Search

We studied ventilatory responses to inspiratory flow-resistive loads in six trained dogs, during quiet wakefulness and non-rapid-eye-movement (NREM) sleep. During studies dogs lay quietly in a lateral position and breathed through an endotracheal tube inserted via a chronic tracheostomy. Linear resistances of 6, 10, 19, and 31 cmH2O X l-1 X s were applied during inspiration for only a single breath to assess the immediate ventilatory response. The highest resistance was also applied for five successive breaths to assess the progressive ventilatory response. Ventilatory responses to hyperoxic progressive hypercapnia were also examined, with and without flow-resistive loading. During loading the maintenance of constant states of quiet wakefulness and NREM sleep was confirmed by electroencephalographic monitoring. Ventilation decreased on the first loaded breath and returned to control in a stepwise manner by the fifth loaded breath. No state-related differences were observed in either the immediate or progressive ventilatory responses. During CO2 rebreathing, the slope of the ventilatory response to CO2 was reduced by loading, with the reduction in slope (as percent of control) greater in the NREM state. We therefore conclude that in the dog immediate and progressive ventilatory responses to resistive loads are unaffected by NREM sleep, whereas the decrease in ventilatory response to CO2 resulting from loading tends to be greater in NREM sleep than in quiet wakefulness.

We studied the effect of intermittent tidal breaths of CO2-enriched air (3-9% CO2) on the duration of expiratory time (TE) in five trained dogs, before and after (3 dogs) bilateral surgical denervation of the carotid bodies (CBD). During studies the dogs lay quietly, either awake or in nonrapid-eye-movement sleep, and breathed through a cuffed endotracheal tube inserted via a chronic tracheostomy. Studies were conducted during bilateral blockade of the cervical vagus nerves (VB), achieved by circulating cold alcohol through radiators placed around exteriorized vagal skin loops. Prior to CBD, single breaths of CO2 significantly shortened TE and thus advanced the onset of the subsequent inspiration. Further, the decrease in TE induced by the CO2 stimulus was in direct proportion to the inspired CO2 concentration. Thus 3% CO2 shortened TE by 1.82 +/- 0.93 (SD) s, and 9% CO2 by 3.44 +/- 1.53 s. Changes in TE occurred in the absence of associated changes in either tidal volume or inspiratory time. After CBD, test breaths of CO2 failed to shorten TE during VB. We conclude that the carotid bodies have the ability to mediate changes in the timing of inspiratory onset in response to a transient CO2 stimulus.

Respiratory responses to hypercapnia were studied in seven chronic in utero fetal lambs between 105 and 138 days' gestation (16 expts). Fetal arterial CO2 tension was raised (mean increase 9.9 Torr) by altering maternal inspired gas concentrations. Diaphragmatic electromyogram (EMG) was recorded as the index of respiratory activity. Electrocortical and electroocular activity (3 fetuses) were monitored in an attempt to define sleep state. Average respiratory rate increased (90%) and fetal apnea decreased (60%) during hypercapnia. Mean respiratory rate during "on" periods (greater than 6 EMG bursts/min) increased significantly during hypercapnia throughout the gestational epoch studied. Mean duration of the inspiratory time (TI) showed no significant change. Variability in both rate and TI decreased in response to CO2 at all gestations. Integrated EMG activity per burst divided by TI increased significantly at all gestations; however, no gestational increase in responsiveness to CO2 was seen. Sleep states were not able to be consistently identified, and a quantifiable electrocortical response to CO2 was not observed. These results indicate a relatively early functional maturation of fetal respiratory responses to CO2.

Respiratory activity (diaphragmatic electromyogram) was recorded in six unanesthetized in utero fetal lambs, between 0.7 of gestation and term. Respiratory patterns generated by the fetus showed developmental changes that included 1) an emergence of a periodic modulation of respiratory rate producing alternating active and quite phases (mean cycle length of 37 min between 130 and 140 days' gestation; 2) an increase in percentage apnea (expiratory time greater than 10 s) from 20% at 110 days to 60% at 140 days; and 3) a linear decrease in the 2-h average respiratory rate, while mean rate during active phases showed no consistent gestational decline. Electrocortical and electroocular activity was monitored in three of six fetuses; however, discrete sleep state patterns could not be consistently identified. The results demonstrate a gestational change in the respiratory patterns of the developing fetus and suggest an orderly maturation of the mechanisms controlling respiratory neuronal output.

We examined the role of metabolic CO2 production in the hyperpnea of muscular exercise by comparing the response of alveolar ventilation to moderate levels of exercise with the response to venous infusion of CO2 at rest. Studies were performed in four awake sheep that were trained to run on a treadmill. The sheep had been cannulated for veno-venous extracorporeal perfusion so that CO2 could be infused into the peripheral venous blood through membrane lungs in the perfusion circuit. The sheep breathed room air through an endo-tracheal tube inserted through a tracheostomy, and samples of expired gas were collected for measurement of the rates of CO2 production and O2 consumption. All measurements were made in the steady state. In each of the four sheep, the relationship between alveolar ventilation and the rate of CO2 production could be described by a single linear function (r greater than 0.99; P less than 0.001), regardless of whether CO2 production was increased by exercise, venous CO2 infusion, or combinations of both procedures. This relationship applied for values of CO2 production up to 350% of control. In contrast, no unique relationship was found between the rate of alveolar ventilation and either the rate of O2 consumption, cardiac output, or mixed venous blood gas pressures. The findings indicate that the hyperpnea of mild to moderate steady-state exercise can be attributed to the associated increase in the rate of CO2 production. Therefore, there is no need to invoke obligatory nonmetabolic stimuli to account for the ventilatory response to steady-state exercise.

