an integral ingredient of many types ofperiodic breathing; (b) apnoeas permit the accumulationof large amounts of chemoreceptor sensory stimuli whichin turn will promote arousal and cause subsequentventilatory overshoots; (c) the marked reductions inrespiratory motor output which initiate the apnoeamay also trigger airway muscle hypotonicity, and causeairway narrowing and even closure (see examples belowunder ‘Ventilatory control instability and obstructive sleepapnoea’). In this brief review we focus on the causes,lability, and consequences of the gain of the CO2 responsebelow eupnoea and the associated change in the CO2

reserve between eupnoea and the apnoeic threshold.Our view of the multiple factors affecting transient

ventilatory overshoots (hyperventilation) and under-shoots (hypoventilation) in NREM sleep are shown inFig. 1 and are based on the observation that significanttransient overshoots in ventilation and blood pressureprecede and terminate most apnoeic and/or hypopnoeicevents. An increased drive to breathe, depending on itsmagnitude and duration, also causes a persistent, centrallymediated excitatory ‘memory’ effect or short-term

C© The Physiological Society 2004

J Physiol 560.1 Sleep-induced apnoeic threshold 3

potentiation (STP) which would normally prevent asudden ventilatory undershoot and maintain ventilatorystability (Eldridge & Millhorn, 1986). There are severalfactors which oppose this stabilizing effect of STP duringthis post-hyperpnoeic period (see Fig. 1). However, asoutlined below, during NREM sleep it is the transienthypocapnia initiated during the ventilatory overshootwhich is the dominant inhibitory influence required tocause the apnoea.

The apnoeic thresholds

The ‘unmasking’ of a highly sensitive apnoeic thresholdin NREM sleep, some 2–5 mmHg PaCO2 below (sleeping)eupnoeic PaCO2 and within 1–2 mmHg of the normalwaking eupnoeic PaCO2 has been documented in healthysleeping subjects in several ways. First, positive-pressuremechanical ventilation through a nasal mask was usedto progressively reduce PaCO2 below eupnoea, whichcaused progressive, linear reductions in the amplitudeof diaphragm EMG until apnoea occurred (Skatrud &Dempsey, 1983). Mechanical ventilation also elicits anon-chemical, neuro-mechanical inhibitory effect on theamplitude of respiratory motor output (Henke et al. 1988),but this can be minimized by using a subject-triggeredpressure support form of mechanical ventilation anda background of continuous positive airway pressure(CPAP) to minimize upper airway resistance (Meza et al.1998). Second, mechanical ventilation was used to controlairway and chest wall mechanics in normal subjectsduring NREM sleep and wakefulness, to demonstratea sleep-induced increase of 2–4 mmHg in the set-pointfor PaCO2 which was independent of any sleep-inducedchanges in airway resistance (Simon et al. 1993). Third,periodic breathing caused by chronic heart failure,hypoxia, or idiopathic central apnoea was alleviated bysmall 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 usedmechanical ventilation to control tidal volume at waking,eupnoeic levels in order to prevent the hypoventilation andincrease in PaCO2 normally experienced upon transitionfrom awake to light sleep. At sleep onset, apnoeas of up to15 s ensued. These observations demonstrate the markedCO2 dependence of ventilatory control at sleep onsetand the critical importance of the normal sleep-inducedhypoventilation as a deterrent to apnoea and instability.

Apnoea really has two PCO2 ‘thresholds’, namely theapnoeic initiation threshold (as outlined above) and thehigher PaCO2 at which apnoea is terminated and respiratoryrhythm re-initiated. In real life when apnoeas are initiatedby transient reductions in alveolar PCO2 (PACO2 ), some ofthe delay in resumption of breathing rhythm is likely tobe due to a persistent alkalinity in the environment of thebrain chemoreceptors at a time when arterial PCO2 (PaCO2 )is restored to eupnoeic levels. However, even when apnoeas

are caused experimentally by purely mechanical feedbackat normocapnic PaCO2 (using controlled mechanicalventilation or upper airway negative pressure) the PaCO2

