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1John Rankin Laboratory of Pulmonary Medicine and Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin; and 2Laboratoire de Physiologie, Faculté de Médecine de Nancy, Université Henri Poincaré, Nancy France
Submitted 4 January 2007 ; accepted in final form 8 May 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal PCO2, 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155–164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep. hypocapnia; carbon dioxide reserve; carbon dioxide sensitivity; sleep-disordered breathing; non-rapid eye movement sleep
These latter data suggest that the hypocapnic-induced apneic threshold of the peripheral chemoreceptors is much more sensitive than that of the central chemoreceptors. However, both of these types of studies have major limitations, which preclude generalization of these findings to the intact sleeping animal or human. For example, carotid body denervation is known to markedly reduce baseline eupneic ventilation and cause CO2 retention (13, 33), to upregulate aortic chemoreceptors (4, 20, 29), to reduce the CO2 responsiveness of central chemoreceptors (16, 25, 38), to alter the response of central chemoreceptors to focal acidosis (18), and to decrease cytochrome oxidase activity in the pre-Bötzinger complex of neonatal rats (21), and it can alter responses to systemic hypoxia and cyanide in CO2-sensitive neurons in the retrotrapezoid nucleus (38).
A major advantage of the Berkenbosch et al. (3) study cited above was that peripheral chemoreceptors were intact. However, their animals were also anesthetized and to maintain ventilatory output as brain perfusate PCO2 was lowered, peripheral chemoreceptors had to be stimulated by maintaining systemic PaCO2 >50 Torr and arterial PO2 (PaO2) <45 Torr. It is important, then, that the relative sensitivities of the two sets of chemoreceptors be quantified under physiological conditions in the intact, sleeping animal.
Accordingly, we tested our hypothesis that the central chemoreceptors are less sensitive than are the peripheral chemoreceptors to dynamic reductions in PaCO2 secondary to transient ventilatory overshoots in unanesthetized, carotid sinus-perfused dogs during normal sleep. In this preparation, the carotid chemoreceptors are intact and provide tonic input to the medulla but are unable to sense imposed changes in systemic PaCO2.
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METHODS |
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Chronic Instrumentation
Our preparation required two surgical procedures performed under general anesthesia and with strict sterile surgical techniques and appropriate postoperative analgesics and antibiotics. In the first procedure, a chronic tracheostomy was created, and a five-lead electroencephalogram-electrooculogram montage was installed. Electroencephalogram leads were tunneled subcutaneously to the cephalad portion of the dog's back where they were exteriorized.
In the second procedure, the left carotid body was denervated and the right carotid sinus was equipped with a vascular occluder and catheter to permit extracorporeal perfusion of the reversibly isolated carotid sinus-carotid body (see below). Indwelling catheters were also placed in the abdominal aorta and abdominal vena cava via branches of the femoral artery and vein, respectively. Catheters were tunneled subcutaneously to the cephalad portion of the dog's back where they were exteriorized. Dogs recovered for at least 4 days before study.
Carotid Body Perfusion
Dogs lay unrestrained on a bed in an air-conditioned, sound-attenuated chamber. The extracorporeal perfusion circuit was primed with 
700 ml of saline, 120 ml of allogenic blood, and 5,000 U of heparin (derived from beef lung), and it was supplemented with 2,500 U/h. PCO2, PO2, and pH in the perfusion circuit were matched to a given dog's eupneic values by adjustment of the gas concentrations supplying the circuit and by addition of NaHCO3. The carotid sinus region was perfused at flow rates <100 ml/min, which raised the pressure in the sinus region by <10 Torr. Before data acquisition, a 30-min period of normal perfusion of the carotid sinus region was used to ensure uniformity between systemic and extracorporeal circuit blood. Intravenous boluses of NaCN (20 mg/kg) were used to confirm isolation of the carotid sinus during perfusion and also served to confirm denervation of the contralateral carotid body. These techniques have been described in detail in previous publications (8, 35, 37).
Use of unilateral carotid body denervation. Our method of carotid body perfusion does require unilateral carotid body denervation on the nonperfused side. Although the potential effect on the central ventilatory control system mentioned in the introduction is a concern, we think it is probably not significant. There is evidence using this preparation in both the goat (6) and the dog (37) showing that unilateral carotid body denervation has little effect on ventilation during control, air-breathing conditions or on ventilatory responses. Apparently, there is sufficient redundancy in the control system to compensate for the loss of one carotid body.