We studied the effects of sleep fragmentation on arousal and ventilatory responses to hyperoxic hypercapnia, isocapnic hypoxia, and chemical stimulation of the larynx during sleep in 5 dogs. Sleep fragmentation was induced by repeatedly arousing the dogs with acoustic stimuli throughout 2 to 3 consecutive nights. Responses to respiratory stimuli were then studied during a subsequent daytime sleep. Arterial O2 saturation was measured with an ear oximeter, and sleep stage was determined by electroencephalographic and behavioral criteria. Hypercapnic and hypoxic ventilatory responses were unimpaired by sleep fragmentation. In contrast, alveolar PCO2 levels at arousal increased after sleep fragmentation, from a mean +/- SEM of 52.2 +/- 1.4 mm Hg to 55.6 +/- 1.5 mm Hg (p < 0.05) during slow-wave sleep, and from 57.9 +/- 1.5 mm Hg to 61.3 +/- 2.2 mm Hg (p < 0.05) during rapid-eye movement sleep. Similarly, arterial O2 saturation at arousal decreased after sleep fragmentation from 80.1 +/- 1.0% to 70.2 +/- 2.7% (p < 0.05) during slow-wave sleep, and from 66.3 +/- 3.6% to < 55% (p < 0.05) during rapid-eye-movement sleep. Arousal responses to laryngeal stimulation were also impaired after sleep fragmentation. We conclude that arousal responses to respiratory stimuli are decreased by sleep fragmentation.

We examined the role of the carotid chemoreceptors in the ventilatory response to changes in venous CO2 load in 12 awake sheep using a venovenous extracorporeal perfusion circuit and two carbon dioxide membrane lungs (CDML). Three of the sheep had undergone surgical denervation of the carotid bodies (CBD). In the nine intact sheep, as CO2 was removed from or added to the peripheral venous blood through the CDML under normoxic conditions, there was a linear relationship between the rate of pulmonary CO2 excretion (VCO2) and the resulting rate of ventilation over a VCO2 range of 0--800% of control, so that arterial PCO2 remained close to isocapnic. In contrast, in the three CBD sheep, the ventilatory response to changes in VCO2 was significantly decreased under normoxic conditions, resulting in marked hypercapnia. The results indicate that the carotid chemoreceptors exert a major influence on the ventilatory response to changes in venous CO2 load.

Previous reports indicate that apnea is induced by high frequency ventilation (HFV) in anesthetized animals. We have studied conscious dogs ventilated with HFV during sleep and wakefulness to determine if this apnea is state related. Eucapnic apnea or very low breathing frequencies were observed during quiet wakefulness, quiet sleep and tonic REM sleep. However, spontaneous breathing at nearly normal rates was invariably seen during phasic REM sleep. We conclude that HFV as administered induces apnea or near apnea in conscious animals and that the inhibitory pathways causing this apnea are probably disabled during phasic REM sleep.

The ability to detect added inspiratory flow-resistive loads during wakefulness was examined in 5 men with laboratory-documented obstructive sleep apnea. The patients were eucapnic, and standard measurements of lung volumes and flow rates were within the normal range. The patients breathed through a circuit, to which each of 5 flow resistances of 0.12 to 5.5 cm H2O/L/s was added at 20- to 30-s intervals for 1 inspiration, following a cue. Each resistance was presented 10 times in random sequence, and the percentage of trials in which each load was detected by the patient was calculated. The threshold level of load detection, defined as the change in resistance that could be detected 50% of the time, was higher in the patients (2.37 +/- 0.41 cmH2O/L/s, mean +/- SE) than in 9 healthy subjects (0.65 +/- 0.08; p less than 0.001), and this difference persisted when the threshold load was corrected for background resistance (1.05 +/- 0.11 versus 0.45 +/- 0.07; p less than 0.001). In addition, the ventilatory response to hypercapnia was less in the patients (1.82 +/- 0.22 L/min/mm Hg) than in the normal subjects (3.87 +/- 0.40; p less than 0.005), and there was a significant negative correlation (r = 0.97; p less than 0.001) between the load detection threshold and the ventilatory response to CO2. The results add to the developing concept that subtle defects in respiratory control can be demonstrated even during wakefulness in eucapnic patients with obstructive sleep apnea.

We studied the effect of an experimentally augmented breath on the duration of expiration (TE) to test the hypothesis that within-breath reductions in alveolar partial pressure of CO2 (PACO2) delay the onset of the subsequent inspiration through a carotid chemoreceptor mechanism. Studies were performed in five carotid body intact (CBI) and three carotid body denervated (CBD) dogs during quiet wakefulness and nonrapid-eye-movement sleep. The vagus nerves were blocked in order to abolish vagal mechanisms capable of modulating TE. In CBI dogs, mechanically augmented breaths [mean tidal volume (VT), 149% of control] induced a mean decrease in PACO2 of 3.3 Torr and prolonged TE by 2.21 s to 127% of control (P less than 0.001). In contrast, in CBD dogs augmented breaths of comparable magnitude failed to change TE. Spontaneous sighs in fully intact dogs (mean VT, 369% of control) produced marked prolongation of TE (to 429% of control). In CBI dogs, there was a direct relationship between VT and the resulting TE across all experimental conditions (control, vagal blockade, augmented breaths, spontaneous sighs), whereas in CBD dogs, changes in VT failed to alter TE. The results indicate that the carotid bodies are able to induce within-breath alterations in TE and that such a mechanism can account for the prolongation of TE by vagal blockade and by spontaneous sighs.