will rise 3–5 mmHg or so above spontaneous eupnoeabefore breathing is re-initiated (Leevers et al. 1994; Satohet al. 2001). What causes this persistent, prolongationof apnoea to occur in the face of rising chemoreceptorstimuli, i.e. a so-called ‘inertial’ or short-term inhibitioneffect, following the cessation of rhythmic respiratorymotor output? Expiratory muscle EMG consistently showstonic activity throughout the apnoea (Satoh et al. 2001),suggesting that inspiratory neuronal activity is activelyand reciprocally inhibited (Sears et al. 1982). Recordingsfrom medullary respiratory neurones during apnoeas may(Remmers et al. 1986) or may not (Orem & Vidruk, 1998)also show tonic activity of expiratory or post-inspiratoryneurones and may even show persistent rhythmic activityof some bulbar inspiratory neurones (Batsel, 1967). So,apnoeas are clearly not quiet, passive events but arealive with a variety of tonic and even rhythmic neuralactivities. Together, these two PCO2 thresholds in sleepmean that even small transient reductions in PaCO2

will initiate apnoea and that prolongation of apnoeawill exacerbate hypercapnia and hypoxaemia leading totransient arousals and ventilatory overshoots upon apnoeatermination.

Lability of the apnoeic threshold and the CO2 reserve

The apnoeic threshold and the CO2 reserve are notfixed quantities. They will change inversely with boththe sensitivity of the ventilatory response to CO2 beloweupnoea and the plant gain. Thus, increasing the driveto breathe and lowering the prevailing steady-state PaCO2

does not mean that one is at greater risk of inducing apnoeaand/or ventilatory instability. Similarly, simply increasingthe background PaCO2 via sustained hypoventilation doesnot protect against crossing the apnoeic threshold. In factquite the opposite occurs. For example, unstable, periodicventilatory patterns during sleep in short-term hypoxiaor chronic heart failure (CHF) are stabilized when furtherhyperventilation and hypocapnia are induced by increasingbackground drive by pharmacological means (Sutton et al.1979; Javaheri et al. 1996) or by sojourning for longerperiods at high altitude (Berssenbrugge et al. 1984).

Influence of background drive

There appear to be two reasons for the increased protectionagainst apnoea and instability afforded by increasedventilatory drive, as illustrated in Fig. 2. First, hyper- orhypoventilation means relocation along the isometabolicV̇A : PaCO2 hyperbola. Accordingly, with increasedbackground drive and therefore high V̇A and low PaCO2 ,plant gain is reduced, i.e. the increase in V̇A requiredfor a given reduction in PaCO2 is increased. Second,



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Figure 2. The effects of changing background ventilatory driveon the gain of the ventilatory responsiveness to CO2 beloweupnoea, on ‘plant gain’ and on the CO2 reserve (∆P ETCO2

eupnoea – apnoea) in sleeping dogs and humansData are plotted on separate isometabolic lines for dogs (CO2 flow(V̇CO2 ) = 150 ml min−1) and for humans (V̇CO2 = 250 ml min−1). Thediagonal dashed or continuous lines join eupnoeic and apnoeic pointsand their slopes indicate the gain below eupnoea of the ventilatoryresponse to hypocapnia in each condition. The height of the verticalbar above the isometabolic line indicates the increase in V̇A required toreduce the P aCO2 to the apnoeic threshold (i.e. the inverse of plantgain). The CO2 reserve is the difference in P ACO2 between eupnoeaand the apnoeic threshold. Note in the sleeping dog: (a) that the slopeof the CO2 response below eupnoea remained unchanged duringhyper- or hypoventilation; (b) the required increase in V̇A to reachapnoea under background conditions of hyperventilation via metabolicacidosis (�V̇A = 1.4 l min−1) is about twice that required in controland almost five times that required with the background condition ofhypoventilation via metabolic alkalosis (0.3 l min−1); (c) the greaterprotection against apnoea during these backgrounds of hyper- versushypoventilation are due solely to the change in Gp. Similarly, almitrineinfusion (see bottom panel) caused hyperventilation, with nosignificant influence on the slope of the ventilatory response to CO2

below eupnoea. However, in hypoxia (bottom panel) note theincreased slope (versus control) of V̇A−P aCO2 relationship betweeneupnoea and the apnoeic threshold in dogs and especially in humansand in chronic heart failure (CHF) patients with Cheyne-Stokes periodicrespiration (CSA). Thus in these latter two examples the CO2 reserve isnarrowed significantly despite the background hyperventilation andreduced plant gain. (Data compiled from Xie et al. 2001, 2002;Nakayama et al. 2003; and from author’s laboratory.)

the slope of the decrease in V̇A with a reduction inend-tidal CO2 pressure (PETCO2 ) below eupnoea showedno significant change from control in the backgroundof hyper- or hypoventilation attending these metabolicacid–base derangements. Thus, the CO2 reserve (i.e.�PETCO2 required between eupnoea and the apnoeicthreshold) changed inversely with the change in plantgain, as �PETCO2 averaged 1.8 times higher in metabolicacidosis (6.7 ± 0.8 mmHg) than in metabolic alkalosis3.7 ± 1.0 mmHg) (Nakayama et al. 2002).

