Chemical and mechanical determinants of apnea during high-frequency ventilation

The factors responsible for the apnea observed during high-frequency ventilation (HFV) were evaluated in 14 pentobarbital sodium-anesthetized cats. A multiple logistic regression analysis provided an estimate of the probability of apnea during HFV as a function of four respiratory variables: mean airway pressure (Paw), tidal volume (VT), frequency, and arterial PCO2 (PaCO2). When mean Paw was 2 cmH2O, PaCO2, VT, and their interaction contributed significantly to the probability of apnea during HFV. At a low value of PaCO2 (25 Torr), the probability of apnea had a minimum value of 0.19 and gradually increased toward 1.0 as VT increased from 0.5 to 7 ml/kg. At higher levels of PaCO2 (30 and 35 Torr) the probability of apnea was zero in the low range of VT but sharply approached 1.0 above a VT of approximately 2.0 ml/kg. However, when Paw was increased to 6 cmH2O, only PaCO2 was an important determinant of apnea. In this case, the probability of apnea was 0.51 when PaCO2 was 25 Torr but decreased to 0.22 when PaCO2 was raised to 25 Torr. At neither Paw was the probability of apnea dependent on frequency. These results suggest that chemoreceptor inputs, in addition to both static and dynamic lung mechanoreceptor afferents, are responsible for determining the output of the central respiratory centers during HFV.     

Maturation of steady-state CO2 sensitivity in vagotomized anesthetized lambs.

The maturation of the respiratory sensitivity to CO2 was studied in three groups of anesthetized (ketamine, acepromazine) lambs 2-3, 14-16, and 21-22 days old. The lambs were tracheostomized, vagotomized, paralyzed, and ventilated with 100% O2. Phrenic nerve activity served as the measure of respiration. The lambs were hyperventilated to apneic threshold, and end-tidal PCO2 was raised in 0.5% steps for 5-7 min each to a maximum 7-8% and then decreased in similar steps to apneic threshold. The sinus nerves were cut, and the CO2 test procedure was repeated. Phrenic activity during the last 2 min of every step change was analyzed. The CO2 sensitivity before and after sinus nerve section was determined as change in percent minute phrenic output per Torr change in arterial PCO2 from apneic threshold. Mean apneic thresholds (arterial PCO2) were not significantly different among the groups: 34.8 +/- 2.08, 32.7 +/- 2.08, and 34.7 +/- 2.25 (SE) Torr for 2- to 3-, 14- to 16-, and 21- to 22-day-old lambs, respectively. After sinus denervation, apneic thresholds were raised in all groups [39.9 +/- 2.08, 40.9 +/- 2.08, and 45.3 +/- 2.25 (SE) Torr, respectively] but were not different from each other. CO2 response slopes did not change with age before or after sinus nerve section. We conclude that carotid bodies contribute to the CO2 response during hyperoxia by affecting the apneic threshold but do not affect the steady-state CO2 sensitivity and the central chemoreceptors are functionally mature shortly after birth.     

Effects of mean airway pressure on gas transport during high-frequency ventilation in dogs

In 10 anesthetized, paralyzed, supine dogs, arterial blood gases and CO2 production (VCO2) were measured after 10-min runs of high-frequency ventilation (HFV) at three levels of mean airway pressure (Paw) (0, 5, and 10 cmH2O). HFV was delivered at frequencies (f) of 3, 6, and 9 Hz with a ventilator that generated known tidal volumes (VT) independent of respiratory system impedance. At each f, VT was adjusted at Paw of 0 cmH2O to obtain a eucapnia. As Paw was increased to 5 and 10 cmH2O, arterial PCO2 (PaCO2) increased and arterial PO2 (PaO2) decreased monotonically and significantly. The effect of Paw on PaCO2 and PaO2 was the same at 3, 6, and 9 Hz. Alveolar ventilation (VA), calculated from VCO2 and PaCO2, significantly decreased by 22.7 +/- 2.6 and 40.1 +/- 2.6% after Paw was increased to 5 and 10 cmH2O, respectively. By taking into account the changes in anatomic dead space (VD) with lung volume, VA at different levels of Paw fits the gas transport relationship for HFV derived previously: VA = 0.13 (VT/VD)1.2 VTf (J. Appl. Physiol. 60: 1025-1030, 1986). We conclude that increasing Paw and lung volume significantly decreases gas transport during HFV and that this effect is due to the concomitant increase of the volume of conducting airways.     

