Long-lasting ventilatory response of humans to a single breath of hypercapnia in hyperoxia.

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.     

Effect of airway impedance on CO2 retention and respiratory muscle activity during NREM sleep

We hypothesized that a sleep-induced increase in mechanical impedance contributes to CO2 retention and respiratory muscle recruitment during non-rapid-eye-movement (NREM) sleep. The effect NREM sleep on respiratory muscle activity and CO2 retention was measured in healthy subjects who increased maximum total pulmonary resistance (RLmax, 1-81 cmH2O.l-1.s) from awake to NREM sleep. We determined the effects of this sleep-induced increase in airway impedance by steady-state inhalation of a reduced-density gas mixture (79% He-21% O2, He-O2). Both arterialized blood PCO2 (PaCO2) and end-tidal PCO2 (PETCO2) were measured. Inspiratory (EMGinsp) and expiratory (EMGexp) respiratory muscle electromyogram activity was measured. NREM sleep caused 1) RLmax to increase (7 +/- 3 vs. 39 +/- 28 cmH2O.l-1.s), 2) PaCO2 and/or PETCO2 to increase in all subjects (40 +/- 2 vs. 44 +/- 3 Torr), and 3) EMGinsp to increase in 8 of 9 subjects and EMGexp to increase in 9 of 17 subjects. Compared with steady-state air breathing during NREM sleep, steady-state He-O2 breathing 1) reduced RLmax by 38%, 2) decreased PaCO2 and PETCO2 by 2 Torr, and 3) decreased both EMGinsp (-20%) and EMGexp (-54%). We concluded that the sleep-induced increase in upper airway resistance accompanied by the absence of immediate load compensation is an important determinant of CO2 retention, which, in turn, may cause augmentation of inspiratory and expiratory muscle activity above waking levels during NREM sleep.     

Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans.

We hypothesized that the acute ventilatory response to hypoxia is enhanced after exposure to episodic hypoxia in awake humans. Eleven subjects completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the partial pressure of carbon dioxide (Pet(CO(2))) below 25 Torr. Subjects then breathed from a bag containing normocapnic (42 Torr), low (50 Torr), or high oxygen (140 Torr) gas mixtures. During the trials, Pet(CO(2)) increased while a constant oxygen level was maintained. The point at which ventilation began to rise in a linear fashion as Pet(CO(2)) increased was considered to be the ventilatory recruitment threshold. The ventilatory response below and above the recruitment threshold was determined. Ventilation did not persist above baseline values immediately after exposure to episodic hypoxia; however, Pet(CO(2)) levels were reduced compared with baseline. In contrast, compared with baseline, the ventilatory response to progressive increases in carbon dioxide during rebreathing trials in the presence of low but not high oxygen levels was increased after exposure to episodic hypoxia. This increase occurred when carbon dioxide levels were above but not below the ventilatory recruitment threshold. We conclude that long-term facilitation of ventilation (i.e., increases in ventilation that persist when normoxia is restored after episodic hypoxia) is not expressed in awake humans in the presence of hypocapnia. Nevertheless, despite this lack of expression, the acute ventilatory response to hypoxia in the presence of hypercapnia is increased after exposure to episodic hypoxia.     

Hypoxic exposure and activation of the afterdischarge mechanism in conscious humans