These changes in plant gain accompanied by no changein the ventilatory sensitivity to reductions in CO2 beloweupnoea markedly enhance the likelihood that the apnoeicthreshold is crossed (with further transient ventilatoryperturbations) in metabolic alkalosis and greatly reducesthis likelihood in metabolic acidosis. For example, asshown by contrasting Fig. 3A and B, the enhancedsusceptibility to apnoea and to periodic breathing duringthe hypoventilation of metabolic alkalosis was manifested:(a) consistently in response to small transient reductionsin PETCO2 accompanying the transient increases in tidalvolume (V T) at even the lowest levels of pressuresupport ventilation (PSV); and (b) occasionally duringspontaneous eupnoea (i.e. with no PSV applied) –periodic breathing occurs over several minutes sometimestriggered by a single augmented breath but other timeswith no apparent triggering other than the backgroundhypoventilation.

Influence of the type of background drive

In hypoxia, the accompanying hyperventilation andreduced plant gain – by itself – protects against apnoea andinstability, just as occurred with increased non-hypoxicstimuli to breathe (e.g. pharmacological carotid chemo-receptor stimulation and metabolic acidosis – see Figs 2and 3A). However, in hypoxia the stabilizing factor ofreduced plant gain is counteracted by an increase in theslope of the ventilatory response to reduced PaCO2 beloweupnoea, thereby greatly reducing the magnitude of theCO2 reserve between eupnoea and apnoea (see Fig. 2;bottom panel and Fig. 3C) (Xie et al. 2001; Nakayamaet al. 2002). The effect of even relatively mild hypoxia(PETO2 54–64 mmHg) was especially evident in thesleeping human in whom the average CO2 reserve betweeneupnoea and apnoea was reduced by two-thirds from3.4 to 1.1 mmHg �PETCO2 . In the presence of hypoxia,the ventilatory response to CO2 above eupnoea is alsoincreased in slope (Cunningham et al. 1986) and thiswould cause greater ventilatory overshoots in responseto transient chemical stimuli, thereby further enhancingopportunities to reach the apnoeic threshold.

Many congestive heart failure (CHF) patientsexperience highly unstable and periodic ‘Cheyne-Stokes’respiration in sleep and this often coincides with



Figure 3. Apneic threshold labilityA, polygraph record in a tracheostomized dog during NREM sleep of apressure support trial (PSV) during 5 h of metabolic acidosis achievedvia oral acetazolamide administration (arterial pH = 7.34, [HCO3

−]16 mequiv l−1, P aCO2 30 mmHg). The protocol used to determine theapnoeic threshold required several trials of incremental increases inPSV. Note that with metabolic acidosis a tracheal pressure (PM) of over

chronic hyperventilation and hypocapnia. As explainedabove, by itself, this hyperventilation in CHF willdecrease plant gain and stabilize breathing pattern.However, several influences apparently override thisprotection. Many investigators have reported thatsevere CHF is accompanied by increased peripheralchemo-responsiveness (Sun et al. 1999) and prolongedcirculation times, both of which would contribute toventilatory overshoot and periodicity. In addition the CO2

reserve below eupnoea is markedly reduced to less thanone-half normal in these patients, for two reasons (Xieet al. 2002). First, as is the case with hypoxia, the ventilatoryresponse slope to CO2 below eupnoea is significantlyincreased in CHF patients (see Fig. 2). Second, thesepatients experience little or no significant hypoventilationand therefore no increase in PaCO2 in the transition fromawake to NREM sleep (also see below).