Triangularis sterni and phrenic nerve responses to progressive brain hypoxia.

Activity of the respiratory muscles that are not normally active during eupnea (genioglossal and abdominal) has been shown to be more vulnerable to hypoxic depression than inspiratory diaphragmatic activity. We hypothesized that respiratory muscles that are active at eupnea would be equally vulnerable to isocapnic progressive brain hypoxia (PBH). Phrenic (PHR) and triangularis sterni nerve (TSN) activity were recorded in anesthetized peripherally chemodenervated vagotomized ventilated cats. Hypercapnia [arterial PCO2 (PaCO2) = 57 +/- 3 (SE) Torr] produced parallel increases in peak PHR and TSN activity. PBH [0.5% CO-40% O2-59.5% N2, arterial O2 content (CaO2) reduced from 13.1 +/- 1.0 to 3.7 +/- 0.3 vol%] resulted in parallel decreases of peak PHR and TSN activity to neural apnea. PBH was continued until PHR gasping ensued (CaO2 = 2.9 +/- 0.2 vol%); TSN activity remained silent during gasping. After 6-12 min of recovery (95% O2-5% CO2; CaO2 = 7.8 +/- 0.8 vol%; PaCO2 = 55 +/- 2 Torr), peak PHR activity was increased to 110 +/- 18% (% of activity at 9% CO2) whereas peak TSN activity was augmented to 269 +/- 89%. The greater augmentation of TSN activity during the recovery period could not be explained solely by hypercapnia. In conclusion, we found that 1) TSN expiratory and PHR inspiratory activities are equally vulnerable to hypoxic depression and 2) recovery from severe hypoxia is characterized by a profound augmentation of TSN expiratory activity.     

Effects of respiratory drive on upper airways in sleep apnea patients and normal subjects

We compared the changes in nasal and pharyngeal resistance induced by modifications in the central respiratory drive in 8 patients with sleep apnea syndrome (SAS) with the results of 10 normal men. Upper airway pressures were measured with two low-bias flow catheters; one was placed at the tip of the epiglottis and the other above the uvula. Nasal and pharyngeal resistances were calculated at isoflow. During CO2 rebreathing and during the 2 min after maximal voluntary hyperventilation, we continuously recorded upper airway pressures, airflow, end-tidal CO2, and the mean inspiratory flow (VT/TI); inspiratory pressure generated at 0.1 s after the onset of inspiration (P0.1) was measured every 15-20 s. In both groups upper airway resistance decreased as P0.1 increased during CO2 rebreathing. When P0.1 increased by 500%, pharyngeal resistance decreased to 17.8 +/- 3.1% of base-line values in SAS patients and to 34.9 +/- 3.4% in normal subjects (mean +/- SE). During the posthyperventilation period the VT/TI fell below the base-line level in seven SAS patients and in seven normal subjects. The decrease in VT/TI was accompanied by an increase in upper airway resistance. When the VT/TI decreased by 30% of its base-line level, pharyngeal resistance increased to 319.1 +/- 50.9% in SAS and 138.5 +/- 4.7% in normal subjects (P less than 0.05). We conclude that 1) in SAS patients, as in normal subjects, the activation of upper airway dilators is reflected by indexes that quantify the central inspiratory drive and 2) the pharyngeal patency is more sensitive to the decrease of the central respiratory drive in SAS patients than in normal subjects.     