After voluntary hyperventilation, normal humans do not develop a significant ventilatory depression despite low arterial CO2 tension, a phenomenon attributed to activation of a brain stem mechanism referred to as the "afterdischarge." Afterdischarge is one of the factors that promote ventilatory stability. It is not known whether physiological stimuli, such as hypoxia, are able to activate the afterdischarge in humans. To test this, breath-by-breath ventilation (VI) was measured in nine young adults during and immediately after a brief period (35-51 s) of acute hypoxia (end-tidal O2 tension 55 Torr). Hypoxia was terminated by switching to 100% O2 (end-tidal O2 tension of first posthypoxic breath greater than 100 Torr). Brief hypoxia increased VI and decreased end-tidal CO2 tension. In all subjects, termination of hypoxia was followed by a gradual ventilatory decay; hyperoxic VI remained higher than the normoxic baseline for several breaths and, despite the negative chemical stimulus of hyperoxia and hypocapnia, reached a new steady state without an apparent undershoot. We conclude that brief hypoxia is able to activate the afterdischarge mechanism in conscious humans. This contrasts sharply with the ventilatory undershoot that follows relief of sustained hypoxia, thereby suggesting that sustained hypoxia inactivates the afterdischarge mechanism. The present findings are of relevance to the pathogenesis of periodic breathing in a hypoxic environment. Furthermore, brief exposure to hypoxia might be useful for evaluation of the role of afterdischarge in other disorders associated with unstable breathing.     

Respiratory instability during sleep onset.

It has been hypothesized that regulatory control in the respiratory system is state dependent. According to this view respiratory instability during sleep onset is a consequence of repeated fluctuations in arousal state. However, these speculations are based primarily on measurements during stable sleep, not during sleep onset itself. The aim of the present study was to assess changes in ventilation and gas tensions during sleep onset as a function of arousal state. Twenty-one subjects (12 males and 9 females, mean age 20 yr) were assessed over an average of 11.3 sleep onsets. The subject's state was classified as alpha, theta, body movement, or stage 2 sleep, and expiratory tidal volume, minute ventilation, respiratory rate, and end-tidal CO2 and O2 were measured by means of a face mask, valve, and pneumotachograph on a breath-by-breath basis. Respiratory instability during sleep onset was found to be a result of two factors. The first factor was a between-state effect in which transitions from alpha to theta were associated with falls, and from theta to alpha with increases, in ventilation. The magnitude of the change was a positive function of metabolic drive at the time of the state change (as indicated by alveolar PCO2 and PO2 levels). The second was a within-state effect in which ventilation fell during consecutive alpha breaths and increased during consecutive theta breaths. These changes were due to the influence of the relative hyperventilation of the alpha state and the relative hypoventilation of the theta state on metabolic drive.     

Pattern of the ventilatory response to transient hypoxia in man: differences from transient hypercapnic test.

The pattern of change in ventilatory variables after inhalation of pure N2 for two breaths was studied in normal children and adults. In six subjects the trends of change were compared to the ventilatory response to transient hypercapnia. We observed differences in the patterns of increasing ventilation with an initial abrupt increase of tidal volume for transient hypoxia and a progressive change for hypercapnia. In both cases respiratory frequency was progressively but unsystematically enhanced. A highly significant positive correlation was demonstrated between individual sensitivities to CO2 and O2, with a greater response to hypercapnia (5.6 time) than to hypoxia. Finally, a very short-latency decrease in expiratory duration occurred in the first breath after inhalation of hypercapnic mixture, supporting the recent data of Cunningham et al. (1977).     

Method for measuring respiration in sleep: capnography for determining ventilation]

Ventilation serves the exchange of gases between the organism and the environment. Oxygen uptake and CO2 elimination are controlled by feedback loops, that keep fluctuations in arterial CO2 pressure (PaCO2) within narrow limits Disorders in the central regulation of breathing, or impairment of the respiratory apparatus, may result in a mismatch between metabolic CO2 production and ventilatory CO2, elimination and thus in fluctuations in the PaCO2: inappropriately increased ventilation (hyperventilation) causes hypocapnia, and reduced ventilation (hypoventilation) causes hypercapnia. In order to detect such disorders during sleep, PCO2 measurement is of great importance, but direct and continuous measurement of the PaCO2 is invasive and thus unsuitable in the clinical setting. An alternative is capnography, the continuous measurement of PCO2 in inhaled and exhaled air on the basis of ultrared light absorption. This paper reviews the method, its features and limitations, and the possibilities of improving capnography to better detect sleep-related breathing disorders. In addition, data obtained from 57 patients with predominantly normal lung function, but suspected sleep disordered breathing are presented. Simultaneous measurements of capnography PETCO2) and capillary PaCO2 revealed a PETCO2 difference of +0.63 +/- 3.3 (SD) Torr. PaCO2 (38.8 +/- 4.1 Torr) and PETCO2 (38.1 +/- 4.3 Torr) were not significantly different with a correlation coefficient of r = 0.68 (p < 0.001). Thus 46% of the variation in PETCO2 was explained by changes in PaCO2. Currently the literature contains few further data on capnography during sleep. It is concluded that, provided the limitations of the method are respected and comparison with the PETCO2 is made, capnography may be a useful, noninvasive and continuous measuring method for assessing ventilation during sleep in patients with suspected sleep related breathing disorders.     