Experimental Setup and Measurements
The dogs breathed via an endotracheal tube inserted into the chronic tracheostomy. Airflow was measured with a heated pneumotachograph system (model 3700, Hans Rudolph, Kansas City, MO; model MP-45-14-871, Validyne, Northridge, CA) connected to the endotracheal tube. The pneumotachograph was calibrated before each study with four known flows. One-milliliter arterial or perfusion circuit samples were analyzed for pH, PO2, and PCO2 on a blood-gas analyzer (model ABL-505, Radiometer, Copenhagen, Denmark). The blood-gas analyzer was validated daily with dog blood tonometered with three different combinations of PO2 and PCO2 covering the range encountered in the experiments. Samples were corrected for both body temperature and systematic errors revealed by tonometry. Ventilation and blood pressure signals were digitized (128-Hz sampling frequency) and stored on the hard disk of a personal computer for subsequent analysis. Key signals were also recorded continuously on a polygraph (model K2G, AstroMed). All ventilatory data were analyzed on a breath-by-breath basis by means of custom analysis software developed in our laboratory.
Experimental Protocols
When the dogs achieved NREM sleep based on electroencephalogram criteria, the apneic threshold was determined by means of multiple trials of pressure support ventilation (PSV; see below). Any trials in which sleep state changed [arousal or rapid eye movement (REM) sleep] were excluded from analysis. These apneic threshold determinations were performed in the nonperfused state such that both central and peripheral chemoreceptors could sense the imposed hypocapnia ("central + peripheral") and, on a different day(s), after a stable carotid sinus perfusion status had been achieved with normocapnic and normoxic blood such that the carotid bodies could not sense the imposed hypocapnia ("central only").
Use of PSV to Define the Apneic Threshold
Dogs breathed room air spontaneously through the open port in the balloon valve (see Measurements). PSV was provided by means of a Hamilton Veolar ventilator (Hamilton Medical, Rhazuns, Switzerland). The ventilator was set in the pressure support mode and the trigger sensitivity was set as low as possible (approximately –1.5 cmH2O) and the expiratory positive airway pressure was set at 0 cmH2O. The gas supplied by the ventilator was ambient air (inspired O2 fraction 0.21). When the balloon was inflated and the low-resistance shunt to the room sealed, the ventilator delivered preset levels of inspiratory pressure support whenever the trigger threshold was reached [i.e., the dog set its own frequency; increased pressure support resulted in increased tidal volume (VT)]. Each pressure support level was maintained for 2 min, and then the balloon was deflated and the dog was allowed to breathe spontaneously again. At least 2 min elapsed before another PSV trial was performed. PSV was varied randomly over a range of 2–20 cmH2O. TE was measured from the end of the inspiratory flow to the onset of the next inspiration.
Under control conditions (in which the carotid chemoreceptors were not isolated, i.e., central + peripheral) the apneic threshold was defined as the end-tidal PCO2 (PETCO2) obtained in the breath immediately preceding the first apneic breath. This was defined as a breath with TE prolonged to >3 SDs beyond the eupneic control TE. In addition, to make our approach more conservative, we further required that this apnea was followed by at least three cycles of alternating hyperpnea and apnea with a consistent cycle length and that the first apnea had to occur <60 s after the initiation of PSV (i.e., hypocapnia).
Under conditions in which the carotid chemoreceptor was isolated, perfused, and with normal blood gases and pH maintained at normal sleeping eupneic levels (i.e., central only), periodic breathing was never observed. Thus, during carotid sinus perfusion, to determine the effect of hypocapnia on TE, we chose the longest TE that occurred in the 20th–60th s following the onset of PSV. We then associated the chosen TE with the lowest PETCO2 observed in this interval that also preceded the longest TE. The first 20 s following the initiation of PSV were excluded from analysis. Thus each trial provided one TE value and a corresponding PETCO2 value. For each dog, we then regressed the 
TE (i.e., longest TE minus mean baseline TE) on the change in PETCO2 (PETCO2) using an exponential function model (5–17 trials, i.e., 5–17 points, per dog). Our intent was to estimate the CO2 reserve by determining the point at which the regression line crossed the TE value observed in the trial used for CO2 reserve determination in the central + peripheral condition (but see RESULTS).
Interpreting the "CO2 Reserve"
We have termed the difference between the eupneic baseline PETCO2 and the PETCO2 at the apneic threshold the CO2 reserve. The CO2 reserve so defined is an index of the propensity for instability at the prevailing eupneic ventilatory drive. It is the result of two factors, namely the gain of the ventilatory response to CO2 below eupnea and the "plant gain" [change in PaCO2/change in alveolar ventilation (PaCO2/
A)] as determined under the prevailing eupneic conditions {i.e., by the point of intersection of PaCO2 with A along a given isometabolic line defined by the alveolar ventilation equation: PaCO2 = [(CO2/A)]·k; where CO2 is CO2 output and k is a constant} (10) (see also DISCUSSION).