Influence of REM sleep

In (phasic) REM sleep the CO2 reserve is widened andmuch more variable than in NREM sleep (Xi et al. 1993).Accordingly, central apnoeas and periodic breathingfollowing a ventilatory overshoot are rare in REM sleep,just as are augmented ventilatory responses to chemo-receptor stimuli (Phillipson & Bowes, 1986). Thus, whiletachypnea and a variable V T are common in REM sleep,apnoea and periodic breathing occur very rarely, evenin CHF or hypoxia or central sleep apnoea syndrome(Berssenbrugge et al. 1983; Hanly et al. 1989). In REMsleep, ponto-medullary inspiratory neurones are markedlyexcited (Orem, 1994) and apparently (like behaviouralinputs in wakefulness) cause dissociation of the respiratorypattern generator from the usual excitatory or inhibitory

20 cmH2O, an increase in VT of over 2× baseline eupnoea and areduction in P ETCO2 of 7 mmHg was required to cause apnoea andsubsequent periodic breathing. B, polygraph record of a pressuresupport trial in NREM sleep during 1 h of metabolic alkalosis via I.V.NaHCO3 (arterial pH = 7.51 [HCO3

−] = 35 mequiv l−1,P CO2 = 44 mmHg). Note that a tracheal pressure of 9 cmH2O inducedvia PSV was required to cause apnoea and subsequent periodicbreathing. Contrast the CO2 reserve of 3 mmHg (eupnoea – apnoeicthreshold �P CO2 ) in this condition of background hypoventilationwith that of 7 mmHg in the condition of background hyperventilationvia metabolic acidosis (Fig. 3A). C, polygraph record of a pressuresupport trial in NREM sleep after ∼1 h of hypoxia (P aO2 = 47 mmHg,P aCO2 = 31 mmHg). Despite a similar level of backgroundhyperventilation as with metabolic acidosis (see Fig. 3A), in hypoxiathe CO2 reserve (eupnoeic P ETCO2 – apnoeic threshold P ETCO2 ) wasreduced by one-half, because hypoxia increased the slope of the CO2

response below eupnoea. (Also see Fig. 2, bottom panel.) Note, in the3 PSV trials shown in Fig. 3A–C, that diaphragm EMG amplitude isreduced on the first breath of PSV, an effect which we also foundwhen P ETCO2 was held normocapnic throughout PSV trials. Thesenon-chemoreceptor, neuro-mechanical inhibitory effects of PSVaveraged reductions of 5–20% in EMGdi and 30% prolongations of TE(Nakayama et al. 2002).



inputs from chemo- and mechano-receptors (Phillipson& Bowes, 1986; Smith et al. 1997).

Causes of changes in ventilatory responsivenessbelow eupnoea and reductions in the CO2 reserve

Why do conditions of sustained hyperventilation elicitedby hypoxia and CHF cause an increased slope ofthe ventilatory response to CO2 below eupnoea anda reduced CO2 reserve in sleep? A popular conceptsuggests that a dominance of peripheral over centralchemoreceptor contributions to the total ventilatorydrive creates instability (Cherniack & Longobordo, 1994;Khoo, 2000). This opinion is based on evidence ofventilatory instability in conditions such as hypoxia,medullary chemoreceptor ablation and carotid chemo-receptor sensitization (via dopamine receptor blockade).However, this hypothesis was not supported by moredirect tests in the sleeping animal. First, as shownin Fig. 2, non-hypoxic pharmacological stimulation ofcarotid chemoreceptors and ventilation using almitrine(which, like hypoxia increases carotid body and ventilatorysensitivity to CO2; Nishino & Lahiri, 1981), did not mimicthe effects of hypoxia by increasing the slope of theventilatory response below eupnoea and narrowing theCO2 reserve (see Fig. 2). Rather, with almitrine-inducedhyperventilation, the slope of the CO2 response beloweupnoea remained unchanged from control and the CO2

reserve was widened in proportion to the decrease in plantgain – 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 causehypoventilation (i.e. increased Gp) and to reduce theCO2 responsiveness of the carotid chemoreceptors (Lahiriet al. 1980, 1989; Nishino & Lahiri, 1981; Sabol & Ward,1987). Like metabolic alkalosis (see above) the slope of theCO2 response below eupnoea remained unchanged fromcontrol (see Fig. 2); thus the CO2 reserve was narrowedin proportion to the increase in plant gain. Duringdopamine infusion, brief apnoeas and periodic breathingoccurred occasionally during spontaneous breathing insleep and consistently with small transient perturbationsin V T and PCO2 provided by low levels of pressuresupport ventilation. This instability in ventilatory controlduring dopamine infusion contrasted with the markedresistance to apnoea and periodic breathing found duringPSV-induced transient hypocapnia following carotid bodydenervation (CBX) (Nakayama et al. 2003). Perhapsthis difference between dopamine and CBX reflectsthe importance to hypocapnic-induced apnoea andperiodicity of at least some level of carotid body CO2

responsiveness – even if markedly subnormal – in the faceof a high plant gain and reduced CO2 reserve.