Role of the carotid chemoreceptors in regulation of inspiratory onset

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.     

Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep.

To investigate the contribution of the peripheral chemoreceptors to the susceptibility to posthyperventilation apnea, we evaluated the time course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired P(O2). We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (arterial O2 saturation = 78-80%), and hyperoxia (inspired O2 fraction = 50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce a single or multiple numbers of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end inspiration of the first augmented breath to the onset of apnea. It was 12.2 +/- 1.1 s during normoxia, which was similar to the lung-to-ear circulation delay of 11.7 s in these subjects. Hypoxia shortened the apnea latency (6.3 +/- 0.8 s; P < 0.05), whereas hyperoxia prolonged it (71.5 +/- 13.8 s; P < 0.01). The apneic threshold end-tidal P(CO2) (Pet(CO2)) was defined as the Pet(CO2)) at the onset of apnea. During hypoxia, the apneic threshold Pet(CO2) was higher (38.9 +/- 1.7 Torr; P < 0.01) compared with normoxia (35.8 +/- 1.1; Torr); during hyperoxia, it was lower (33.0 +/- 0.8 Torr; P < 0.05). Furthermore, the difference between the eupneic Pet(CO2) and apneic threshold Pet(CO2) was smaller during hypoxia (3.0 +/- 1.0 Torr P < 001) and greater during hyperoxia (10.6 +/- 0.8 Torr; P < 0.05) compared with normoxia (8.0 +/- 0.6 Torr). Correspondingly, the hypocapnic ventilatory response to CO2 below the eupneic Pet(CO2) was increased by hypoxia (3.44 +/- 0.63 l.min(-1).Torr(-1); P < 0.05) and decreased by hyperoxia (0.63 +/- 0.04 l.min(-1).Torr(-1); P < 0.05) compared with normoxia (0.79 +/- 0.05 l.min(-1).Torr(-1)). These findings indicate that posthyperventilation apnea is initiated by the peripheral chemoreceptors and that the varying susceptibility to apnea during hypoxia vs. hyperoxia is influenced by the relative activity of these receptors.     

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

Exercise-induced hypercapnia in the horse

The effects of exercise intensity and duration on blood gases in thoroughbred horses were studied to characterize the apparent exercise-induced failure in pulmonary gas exchange that occurs in these animals. In response to 2 min of exercise, arterial CO2 tension (PaCO2) decreased in mild and moderate exercise, returned to normocapnic levels in moderate to heavy exercise, and rose 5-10 Torr above resting values during very heavy exercise when CO2 production (VCO2) exceeded 20 times the resting value, and mixed venous CO2 tension approximated 140 Torr. Exercise-induced hypoxemia occurred at the onset of heavy exercise and was associated with the absence of a hyperventilatory response and an alveolar-arterial PO2 difference that increased four to six times above rest with very heavy exercise. PaCO2 was related to VCO2 but not fb, as changes in breathing frequency (fb) of 8-20 breaths/min at comparable VCO2 did not affect PaCO2. Prolonging very heavy exercise from 2 to 4 min caused a severe metabolic acidosis (arterial pH less than 7.15) and hypoxemia was maintained; however, CO2 was no longer retained, as PaCO2 gradually fell to below resting levels, due to an increased tidal volume at constant fb. We conclude that a truly compensatory hyperventilation to very heavy exercise in the horse is not achieved because of the excessive volumes and flow rates required by their extraordinarily high VCO2 and VO2. On the other hand, the frank CO2 retention during short-term high-intensity exercise occurs even though the horse is not apparently mechanically obligated to tolerate it.     