Statistics
Statistical comparison were made using the paired t-test with a significance level of P 
0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The effect of extracorporeal perfusion of the carotid chemoreceptors on eupneic ventilation is shown in Tables 1 and 2. Perfusion of the vascularly isolated carotid sinus (and therefore the carotid chemoreceptors) with normocapnic, normoxic, and normohydric blood had no systematic effect on arterial blood gases or minute ventilation, although there were some random changes in VT and breathing frequency in two of the animals. These data show a lack of a systematic effect of carotid body perfusion, per se, and are consistent with our laboratory's previous findings in larger numbers of awake and sleeping dogs undergoing carotid sinus perfusion (8, 37).
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Figure 1, A–C, shows representative examples in all three dogs of the effects of several trials of PSV during NREM sleep on the apneic threshold and the CO2 reserve under control conditions with no exogenous carotid body perfusion (i.e., central + peripheral). We performed a total of 39 trials in this condition in the 3 dogs. In nine of these trials, the PETCO2 was reduced <4.3 Torr, and periodic breathing did not occur in any of these trials, although isolated, prolonged TE values were noted in about half of the trials. In all central + peripheral trials with >4.3- to 4.7-Torr decreases in PETCO2, produced by 9 to 13 cmH2O of PSV, clear apnea and periodicity developed (middle panels). Apneas were longer and periodicity became more marked as hypocapnia became more severe (bottom panels). We completed a total of 29 central + peripheral trials in all 3 dogs with a decrease in PETCO2 of >4.3 Torr. In 27 of these 29 trials, significant TE prolongation occurred (11 of 13, 7 of 7, and 9 of 9 trials in dogs B, C, and D, respectively). In 20 of the 29 trials clear periodic breathing ensued (8 of 13, 7 of 7, and 5 of 9 trials in dogs B, C, and D, respectively). The latency to significant TE prolongation occurred on average at 14.2, 16.4, and 17.7 s following the decreases in PETCO2 caused by PSV for dogs B, C, and D, respectively.
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PETCO2 exceeded 4.3 Torr for 2 min. Furthermore, in the seven trials in which TE was significantly prolonged the prolongations differed in three important respects from those in the central + peripheral trials. 1) On average, the latencies were twofold longer in the Central only condition (36.8 ± 11.8 s) and in three of the seven trials latencies were >45 s. 2) The lengths of the TE prolongations for any given reduction of PETCO2 were less than half those observed in the central + peripheral condition (also see Fig. 2). 3) There was no clear stimulus-response relation between TE prolongation and decreases in PETCO2 in the central only condition.
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4.3–4.7 Torr. During central only conditions, no consistent TE prolongation-PETCO2 relationship was detected despite PETCO2 of up to 12 Torr, and the magnitudes of TE prolongations did not approach those observed in the central + peripheral condition for any given PETCO2 when the PETCO2 was >4.3 Torr.
The mean values for eupneic PETCO2 and the apneic threshold PCO2 are shown for each of the three dogs in Fig. 3. Note that the CO2 reserve, i.e., the PETCO2 below eupnea required to cause apnea, ranges between 4.3 and 4.7 Torr in the three dogs studied under central + peripheral conditions. In contrast, when the carotid chemoreceptors were not involved in sensing transient reductions of PETCO2 during PSV, the CO2 reserve was increased substantially; in fact, we were unable to increase PSV and lower the PETCO2 sufficiently to determine a clear apneic threshold without arousal even when the PSV-induced hypocapnia was maintained for >90 s (also see Fig. 1).
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During PSV, breath timing may be influenced by both the reduction in PaCO2 as well as by the mechanical feedback associated with an increase in VT. The latter so-called neuromechanical effect is reflected in the first breath of PSV, i.e., before the effects of hypocapnia are sensed by the peripheral chemoreceptors (see Fig. 1).