Respiratory responses to ventilatory loading following low cervical spinal cord injury

This study compared the respiratory responses to ventilatory loading in 8 normal subjects and 11 quadriplegic patients with low cervical spinal cord transection. Progressive hypercapnia was produced by rebreathing. Rebreathing trials were carried out with no added load and with inspiratory resistive loads of 5 and 16 cmH2O. l-1 X s. Measurements were made of ventilation and of diaphragmatic electromyographic activity. Base-line hypercapnic ventilatory responses were significantly lower than normal in the quadriplegic patients, but the effects of resistive loading on the ventilatory responses were comparable in the two groups. The change in peak moving-average diaphragmatic electrical activity (DI peak) for a given change in CO2 partial pressure (PCO2) and DI peak at PCO2 55 Torr increased significantly with resistive loading both in the normal subjects and the quadriplegic patients. In the normal subjects, but not in the quadriplegic patients, inspiratory duration increased progressively with increasing resistance. The increase in DI peak during ventilatory loading in the normal subjects was a consequence of inspiratory prolongation. In contrast, in the quadriplegic patients during breathing against the larger resistive load, there was a significant increase in the average rate of rise (DI peak divided by the time from onset to peak) of diaphragmatic activity. The change in DI rate of rise for a given change in PCO2 increased to 137 +/- 13% (SE), and the DI rate of rise at PCO2 55 Torr increased to 128 +/- 8% (SE) of control values. These results indicate that compensatory increases in diaphragmatic activation during ventilatory loading occur in quadriplegic patients in whom afferent feedback from rib cage receptors is disrupted.     

Tracheal constrictor drive above the apneic threshold in anesthetized dogs.

We have previously shown that raising arterial PCO(2) (Pa(CO(2))) by small increments in dogs ventilated below the apneic threshold (AT) results in almost complete tracheal constriction before the return of phrenic activity (Dickstein JA, Greenberg A, Kruger J, Robicsek A, Silverman J, Sommer L, Sommer D, Volgyesi G, Iscoe S, and Fisher JA. J Appl Physiol 81: 1844-1849, 1996). We hypothesized that, if increasing chemical drive above the AT mediates increasing constrictor drive to tracheal smooth muscle, then pulmonary slowly adapting receptor input should elicit more tracheal dilation below the AT than above. In six methohexital sodium-anesthetized, paralyzed, and ventilated dogs, we measured changes in tracheal diameter in response to step increases in tidal volume (VT) or respiratory frequency (f) below and above the AT at constant Pa(CO(2)) ( approximately 40 and 67 Torr, respectively). Increases in VT (400-1,200 ml) caused significantly more (P = 0.005) tracheal dilation below than above AT (7.0 +/- 2.2 vs. 2.8 +/- 1.0 mm, respectively). In contrast, increases in f (14-22 breaths/min) caused similar (P = 0.93) tracheal dilations below and above (1.0 +/- 1.3 and 1.0 +/- 0.8 mm, respectively) AT. The greater effectiveness of dilator stimuli below compared with above the AT is consistent with the hypothesis that drive to tracheal smooth muscle increases even after attainment of maximal constriction. Our results emphasize the importance of controlling PCO(2) with respect to the AT when tracheal smooth muscle tone is experimentally altered.     

Brain hypoxia preferentially stimulates genioglossal EMG responses to CO2

Although the dominant respiratory response to hypoxia is stimulation of breathing via the peripheral chemoreflex, brain hypoxia may inhibit respiration. We studied the effects of two levels of brain hypoxia without carotid body stimulation, produced by inhalation of CO, on ventilatory (VI) and genioglossal (EMGgg) and diaphragmatic (EMGdi) responses to CO2 rebreathing in awake, unanesthetized goats. Neither delta VI/delta PCO2 nor VI at a PCO2 of 60 Torr was significantly different between the three conditions studied (0%, 25%, and 50% carboxyhemoglobin, HbCO). There were also no significant changes in delta EMGdi/delta PCO2 or EMGdi at a PCO2 of 60 Torr during progressive brain hypoxia. In contrast, delta EMGgg/delta PCO2 and EMGgg at a PCO2 of 60 Torr were significantly increased at 50% HbCO compared with either normoxia or 25% HbCO (P less than 0.05). The PCO2 threshold at which inspiratory EMGgg appeared was also decreased at 50% HbCO (45.6 +/- 2.6 Torr) compared with normoxia (55.0 +/- 1.4 Torr, P less than 0.02) or 25% HbCO (53.4 +/- 1.6 Torr, P less than 0.02). We conclude that moderate brain hypoxia (50% HbCO) in awake, unanesthetized animals results in disproportionate augmentation of EMGgg relative to EMGdi during CO2 rebreathing. This finding is most likely due to hypoxic cortical depression with consequent withdrawal of tonic inhibition of hypoglossal inspiratory activity.     