So, contrary to predictions based on theperipheral–central chemoreceptor imbalance concept

(Khoo, 2000), non-hypoxic stimulation of the carotidchemoreceptors combined with hypocapnic inhibitionof the central chemoreceptors, widened the CO2

reserve and enhanced ventilatory stability. Furthermore,non-hypoxic inhibition of the peripheral chemoreceptorscombined with hypercapnoeic stimulation of the centralchemoreceptors narrowed the CO2 reserve and madethe control system more susceptible to apnoea andperiodicity.

Through what other mechanisms might hypoxiaincrease the slope of the ventilatory response to reducedPCO2 below eupnoea and move the eupnoeic PaCO2 soclose to the apnoeic threshold? First, perhaps a uniquesensory output from the carotid chemoreceptors is elicitedby hypoxia which is quite different from pharmacologicalstimuli. Certainly different stimuli such as hypoxia, PCO2

and pH have been shown to activate quite different typesof receptors within the carotid chemoreceptor (Summerset al. 2002).

A second potential mediator of these effects mightbe found in the central inhibitory effects of hypoxiaon ventilatory control, as has been well documented inanaesthetized animals (Neubauer & Bisgard, 1994), but atpresent the findings on this question in unanaesthetizedpreparations are contradictory. On the one hand, thewell-known cerebral vasodilatory effects of hypoxia wouldbe expected to inhibit breathing by reducing medullaryPCO2 for any given arterial PCO2 . For example, 30–40%swings in middle cerebral artery blood flow were recentlyfound to accompany periodic breathing in NREM sleep(mostly Stage II) in hypoxic humans (see Fig. 4). Theobserved increases in cerebral blood flow correspond tolarge reductions of 6–8 mmHg in the PCO2 differencebetween arterial and jugular venous blood (Chapmanet al. 1979). In awake humans we reduced the slope ofthe cerebral blood flow response to hypercapnia by about65% via indomethicin administration, and this causedan average 50% increase in the steady-state ventilatoryresponse to inhaled CO2 (Xie et al. 2003). This studyand other earlier studies using fixed reductions in cerebralblood flow in awake goats (Chapman et al. 1979) showthat changes in cerebral blood flow clearly influence thechemical control of breathing, presumably acting viachanges in brain chemoreceptor PCO2 . On the other hand,in sleeping unanaesthetized dogs in which the isolated andextra-corporally perfused carotid chemoreceptors weremaintained normocapnic and normoxic (Curran et al.2000), cerebral hypoxia per se was found to stimulate – notdepress – eupnoeic ventilation. A similar intact, isolatedcarotid chemoreceptor preparation used in the awake goatshowed that short-term potentiation of ventilatory outputimmediately following carotid chemoreceptor stimulationwas not affected by CNS hypoxia (Engwall et al. 1994). Thisfundamental question concerning the influence of CNShypoxia and cerebral blood flow on ventilatory control



Figure 4. The effects of one night of hypoxic exposure(F IO2 = 0.11) on periodic breathing and middle cerebral artery(MCA) blood flow during NREM sleep in the healthy humanShown are signal averaged data over 150 periodic breathing cycles ina single healthy subject. These data are representative of those foundin six additional subjects. Each periodic cycle averaged 22 s in durationand consisted of three hyperpnoeic tidal breaths followed by an8–12 s apnoea. Note the average 30% increase in MCA blood velocity(CBF) as determined by Doppler ultra-sound measurements and theincrease in mean arterial pressure (MAP) which began at thetermination of the apnoea and peaked during the ventilatoryovershoot phase. Immediately following the ventilatory overshoot, CBFfell 10% below baseline control (data from authors’ laboratory).A transfer function analysis of the gain, phase and coherence betweenMCA flow velocity and MAP changes showed that changes in cerebralblood flow throughout the cycle always led those in MAP. Based on

needs to be further addresed in physiological preparations– both awake and asleep.

Why a reduced CO2 reserve in CHF?