The first breath of PSV tended to prolong the TE of the first breath for all dogs in the central + peripheral condition by 10.8 ± 1.5% relative to control TE. Similarly, the first breath of PSV tended to prolong TE for all dogs in the central only condition by 9.9 ± 1% relative to control TE. These "nonchemical" effects of PSV on TE were always substantially less than the two- to fourfold prolongation of TE observed when PETCO2 was reduced for a few breaths and the apneic threshold was reached. These findings are consistent with the significant but relatively small effects of PSV per se reported by Nakayama et al. (27), who raised the inspired CO2 fraction to prevent hypocapnia during PSV.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Cerebral Blood Flow
The hypocapnia that accompanied PSV may well have caused transient reductions in cerebral blood flow, which in turn would have decreased the fall in brain PCO2 relative to that in PaCO2. The majority of the literature does not support a role for carotid body chemoreceptor stimulation affecting cerebral blood flow (1, 17, 19, 32). Accordingly, we do not believe that these hypocapnia-induced decreases in cerebral blood flow would affect our conclusions because we expect this effect to be similar whether the carotid body was or was not held normocapnic.
Determining the Peripheral and Central Chemoreceptor Apneic Threshold in Intact and Carotid Body-Denervated Experimental Models
Our present findings in the intact, isolated, and perfused carotid chemoreceptor model are consistent with the increase in CO2 reserve our laboratory previously reported in the carotid body-denervated animal (26). We compare the results from these two preparations in Fig. 4. In the denervated dog, eupneic PaCO2 was elevated significantly (+5.6 to +11.2 Torr eupneic PaCO2). However, in response to transient reductions in PETCO2 via varying levels of PSV, we also found that the CO2 reserve was markedly widened in the carotid body-denervated dogs (26). This widening of the CO2 reserve occurred despite a significantly elevated eupneic PaCO2, which, by itself, would have increased plant gain and markedly reduced the CO2 reserve and rendered the animal much more susceptible (not less susceptible as observed) to ventilatory instability and apnea (see section below on loop gain).
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In the central only intact dogs of the present study, even when significant TE prolongations were noted they differed in latency and pattern relative to prolonged TE values observed in central + peripheral conditions. Specifically, TE prolongations in the central only condition were much shorter for any given reduction in PETCO2 than in the central + peripheral condition and a clear stimulus-response relationship of PETCO2 to TE was not obvious. Latencies from the onset of hypocapnia to TE prolongation were longer in the central only, as would be expected, but they were also more variable. In some instances, the latencies were >45 s, a much longer latency than one would predict for central CO2 chemoreception based on our laboratory's previous work in the same isolated and perfused carotid sinus model in the sleeping dog (36). In these studies, step increases in PETCO2 were used to determine that ventilatory response latencies for central chemoreception averaged 30.9 ± 8.8 s. Accordingly, we speculate that at least some of the TE prolongations we observed in the central only condition may have been random events not specifically attributable to hypocapnia such as one encounters in any long run of breathing and unrelated to central chemoreception. We propose that periodic breathing requires the carotid chemoreceptors to be exposed to the transient reduction in PaCO2 induced by the ventilatory overshoot. Finally, our findings are also consistent with the markedly depressed apneic threshold (<10 Torr PaCO2) reported in the intact, anesthetized cat whose "central" PCO2 was reduced via isolated pontomedullary perfusion at the same time as breathing rhythm was maintained by a high systemic PaCO2 and low PaO2 (3) (also see the introduction).
Peripheral vs. Central Chemoreceptor Loop Gain and Apnea Susceptibility
According to control system theory, overall loop gain determines ventilatory stability. In turn loop gain is determined by the product of controller gain (conventionally defined by the CO2 response slope above eupnea) and plant gain, which is critically dependent on the position of eupneic PaCO2 on the isometabolic line relating A to alveolar PCO2. Figure 5 is a theoretical representation of how differences in controller gain below eupnea can be affected by whether or not both peripheral and central chemoreceptors or central chemoreceptors alone sense the hypocapnia resulting from a ventilatory overshoot. Note the marked decrease (down to at most 58% of control; see RESULTS) in the PETCO2/A response slope (i.e., controller gain) when only the central chemoreceptors can sense the transient hypocapnia. In the absence of any change in plant gain, this change in controller gain accounts for the entire reduction in apneic threshold that we observed for the central only condition.
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There are many types of interactive effects that may be required to cause cessation of respiratory rhythm, at least in the physiological preparation. These likely include non-chemical inhibitory inputs in addition to those from chemoreceptors and may also involve communication between the peripheral and central chemoreceptors themselves.