Effect of locomotor respiratory coupling on respiratory evaporative heat loss in the sheep.

During galloping, many animals display 1:1 coupling of breaths and strides. Locomotor respiratory coupling (LRC) may limit respiratory evaporative heat loss (REHL) by constraining respiratory frequency (f). Five sheep were exercised twice each, according to a five-step protocol: 5 min at the walk, 5 min at the trot (trot1), 10 min at the gallop, 5 min at the trot (trot2), and 5 min at the walk. Rectal temperature (T(re)), stride frequency, f, REHL, and arterial CO(2) tension and pH were measured at each step. Tidal volume (VT) was calculated. LRC was observed only during galloping. The coupling ratio remained at 1:1 while VT increased continuously during galloping, causing REHL to increase from 2.9 +/- 0.2 (SE) W/kg at the end of trot1 to a peak of 5.3 +/- 0.3 W/kg. T(re) rose from 39.0 +/- 0.1 degrees C preexercise to 40.2 +/- 0.2 degrees C at the end of galloping. At the gallop-trot2 transition, VT fell and f rose, despite a continued rise in T(re). Arterial CO(2) tension fell from 36.5 +/- 1.1 Torr preexercise to 31.8 +/- 1.4 Torr by the end of trot1 and then further to 21.5 +/- 1.2 Torr by the end of galloping, resulting in alkalosis. In conclusion, LRC did not prevent increases in REHL in sheep because VT increased. The increased VT caused hypocapnia and presumably elevated the cost of breathing.     

Effect of mean airway pressure on gas exchange during high-frequency oscillatory ventilation

We studied the effect of mean airway pressure (Paw) on gas exchange during high-frequency oscillatory ventilation in 14 adult rabbits before and after pulmonary saline lavage. Sinusoidal volume changes were delivered through a tracheostomy at 16 Hz, a tidal volume of 1 or 2 ml/kg, and inspired O2 fraction of 0.5. Arterial PO2 and PCO2 (PaO2, PaCO2), lung volume change, and venous admixture were measured at Paw from 5 to 25 cmH2O after either deflation from total lung capacity or inflation from relaxation volume (Vr). The rabbits were lavaged with saline until PaO2 was less than 70 Torr, and all measurements were repeated. Lung volume change was measured in a pressure plethysmograph. Raising Paw from 5 to 25 cmH2O increased lung volume by 48-50 ml above Vr in both healthy and lavaged rabbits. Before lavage, PaO2 was relatively insensitive to changes in Paw, but after lavage PaO2 increased with Paw from 42.8 +/- 7.8 to 137.3 +/- 18.3 (SE) Torr (P less than 0.001). PaCO2 was insensitive to Paw change before and after lavage. At each Paw after lavage, lung volume was larger, venous admixture smaller, and PaO2 higher after deflation from total lung capacity than after inflation from Vr. This study shows that the effect of increased Paw on PaO2 is mediated through an increase in lung volume. In saline-lavaged lungs, equal distending pressures do not necessarily imply equal lung volumes and thus do not imply equal PaO2.     