The reduced CO2 reserve observed with CHF patientscannot be attributed to arterial hypoxaemia whichusually is absent in CHF. Correlative evidence suggeststhat elevated pulmonary capillary wedge pressures maystimulate a vagally mediated hyperventilation in thesepatients (Solin et al. 1999). Whether this specific stimuluswould, like hypoxia, sensitize the slope of the CO2 responsebelow eupnoea and reduce the CO2 reserve remainsunknown.

Another promising explanation for the reducedCO2 reserve in CHF might be found in a bluntedcerebrovascular endothelial response to CO2. The effectsof CO2 on cerebral blood flow provide an importantcounter-regulatory mechanism which serves to minimizechanges in brain [H+], thereby stabilizing the breathingpattern in the face of perturbations in PaCO2 . Forexample, hypocapnia normally causes marked cerebralvasoconstriction and reduced cerebral blood flow whichattenuates the fall in brain PCO2 relative to that in arterialblood. Accordingly, ventilatory inhibition in response toreduced PCO2 will be lessened because of the attenuateddecrease in central chemoreceptor [H+]. Patients withCHF (Georgiadis et al. 2000) and an animal model ofCHF (Caparas et al. 2000) show reduced cerebral bloodflow responses to CO2. More specifically, our recent datashowed that CHF patients with periodic breathing insleep demonstrate a significantly attenuated reduction incerebral blood flow response to hypocapnia relative toCHF patients without periodicity (Xie et al. 2003).

Again, an important potential role for cerebral bloodflow in the regulation of breathing and breathing stabilityis implicated. Its true contributions will depend uponthe relative importance of central chemoreceptor PCO2 incausing apnoea. In this regard, the elegantly documentedincrease in carotid chemoreceptor responsiveness in ananimal model of CHF (Sun et al. 1999) points tosensitization of peripheral chemoreceptor inputs as apotentially important determinant of a sensitized apnoeicthreshold and reduced CO2 reserve.

To summarize the findings of changing susceptibilitiesto apnoea and periodic breathing, we believe there isno easily determined, single index such as loop gain, at

this correlative analysis and previous ganglionic blockade studies ofbreath-hold apnoea in awake subjects (Przybylowski et al. 2003), weattribute the increases in CBF to the transient hypoxaemia caused bythe apnoeas and the subsequent decreases in CBF below baseline tothe transient hypocapnia caused by the ventilatory overshoot. Thesemarked increases in CBF may exacerbate brain extra-cellular fluid (ECF)hypocapnia, thereby reducing the CO2 reserve and precipitatingapnoea and periodic breathing. SaO2, arterial O2 saturation.



least as presently conceived, which predicts ventilatoryinstability in sleep. Rather, at a minimum it is importantto consider plant gain together with several elements ofcontroller gain in response to �PCO2 both above eupnoea(i.e. the gain of the response to increased ventilatorystimuli – both chemical and state-related) and beloweupnoea. The change in the spontaneous, eupnoeic PaCO2

in the transition from wakefulness to sleep may also havean important bearing on the magnitude of the CO2 reserveand ventilatory stability during sleep. All of these variablesare significant determinants of the propensity for bothventilatory overshoot and undershoot.

Ventilatory control instability and obstructivesleep apnoea

How might the occurrence of instability in centralrespiratory motor output during sleep relate to the majorclinical problem of repetitive airway obstruction and highresistance hypopnoeas in the ‘obstructive sleep apnoeasyndrome’ (OSA)? Conventional opinion would cite thehighly significant risk factors of obesity and the volumeof upper airway soft tissue structures and cranio-facialabnormalities in OSA (Dempsey et al. 2002; Schwab, 2003)to support the idea that the inherent passive collapsibilityof upper airway is the dominant determinant of OSAand that sleep promotes the obstruction by removing theabnormally augmented activation of upper airway dilatormuscles present during wakefulness in OSA patients(White, 2002). However, there is accumulating evidenceto demonstrate that neuro-mechanical control of thestability and coordination of motor output to both therespiratory pump muscles and the resistance musclesof the upper airway during sleep is also likely to be asignificant player in many types of repetitive sleep apnoeas.For example, many OSA patients display an enhancedcontroller (and therefore loop) gain during sleep, whichwould predispose to periodic breathing (Younes et al.2001). When these types of patients were tracheostomizedin order to bypass the upper airway, marked periodicbreathing during sleep was revealed (Onal & Lopata, 1982).Furthermore, the severe OSA patient’s ability to effectivelycompensate (via effective neural control of the respiratorymuscles of both the upper airway and the pump,without EEG arousal) for airway narrowing and increasedmechanical load was shown by correlational analysis to bea more important determinant of the degree of cyclingbehaviour of airway patency and ventilation than wasthe inherent passive collapsibility of the airway (Younes,2003).