Pulmonary gas exchange in panting dogs

Pulmonary gas exchange during panting was studied in seven conscious dogs (32 kg mean body wt) provided with a chronic tracheostomy and an exteriorized carotid artery loop. The animals were acutely exposed to moderately elevated ambient temperature (27.5 degrees C, 65% relative humidity) for 2 h. O2 and CO2 in the tracheostomy tube were continuously monitored by mass spectrometry using a special sample-hold phase-locked sampling technique. PO2 and PCO2 were determined in blood samples obtained from the carotid artery. During the exposure to heat, central body temperature remained unchanged (38.6 +/- 0.6 degrees C) while all animals rapidly switched to steady shallow panting at frequencies close to the resonant frequency of the respiratory system. During panting, the following values were measured (means +/- SD): breathing frequency, 313 +/- 19 breaths/min; tidal volume, 167 +/- 21 ml; total ventilation, 52 +/- 9 l/min; effective alveolar ventilation, 5.5 +/- 1.3 l/min; PaO2, 106.2 +/- 5.9 Torr; PaCO2, 27.2 +/- 3.9 Torr; end-tidal-arterial PO2 difference [(PE' - Pa)O2], 26.0 +/- 5.3 Torr; and arterial-end-tidal PCO2 difference, [(Pa - PE')CO2], 14.9 +/- 2.5 Torr. On the basis of the classical ideal alveolar air approach, parallel dead-space ventilation accounted for 54% of alveolar ventilation and 66% of the (PE' - Pa)O2 difference. But the steepness of the CO2 and O2 expirogram plotted against expired volume suggested a contribution of series in homogeneity due to incomplete gas mixing.     

Effect of aging on estimates of hypercapnic ventilatory response during sleep

By recording only inspired PCO2 (PICO2) in a hood and transcutaneous PCO2 (PsCO2) the Hazinski method was used to estimate nonintrusively the slope (Sr) per Torr PsCO2 of the fractional ventilatory response to approximately 18 and 30 Torr PICO2 in 17 healthy elderly subjects (10 women) and 17 younger controls (9 women) during wakefulness, slow-wave sleep (SWS), and rapid-eye-movement (REM) sleep. Eight of the older subjects had sleep disturbance indexes (RDI) greater than 5. Sr fell with SWS from 0.90 +/- 0.34 to 0.60 +/- 0.29 (P less than 0.006) in the younger group (n = 16) but in the older subjects was 0.60 +/- 0.27 awake and 0.58 +/- 0.34 (NS) asleep (n = 15). The changes from awake to REM in subsets of 9 younger and 10 older subjects who successfully completed REM tests were from 0.95 +/- 0.32 to 0.70 +/- 0.38 (P less than 0.03) and 0.53 +/- 0.31 to 0.57 +/- 0.25 (NS), respectively. We conclude that the increased incidence of respiratory disturbance during sleep in these older subjects cannot be attributed to greater sleep-induced reduction of CO2 sensitivity.     

