We analyzed breath-to-breath inspiratory time (TI), expiratory time (TE), inspiratory volume (VI), and minute ventilation (Vm) from 11 normal subjects during stage 2 sleep. The analysis consisted of 1) fitting first- and second-order autoregressive models (AR1 and AR2) and 2) obtaining the power spectra of the data by fast-Fourier transform. For the AR2 model, the only coefficients that were statistically different from zero were the average alpha 1 (a1) for TI, VI, and Vm (a1 = 0.19, 0.29, and 0.15, respectively). However, the power spectra of all parameters often exhibited peaks at low frequency (less than 0.2 cycles/breath) and/or at high frequency (greater than 0.2 cycles/breath), indicative of periodic oscillations. After accounting for the corrupting effects of added oscillations on the a1 estimates, we conclude that 1) breath-to-breath fluctuations of VI, and to a lesser extent TI and Vm, exhibit a first-order autoregressive structure such that fluctuations of each breath are positively correlated with those of immediately preceding breaths and 2) the correlated components of variability in TE are mostly due to discrete high- and/or low-frequency oscillations with no underlying autoregressive structure. We propose that the autoregressive structure of VI, TI, and Vm during spontaneous breathing in stage 2 sleep may reflect either a central neural mechanism or the effects of noise in respiratory chemical feedback loops; the presence of low-frequency oscillations, seen more often in Vm, suggests possible instability in the chemical feedback loops. Mechanisms of high-frequency periodicities, seen more often in TE, are unknown.

We tested the hypothesis that breath-to-breath variations in arterial CO2 partial pressure (PaCO2) during spontaneous breathing of awake humans cause a significant portion of spontaneous ventilatory variability (including periodic oscillations). This hypothesis was tested in two ways. First, using a recently developed adaptive PaCO2 buffering technique we reduced the spontaneous variability in PaCO2 of six awake normal young human subjects during hyperoxia and observed a corresponding decrease in their breath-to-breath ventilatory variations. Second, we predicted the ventilatory responses to CO2 disturbances by using a model of chemical control of ventilation, both examining the hyperoxic condition (similar to experimental studies) and predicting the responses to CO2 variations of a normal subject breathing room air. In all experimental and theoretical studies, we found that small random disturbances to PaCO2 have significant effects on ventilation, including the potential for such PaCO2 disturbances to elicit oscillatory fluctuations in ventilation even though the ventilatory chemical control system was stable (i.e., a brief disturbance to PaCO2 did not elicit sustained ventilatory oscillations). On the basis of these results we propose that the stability of chemoreflex ventilatory control loops depends on both "loop gain" factors and the characteristics of random disturbances to PaCO2.

Oscillatory ventilatory pattern occurs more frequently in sleep despite the stabilizing factor of sleep-induced reduction in CO2 chemosensitivity. In nine young normal humans, we have tested the hypothesis that, despite a sleep-induced reduction in chemosensitivity, the transient central chemoreceptor-mediated change inspiratory ventilation (VI) caused by a standardized disturbance to chemoreflex ventilatory control is similar in quiet sleep and wakefulness. The equivalent VI response to a single-breath hyperoxic hypercapnic stimulus (i.e., inhaling a single breath of 0.01 liter of CO2 in O2--a direct measure of "closed-loop" dynamic response) was determined using pseudorandom binary CO2 stimulation and the prediction-error method of transfer function estimation. From these data, the response of VI to a single-breath increase of 1 Torr in end-tidal PCO2 was also derived, from which "dynamic" central chemosensitivity was calculated. Despite a 43% reduction in dynamic central chemosensitivity, the peak and the area under the closed-loop VI response are similar in wakefulness and quiet sleep, whereas sleep increases the duration of the response by 48%. Thus hyperoxic ventilatory stability is not reduced in quiet sleep relative to wakefulness. We propose that changes in dynamics of pulmonary gas exchange in sleep substantially offset the decreased chemosensitivity, thereby maintaining the gains and time constants of the central chemoreceptor-mediated component of the closed-loop ventilatory control system similar to those during wakefulness.

It has often been assumed that under normoxia, closed-loop ventilatory responses to transient CO2 stimulation (i.e., lasting for 1-3 breaths) are less likely to be mediated by the slow-responding central (medullary) chemoreflex. This assumption, however, has not been quantitatively examined in humans. We hypothesized that in the closed-loop respiratory chemical feedback system [in which the centrally mediated ventilatory response to transient changes in the arterial PCO2 levels (PaCO2) will in turn affect the pulmonary CO2 and hence PaCO2], the contribution of the central chemoreflex pathways to brief disturbances in blood gases may be more important than considered previously. Using the technique of pseudorandom binary CO2 stimulation, we quantified the ventilatory response of normal humans to brief disturbances in arterial CO2 during hyperoxia. Tidal volume (VI), inspiratory ventilation (VI), inspiratory time (TI), expiratory time (TE), and end-tidal CO2 fraction (FETCO2) were measured in subjects who inhaled a mixture that was pseudorandomly switched between 95% O2-5% CO2 and 100% O2 (63 breath sequences). From these data, we calculated the responses of VI, VI, TI, TE, and FETCO2 to a single-breath inhalation of 1% CO2 in O2. Our results showed that in response to a brief increase of 0.75 Torr in alveolar CO2, VI showed a transient increase (average peak response of 0.12 1/min) that persisted for greater than or equal to 80 s in every subject. The response of VI was similar to that of VI, whereas TI and TE showed no consistent changes. Using these results we calculated that central chemoreflex pathways may contribute significantly to typical transient CO2 stimulation tests in hyperoxic and normoxic humans.

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