An implication of these clinical data is that aninherently collapsible airway may allow for significantairway narrowing and even obstruction in sleep, but anysubsequent repetitive cycling behaviour in airwaypatency and ventilation is critically dependent upon

neuro-chemical control mechanisms. What is not knownfrom these reports in long-standing OSA patients is theextent to which their predisposition towards instability inneural control is inborn and/or is exacerbated by chronicintermittent hypoxia – a well-known cause of increasedcarotid chemoreceptor gain and CNS neuro-transmitterturnover (Ling et al. 2001; Peng et al. 2001).

In addition to these clinical examples outlinedabove, there are many experimentally documented linksbetween respiratory neural control and airway patency.First, unstable oscillations in respiratory motor outputproduced in sleep during the transition from normoxiato hypoxia (and from steady-state hypoxia to normoxia)will cause airway obstruction which occurs at the nadirof the cycling respiratory motor output (Warner et al.1987). Likewise, in OSA patients the nadir of upperairway muscle EMG activity coincides with the onset ofairway obstruction (Suratt et al. 1985). We emphasizethat an oscillating respiratory motor output precipitatedby transient hypoxia caused airway obstruction duringperiods of low respiratory motor output only in thosesubjects who had upper airways that were highly compliantand already narrowed prior to the induction of anoscillating respiratory drive (e.g. a snorer with an airwayresistance (Rua) of 20–50 cmH2O l−1 s−1 during sleep).However, even in these subjects, if the hypoxia wascontinued for several minutes leading to full-blown,cluster-type periodic breathing, airway obstruction did notpersist. On the contrary, upon re-initiation of breathingrhythm at the termination of each apnoea, inspiratorymotor 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 (plusarousal)-driven inspiratory motor output upon apnoeacessation must include marked and near-simultaneousactivation of both pharyngeal dilator and inspiratorypump muscles.

Second, bronchoscopy performed during induced ornaturally occurring central apnoeas, revealed that upperairway obstruction occurs early (< 10 s) during the centralapnoeic period and even in the absence of inspiratoryefforts (Badr et al. 1995). Apparently, all so-called ‘central’apnoeas have an ‘obstructive’ airway component, but thisis usually not detectable in the absence of inspiratoryeffort.

Third, obstructive apnoeas will precipitate centralapnoeas and oscillatory ventilation. For example, withairway obstruction, accumulation of chemoreceptorstimuli will cause ventilatory overshoots and hypocapnia,followed by central apnoea or hypopnoea (Iber et al. 1986).Transient arousals at apnoea termination are likely toenhance the magnitude of the overshoot and subsequentcycling. In addition, the mechanical events occurringin a narrowed or obstructed airway, such as negativepressure, pharyngeal tissue deformation and/or palatal



tissue vibration at high frequency (simulating snoring) areexcitatory to pharyngeal muscle activity but inhibitory torespiratory pump muscles (Eastwood et al. 1999). Thesedual reflex responses to airway pressures serve to preserveor restore airway patency (Brouillette & Thach, 1979) butalso act to reduce respiratory motor output to the pumpmuscles and will even cause central apnoea if the airwaypressure changes occur during the expiratory phase(Harms et al. 1996).

These many links between the stability of respiratorymotor output and airway resistance have implicationsfor both the diagnosis and treatment of OSA. Forexample, routine non-invasive polysomnography does notinclude independent, sensitive, measures of respiratorymotor output or effort; nor does it provide accurateassessment of airway calibre during an apnoea in theabsence of inspiratory effort (Kryger, 1994; Morrell et al.1995). Accordingly, reductions in central respiratory drivepreceding an obstruction or the prevalence of truly ‘mixed’(central plus obstructive) apnoeas are likely to be under-estimated. Future treatment of OSA may need to focuson both optimizing neural drive to the upper airwaymuscles and on preventing subsequent apnoeas andcycling by stabilizing respiratory motor output (Strohl,2003).

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Acknowledgements

Original research from the author’s laboratory reported inthis review was supported by NHLBI, the American HeartAssociation, and the Veterans Administration Merit Review. Weare indebted to Kathy Henderson and Ben Dempsey for technicalassistance.


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