Effects of voluntary constraining of thoracic displacement during hypercapnia

The study evaluated the interrelationships between the extent of thoracic movements and respiratory chemical drive in shaping the intensity of the sensation of dyspnea. Normal subjects rated their sensations of dyspnea as PCO2 increased during free rebreathing and during rebreathing while ventilation was voluntarily maintained at a constant base-line level. Another trial evaluated the effects on the intensity of dyspnea, of voluntary reduction in the level of ventilation while PCO2 was held constant. During rebreathing, there was a power function relationship between changes in PCO2 and the intensity of dyspnea. At a given PCO2, constraining tidal volume and breathing frequency to the prerebreathing base-line level resulted in an increase in dyspnea. The fractional differences in the intensity of dyspnea between free and constrained rebreathing were independent of PCO2. However, the absolute difference in the intensity of dyspnea between free and constrained rebreathing enlarged with increasing hypercapnia. At PCO2 of 50 Torr, this difference correlated significantly with the increase in both minute ventilation (r = 0.675) and tidal volume (r = 0.757) above the base line during free rebreathing. Similarly, during steady-state hypercapnia at 50 Torr PCO2, the intensity of dyspnea increased progressively as ventilation was voluntarily reduced from the spontaneously adopted free-breathing level. These results indicate that dyspnea increases with the level of respiratory chemical drive but that the intensity of the sensation is further accentuated when ventilation is constrained below that demanded by the level of chemical drive. This may be explained by a loss of inhibitory feedback from lung or chest wall mechanoreceptors acting on brain stem and/or cortical centers.     

Furosemide and cerebrospinal fluid ions during acute respiratory acidosis

The purpose of this study was to investigate the effects of furosemide, an inhibitor of NaCl cotransport, on cisternal cerebrospinal fluid (CSF) acid-base balance during acute respiratory acidosis (ARA). We measured blood and CSF acid-base variables in two groups (n = 7 in each) of anesthetized, paralyzed, and mechanically ventilated dogs with bilateral ligation of renal pedicles (to eliminate saluresis). After base-line samples were obtained (-1 h), furosemide (50 mg/kg) was administered intravenously within 15 min (group II); group I received an equal volume of half-normal saline. ARA was induced 1 h later (0 h) and arterial CO2 tension was maintained between 55 and 60 Torr for 5 h. Mean cisternal CSF PCO2 was 42.8 +/- 2.6 and 39.5 +/- 1.7 Torr, respectively in groups I and II and rose approximately 20 Torr during ARA. In group I, CSF [HCO3-] was 22.0 +/- 1.0, 24.8 +/- 0.6, and 25.4 +/- 1.6 meq/l, respectively at 0, 2.5, and 5 h. Respective values for group II were 22.2 +/- 1.3, 24.3 +/- 1.8, and 24.6 +/- 1.0 meq/l. These values were not significantly different from each other. In each group, CSF [Na+-Cl-] increased significantly during ARA, but the changes were not significantly different when the two groups were compared. We conclude that furosemide at the dose used in the present study does not change ionic composition and acid-base balance of cisternal CSF compared with control. Because changes in CSF [Na+-Cl-] during ARA were similar in both groups, any inhibition of Cl- influx into CSF by furosemide should have been proportional to that of Na+.     

Time-course of blood acid-base state during arousal from hibernation in the European hamster

1. Arterial blood was sampled at 15 min-intervals in European hamsters Cricetus cricetus fitted with indwelling catheters, from deep hibernation to full arousal. Temperature-corrected pH and PCO2, respectively pH* and P*CO2, were directly measured at 37 degrees C. 2. Deep hibernation corresponded to a respiratory acidosis: pH* = 7.01 +/- 0.01 (mean +/- SE), P*CO2 = 160 +/- 4 Torr (n = 9 animals). 3. Three periods could be distinguished in the arousal: (i) a period of hyperventilation (28 +/- 5 min), in which P*CO2 was reduced to 79 +/- 4 Torr, while cheek pouch temperature increased only by 0.9 +/- 0.2 degrees C; (ii) a period of metabolic acidification by lactate accumulation (84 +/- 6 min), corresponding to the period of peak thermogenesis; (iii) a progressive return to euthermic conditions (104 +/- 10 min), by simultaneous respiratory and metabolic alkalinization. 4. Over 60% of the blood CO2 stores accumulated at the beginning of the hibernation bout were released by hyperventilation during the first period, prior to the full development of thermogenesis. This is in agreement with the hypothesis of an inhibitory role of the respiratory acidosis in hibernation.     