Effects of sleep-induced increases in upper airway resistance on ventilation

To determine the effects of the sleep-induced increases in upper airway resistance on ventilatory output, we studied five subjects who were habitual snorers but otherwise normal while awake (AW) and during non-rapid-eye-movement (NREM) sleep under the following conditions: 1) stage 2, low-resistance sleep (LRS); 2) stage 3-4, high-resistance sleep (HRS) (snoring); 3) with continuous positive airway pressure (CPAP); 4) CPAP + end-tidal CO2 partial pressure (PETCO2) mode isocapnic to LRS; and 5) CPAP + PETCO2 isocapnic to HRS. We measured ventilatory output via pneumotachograph in the nasal mask, PETCO2, esophageal pressure, inspiratory and expiratory resistance (RL,I and RL,E). Changes in PETCO2 were confirmed with PCO2 measurements in arterialized venous blood in all conditions in one subject. During wakefulness, pulmonary resistance (RL) remained constant throughout inspiration, whereas in stage 2 and especially in stage 3-4 NREM sleep, RL rose markedly throughout inspiration. Expired minute ventilation (VE) decreased by 12% in HRS, and PETCO2 increased in LRS (3.3 Torr) and HRS (4.9 Torr). CPAP decreased RL,I to AW levels and increased end-expiratory lung volume 0.25-0.93 liter. Tidal volume (VT) and mean inspiratory flow rate (VT/TI) increased significantly with CPAP. Inspiratory time (TI) shortened, and PETCO2 decreased 3.6 Torr but remained 1.3 Torr above AW. During CPAP (RL,I equal to AW), with PETCO2 returned to the level of LRS, VT/TI and VE were 83 and 52% higher than during LRS alone. Also on CPAP, with PETCO2 made equal to HRS, VT, VT/TI, and VE were 67, 112, and 67% higher than during HRS alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Single breath of CO2 as a clinical test of the peripheral chemoreflex

Peripheral chemoreceptor responsiveness is usually examined clinically by hypoxic testing, but the usefulness of this approach is limited by safety considerations, and the interpretation of results may be confounded by the direct central nervous system effects of hypoxia. Therefore we examined the single-breath (SB) CO2 test to determine its reproducibility and applicability as a clinical test of peripheral chemoreceptor function. The technique involved the inhalation of a SB of 13% CO2 in air. The ventilatory response was determined from the increase in ventilation (VE) during the first 20 s after the test breath and from the difference in end-tidal PCO2 between the test breath and preceding control breaths. The peak increase in VE occurred during the second or third breath after the test breath, corresponding to a delay of approximately 10 s. The mean of 10 SB tests administered at 2- to 3-min intervals was taken as the subject's response. Five healthy subjects were tested in this manner on each of 6 consecutive days with the response having an interday coefficient of variation of 25 +/- 6% (SD). The response in 26 healthy females (aged 22-61 yr) was 0.32 +/- 0.11 l.min-1.Torr-1, and in 26 healthy males (aged 24-69 yr) the response was 0.38 +/- 0.14 (P NS). No significant correlation was found between the age of the subjects and their ventilatory response. Thirty-six of the subjects also underwent hyperoxic CO2 rebreathing tests, the response to which is dependent on central chemoreceptor function. No correlation was found between rebreathing and SB tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of altered CSF [H+] on ventilatory responses to exercise in the awake goat

We investigated the effects of selective large changes in the acid-base environment of medullary chemoreceptors on the control of exercise hyperpnea in unanesthetized goats. Four intact and two carotid body-denervated goats underwent cisternal perfusion with mock cerebrospinal fluid (CSF) of markedly varying [HCO-3] (CSF [H+] = 21-95 neq/l; pH 7.68-7.02) until a new steady state of alveolar hypo- or hyperventilation was reached [arterial PCO2 (PaCO2) = 31-54 Torr]. Perfusion continued as the goats completed two levels of steady-state treadmill walking [2 to 4-fold increase in CO2 production (VCO2)]. With normal acid-base status in CSF, goats usually hyperventilated slightly from rest through exercise (-3 Torr PaCO2, rest to VCO2 = 1.1 l/min). Changing CSF perfusate [H+] changed the level of resting PaCO2 (+6 and -4 Torr), but with few exceptions, the regulation of PaCO2 during exercise (delta PaCO2/delta VCO2) remained similar regardless of the new ventilatory steady state imposed by changing CSF [H+]. Thus the gain (slope) of the ventilatory response to exercise (ratio of change in alveolar ventilation to change in VCO2) must have increased approximately 15% with decreased resting PaCO2 (acidic CSF) and decreased approximately 9% with increased resting PaCO2 (alkaline CSF). A similar effect of CSF [H+] on resting PaCO2 and on delta PaCO2/VCO2 during exercise also occurred in two carotid body-denervated goats. Our results show that alteration of the gain of the ventilatory response to exercise occurs on acute alterations in resting PaCO2 set point (via changing CSF [H+]) and that the primary stimuli to exercise hyperpnea can operate independently of central or peripheral chemoreception.     