The data from the central + peripheral and central only sleeping dog (Fig. 1) clearly show that carotid chemoreceptor hypocapnia was required for the apnea that normally follows a transient ventilatory overshoot in NREM sleep. However, when the isolated carotid chemoreceptors were made progressively hypocapnic (or hyperoxic) in the sleeping dog, VT was reduced but apnea did not occur (35). Accordingly, we have speculated that an interactive effect between carotid body hypocapnia and lung stretch are required to cause apnea, and this proposal is supported by two kinds of evidence. First Mitchell and colleagues (22–24), using an isolated in situ lung preparation in the decerebrate dog to independently manipulate blood gasses and lung stretch, have demonstrated that increased PaCO2 reduced the slope of the relationship between TE and airway pressure; i.e., lower PaCO2 promoted longer TE at any given airway pressure or lung stretch. Second, an interaction between carotid chemoreceptor afferents and pulmonary stretch receptor afferents has also been demonstrated to influence neuronal activity in the dorsal respiratory group and ventral respiratory group neurons of anesthetized dogs (2).
Our present findings distinguish central from peripheral chemoreceptor CO2 sensitivity by showing that cerebral hypocapnia and, presumably, the central chemoreceptors by themselves are not significant contributors to the apnea attending a ventilatory overshoot. We propose two potential explanations for this apparent insensitivity. One possibility, as reported by Fukuda et al. (14), is that neural discharge from CO2-sensitive medullary neurons on the ventral surface persisted even when the pH in the medium perfusing the brain slice was raised >7.6. This finding is controversial however, as Guyenet et al. (15) and Mulkey et al. (25) reported that CO2 sensitive medullary neurons in the retrotrapezoid nucleus stopped discharging when the PETCO2 was reduced below 30 Torr and arterial pH exceeded 7.5. An alternative explanation is that, unlike the interaction proposed for the peripheral chemoreceptors (see above), the central chemoreceptor input to the rhythm generator does not interact sufficiently with additional nonchemical inhibitory inputs that accompany the ventilatory overshoot (such as lung stretch) to cause a complete cessation of respiratory rhythm.
Finally, we should point out that it may not be entirely appropriate to attempt to completely separate out the relative contributions from peripheral and central chemoreceptors to ventilatory control in the intact animal. Indeed, the recent findings of Guyenet et al. (15) and Takakura et al. (38) in the anesthetized rat show that CO2-sensitive neurons in the retrotrapezoid nucleus increased their activity in response to systemic hypoxia or sodium cyanide and that this increased activity no longer occurred when the carotid bodies were denervated. Given this demonstration of a direct neural link between peripheral and putative central chemoreceptors, it is feasible that when PaCO2 is reduced during a transient ventilatory overshoot and peripheral chemoreceptors are inhibited, inhibition of the central chemoreceptors may have also occurred nearly simultaneously. Theoretically, then, both chemoreceptor sites are likely to contribute to some degree to the ensuing apnea. A caveat to this proposal is the observation that systemic effects of hypercapnia (as opposed to hypoxia or sodium cyanide; see above) on the retrotrapezoid nucleus CO2 sensitive neurons was not influenced by the absence of peripheral chemoreceptors (38).
Implications for Sleep Apnea
The findings of the present study together with previous work from our laboratory have established the preeminent role of the carotid body chemoreceptors in initiating apnea following ventilatory overshoots within the time interval observed in essentially all types of unstable/periodic breathing in sleep. We have shown that the carotid body chemoreceptors possess the characteristics required to initiate apnea quickly following a ventilatory overshoot, namely: 1) marked attenuation of VT when exposed to carotid-body specific hypocapnia (37); 2) a quick response to increases or decreases in PaCO2 (36); 3) a high response gain to reductions in PaCO2 below eupnea that are achieved during transient hyperventilation (Fig. 5). Accordingly, carotid bodies were shown to be required to initiate apnea in the time interval encountered in naturally occurring sleep apnea following a ventilatory overshoot and decreased PaCO2 (26).
These same characteristics might also indicate a role for the carotid body chemoreceptors in the cycling of ventilatory overshoots and undershoots observed in many forms of periodic breathing such as those that occur during sleep in congestive heart failure; in hypoxia; and in central, obstructive, or mixed sleep apnea. For example, they probably play a role in the ventilatory overshoot that inevitably follows apnea/hypopnea not only because of their rapid response and high gain but because they are also the site of hypoxic/hypercapnic interaction (9) and therefore would provide a substantial ventilatory overshoot in response to asphyxic stimuli present during periods of apnea or hypoventilation.
Our findings should not be construed to mean that there is no role for the central chemoreceptors in unstable/periodic breathing during sleep. The central chemoreceptors remain the major CO2/H+ chemoreceptor in the steady state. Once an apnea is initiated the delay or phase lag between the peripheral and central CO2 responses (36) could contribute to prolongation of the apnea and a subsequent additional increase in asphyxic stimuli which, in conjunction with interactive effects at the carotid body, could promote a ventilatory overshoot and repeating episodes of unstable/periodic breathing.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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