Splanchnic hemodynamics and gut mucosal-arterial PCO(2) gradient during systemic hypocapnia.

The effects of hypocapnia [arterial PCO(2) (Pa(CO(2))) 15 Torr] on splanchnic hemodynamics and gut mucosal-arterial P(CO(2)) were studied in seven anesthetized ventilated dogs. Ileal mucosal and serosal blood flow were estimated by using laser Doppler flowmetry, mucosal PCO(2) was measured continuously by using capnometric recirculating gas tonometry, and serosal surface PO(2) was assessed by using a polarographic electrode. Hypocapnia was induced by removal of dead space and was maintained for 45 min, followed by 45 min of eucapnia. Mean Pa(CO(2)) at baseline was 38.1 +/- 1.1 (SE) Torr and decreased to 13.8 +/- 1.3 Torr after removal of dead space. Cardiac output and portal blood flow decreased significantly with hypocapnia. Similarly, mucosal and serosal blood flow decreased by 15 +/- 4 and by 34 +/- 7%, respectively. Also, an increase in the mucosal-arterial PCO(2) gradient of 10.7 Torr and a reduction in serosal PO(2) of 30 Torr were observed with hypocapnia (P < 0.01 for both). Hypocapnia caused ileal mucosal and serosal hypoperfusion, with redistribution of flow favoring the mucosa, accompanied by increased PCO(2) gradient and diminished serosal PO(2).     

Ventilatory failure during loaded breathing: the role of central neural drive

Minute ventilation (VE), arterial blood gases, diaphragmatic electromyogram (EMG) activity, centroid frequency (Fc) and peak inspiratory airway pressures (Paw) were measured in five unanesthetized tracheostomized infant monkeys during various intensities of inspiratory resistive loaded breathing (IRL) until either 1) ventilatory failure occurred (failed trial) or 2) normocapnia was sustained for 1 h (successful trial). During successful trials VE and arterial PCO2 (PaCO2) were sustained at base-line levels, and an increase in peak integrated diaphragmatic EMG activity and peak inspiratory Paw occurred. In contrast, during ventilatory failure runs, VE decreased and PaCO2 rose compared with their respective base-line values. The fall in VE occurred secondary to a significant decline in breathing frequency. Tidal volume was sustained at base-line levels during all trials (both successful and failed groups). Inspiratory Paw's and peak moving time average EMG were sustained at elevated levels during ventilatory failure runs, suggesting that the respiratory muscles did not fail as pressure generators. Furthermore, the EMG Fc did not change from base line during either successful or failed trials. These data suggest that peripheral muscle fatigue did not occur, although in the absence of a more direct test of muscle performance, i.e., a force-frequency curve, we cannot rule out the possibility that a component of peripheral failure contributed to our results. Ventilatory failure during severe IRL in the infant monkey was most clearly associated with an alteration in the respiratory center timing mechanism, i.e., such failure was a function of a decline in respiratory frequency.     

Effect of withdrawal of respiratory CO2 oscillations on respiratory control at rest

We examined the effect of sudden withdrawal of respiratory oscillations of arterial PCO2 (CO2 oscillations) at resting metabolic rate on the control of respiration in 11 anesthetized paralyzed vagotomized dogs in normoxic normocapnia. A double-lumen endotracheal tube was inserted so that the left and right lungs were ventilated independently. By alternately ventilating each lung, we could completely abolish CO2 oscillations without affecting the mean blood gas levels (withdrawal of CO2 oscillations). The CO2 oscillation was calculated from arterial pH oscillation measured by a rapidly responding intra-arterial pH electrode. Respiratory center output was monitored by use of a moving time average of the phrenic neurogram. A 3-min period of withdrawal of CO2 oscillations was bracketed by two control periods (simultaneous ventilation of lungs for 3 min) to avoid the confounding effect of the baseline drift in the respiratory center output. The amplitude of the CO2 oscillations in the control was 2.33 +/- 0.89 (SD) Torr. When the difference in the mean level of arterial PCO2 between the control and withdrawal of CO2 oscillations was minimized (-0.09 +/- 0.54 Torr; P greater than 0.25), we found negligible change in the minute phrenic activity during withdrawal of CO2 oscillations (-0.02 +/- 6.11% of the control, P greater than 0.98, n = 49; 99% confidence interval -2.36 to 2.32%). Thus we conclude that the maintenance of normal respiration at rest is not critically dependent on a phasic afferent input to the respiratory center arising from respiratory CO2 oscillations.     