Ventilatory control during exercise with peripheral chemoreceptor stimulation: hypoxia vs. domperidone

Hypoxia potentiates the ventilatory response to exercise, eliciting a greater decrease in arterial PCO2 (PaCO2) from rest to exercise than in normoxia. The mechanism of this hypoxia-exercise interaction requires intact carotid chemoreceptors. To determine whether carotid chemoreceptor stimulation alone is sufficient to elicit the mechanism without whole body hypoxia, ventilatory responses to treadmill exercise were compared in goats during hyperoxic control conditions, moderate hypoxia (PaO2 = 38-44 Torr), and peripheral chemoreceptor stimulation with the peripheral dopamine D2-receptor antagonist, domperidone (Dom; 0.5 mg/kg iv). Measurements with Dom were made in both hyperoxia (Dom) and hypoxia (Dom/hypoxia). Finally, ventilatory responses to inspired CO2 at rest were compared in each experimental condition because enhanced CO2 chemoreception might be expected to blunt the PaCO2 decrease during exercise. At rest, PaCO2 decreased from control with Dom (-5.0 +/- 0.9 Torr), hypoxia (-4.1 +/- 0.5 Torr), and Dom/hypoxia (-11.1 +/- 1.2 Torr). The PaCO2 decrease from rest to exercise was not significantly different between control (-1.7 +/- 0.6 Torr) and Dom (-1.4 +/- 0.8 Torr) but was significantly greater in hypoxia (-4.3 +/- 0.7 Torr) and Dom/hypoxia (-3.5 +/- 0.9 Torr). The slope of the ventilation vs. CO2 production relationship in exercise increased with Dom (16%), hypoxia (18%), and Dom/hypoxia (68%). Ventilatory responses to inspired CO2 at rest increased from control to Dom (236%) and Dom/hypoxia (295%) and increased in four of five goats in hypoxia (mean 317%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Control of exercise hyperpnea during hypercapnia in humans

Previous studies have yielded conflicting results on the ventilatory response to CO2 during muscular exercise. To obviate possible experimental errors contributing to such variability, we have examined the CO2-exercise interaction in terms of the ventilatory response to exercise under conditions of controlled hypercapnia. Eight healthy male volunteers underwent a sequence of 5-min incremental treadmill exercise runs from rest up to a maximum CO2 output (VCO2) of approximately 1.5 l . min-1 in four successive steps. The arterial PCO2 (PaCO2) at rest was stabilized at the control level or up to 14 Torr above control by adding 0-6% CO2 to the inspired air. Arterial isocapnia (SD = 1.2 Torr) throughout each exercise run was maintained by continual adjustment of the inspired PCO2. At all PaCO2 levels the response in total ventilation (VE) was linearly related to exercise VCO2. Hypercapnia resulted in corresponding increases in both the slope (S) and zero intercept (V0) of the VE-VCO2 curve; these being directly proportional to the rise in PaCO2 (means +/- SE: delta S/ delta PaCO2, 2.73 +/- 0.28 Torr-1; delta V0/ delta PaCO2, 1.67 +/- 0.18 l . min-1 . Torr-1). Thus the ventilatory response to concomitant hypercapnia and exercise was characterized by a synergistic (additive plus multiplicative) effect, suggesting a positive interaction between these stimuli. The increased exercise sensitivity in hypercapnia is qualitatively consistent with the hypothesis that VE is controlled to minimize the conflicting challenges due to chemical drive and the mechanical work of breathing (Poon, C. S. In: Modelling and Control of Breathing, New York: Elsevier, 1983, p. 189-196).