Effect of gender on the development of hypocapnic apnea/hypopnea during NREM sleep.

We hypothesized that a decreased susceptibility to the development of hypocapnic central apnea during non-rapid eye movement (NREM) sleep in women compared with men could be an explanation for the gender difference in the sleep apnea/hypopnea syndrome. We studied eight men (age 25-35 yr) and eight women in the midluteal phase of the menstrual cycle (age 21-43 yr); we repeated studies in six women during the midfollicular phase. Hypocapnia was induced via nasal mechanical ventilation for 3 min, with respiratory frequency matched to eupneic frequency. Tidal volume (VT) was increased between 110 and 200% of eupneic control. Cessation of mechanical ventilation resulted in hypocapnic central apnea or hypopnea, depending on the magnitude of hypocapnia. Nadir minute ventilation in the recovery period was plotted against the change in end-tidal PCO(2) (PET(CO(2))) per trial; minute ventilation was given a value of 0 during central apnea. The apneic threshold was defined as the x-intercept of the linear regression line. In women, induction of a central apnea required an increase in VT to 155 +/- 29% (mean +/- SD) and a reduction of PET(CO(2)) by -4.72 +/- 0.57 Torr. In men, induction of a central apnea required an increase in VT to 142 +/- 13% and a reduction of PET(CO(2)) by -3.54 +/- 0.31 Torr (P = 0.002). There was no difference in the apneic threshold between the follicular and the luteal phase in women. Premenopausal women are less susceptible to hypocapnic disfacilitation during NREM sleep than men. This effect was not explained by progesterone. Preservation of ventilatory motor output during hypocapnia may explain the gender difference in sleep apnea.     

Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea.

We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea.     

Arterial-alveolar CO2 equilibration in exercising dogs during prolonged rebreathing

Arterial-alveolar equilibration of CO2 during exercise was studied by normoxic CO2 rebreathing in six dogs prepared with a chronic tracheostomy and exteriorized carotid loop and trained to run on a treadmill. In 153 simultaneous measurements of PCO2 in arterial blood (PaCO2) and end-tidal gas (PE'CO2) obtained in 46 rebreathing periods at three levels of mild-to-moderate steady-state exercise, the mean PCO2 difference (PaCO2-PE'CO2) was -1.0 +/- 1.0 (SD) Torr and was not related to O2 uptake or to the level of PaCO2 (30-68 Torr). The small negative PaCO2-PE'CO2 is attributed to the lung-to-carotid artery transit time delay which must be taken into account when both PaCO2 and PE'CO2 are continuously rising during rebreathing (average rate 0.22 Torr/s). Assuming that blood-gas equilibrium for CO2 was complete, a lung-to-carotid artery circulation time of 4.6 s accounts for the observed uncorrected PaCO2-PE'CO2 of -1.0 Torr. The results are interpreted to indicate that in rebreathing equilibrium PCO2 in arterial blood and alveolar gas are essentially identical. This conclusion is at variance with previous studies in exercising humans during rebreathing but is in full agreement with our recent findings in resting dogs.     

Effects of CO2 rebreathing on pulmonary mechanics in premature infants

The effects of hypercapnia produced by CO2 rebreathing on total pulmonary, supraglottic, and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk, weight at study 1,950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr, respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive, thereby improving the infant's response to CO2.