Sleep and maturation of eucapnic ventilation and CO2 sensitivity in the premature primate

The effects of sleep state and postnatal maturation on steady-state CO2 sensitivity, "inspiratory drive" (VT/TI), and the inspiratory "duty cycle" (TI/Ttot) were examined in nine unanesthetized premature Macaca nemestrina in the first 3 wk of life. Minute volume (VE) in room air was less in NREM sleep than in the awake state but there were no differences in VE, VT/TI, or TI/Ttot between REM and NREM sleep. VE and VT/TI corrected for body weight increased in REM and NREM sleep with postnatal maturation whereas TI/Ttot did not vary. Concomitant with this increase in room air VE and VT/TI, an increase in CO2 sensitivity (delta V/delta Paco2) with postnatal maturation was documented in NREM sleep. CO2 sensitivity was similar between REM and NREM states at each postnatal age. The increase in VE following inhalation of 2-5% CO2 was mediated by an increase in VT/TI, whereas TI/Ttot remained constant. The differences in the effect of sleep on CO2 sensitivity between neonates and adults are discussed and possible mechanisms for the observed developmental increase in CO2 sensitivity are proposed.     

Phonospirometry for noninvasive measurement of ventilation: methodology and preliminary results.

We measured tracheal flow from tracheal sounds to estimate tidal volume, minute ventilation (VI), respiratory frequency, mean inspiratory flow (VT/TI), and duty cycle (TI/Ttot). In 11 normal subjects, 3 patients with unstable airway obstruction, and 3 stable asthmatic patients, we measured tracheal sounds and flow twice: first to derive flow-sound relationships and second to obtain flow-volume relationships from the sound signal. The flow-volume relationship was compared with pneumotach-derived volume. When subjects were seated, facing forward and with neck rotation, flexion, and standing, flow-volume relationship was within 15% of pneumotach-derived volume. Error increased with neck extension and while supine. We then measured ventilation without mouthpiece or nose clip from tracheal sounds during quiet breathing for up to 30 min. Normal results +/- SD revealed tidal volume = 0.37 +/- 0.065 liter, respiratory frequency = 19.3 +/- 3.5 breaths/min, VI = 6.9 +/- 1.2 l/min, VT/TI = 0.31 +/- 0.06 l/s, and TI/Ttot = 0.37 +/- 0.04. Unstable airway obstruction had large VI due to increased VT/TI. With the exception of TI/Ttot, variations in ventilatory parameters were closer to log normal than normal distributions and tended to be greater in patients. We conclude that phonospirometry measures ventilation reasonably accurately without mouthpiece, nose clip, or rigid postural constraints.     

Heart rate and breathing pattern: interactions and sex differences

Ten subjects (five males, five females) were studied in resting conditions. Ventilation (VT, f, TI, TE), heart rate (HR) and RR interval were recorded or measured. Each subject voluntarily breathed with spontaneous frequency at different ratios of his spontaneous tidal volume (VrT). The results show that sinus arrhythmia increases with lung volume but without effect on mean heart rate. When VT is increased by two times its spontaneous value, the ventilatory drive (VT/TI) is raised in both sexes; the relative duration of inspiration (TI/Ttot) is modified (+20%) in females only. Thus with the cardiac effects of increasing lung volume being similar in both sexes, we conclude that sinus arrhythmia is not generated by sensory inputs from pulmonary structures, but that its origin is at the CNS level. Moreover, there may be a sex difference in the control of voluntary ventilation, a suggestion requiring further investigation.     

The pattern of breathing during hypoxic exercise

Breathing pattern was studied in six subjects in normoxia (FIO2 = 0.21) and hypoxia (FIO2 = 0.12) at rest and during incremental work-rate exercise. Ventilation (V) as well as mean inspiratory flow (VT/TI) increased with exercise intensity and were augmented in the hypoxic environment, whereas the ratio between inspiratory (TI) and total (Ttot) breath durations increased with exercise intensity but was unaffected by hypoxia. The relationship of tidal volume (VT) and inspiratory time duration (TI) showed linear, coinciding ranges for the normoxic and hypoxic conditions up to VT/TI values of about 2.5 1.s-1. At higher VT/TI values TI continued to decrease, whereas VT tended to level off, an effect which was more evident in the hypoxic condition. The results suggest that the hypoxic augmentation of exercise hyperpnea is primarily brought about by an enhancement of central inspiratory drive, the timing component being largely unaffected by the hypoxic environment, and that at low to moderate levels of exercise hyperpnea inspiratory off-switch mechanisms are essentially unaffected by moderate hypoxia.     

Control of respiratory pattern in conscious dog: effects of heat and CO2

We measured tidal volume (VT) and inspiratory (TI) and expiratory (TE) durations in five conscious tracheostomized dogs breathing air or 5% CO2 in air either at normal (20 degrees C) or elevated (30 degrees C) ambient temperatures. Respiratory frequency ranged between 16 and 333/min due to changes in both TI and TE. During panting TI exceeded TE. During air inhalation instantaneous ventilation (V) spontaneously ranged from 100 to 1,600 ml . kg-1 . min-1. Hypercapnia, heat stress, or both, increased this range of V by increasing maximum V, primarily due to increases in mean inspiratory flow. Under these conditions, changes in TI accounted for more of the spontaneous changes in breath duration. During inhalation of air and 5% CO2, a positive correlation between VT and TI was obtained for TI between 0.13 and 1.05 s; above 1.05 s VT decreased. Heat stress increased VT at a given TI. We suggest that either the decay rate or position of the inspiratory off-switch threshold curve (Clark and von Euler, J. Physiol. London 222: 267, 1972) varies in conscious dogs. Shifts in either the reset (onset) value or decay rate of the curve yield a positive correlation between VT and TI. This modification to the Clark-von Euler model implies that the primary effect of anesthesia on respiratory control is fixation of the inspiratory off-switch threshold curve.     

Ventilation and respiratory pattern and timing in resting awake cats

The purpose of this study was to characterize the variability and patterns of spontaneous respiratory behaviour in awake cats. Respiration was measured in six cats over 80 or 90 min by the plethysmographic technique. In three cats, arterial blood gases were measured. Breath frequency (f) and tidal volume (VT) varied considerably breath-to-breath, although on average, these measurements as well as average ventilation remained relatively constant. The incidence of breath ventilation (VT X 60/TTOT) and VT were distributed unimodally but the incidence of breath f had a bimodal distribution. In the low f range, average f was 22.5 breaths/min, and in the high f range, average f was 41.6 breaths/min. The latter range appeared to be associated with purring. Inspiratory duration (TI) was less than expiratory duration (TE) at low f but exceeded TE at high f. For a given breath ventilation there was a predictable f and VT. At shorter TI (higher f) mean inspiratory flow, an index of central respiratory drive, increased but VT decreased. This study indicates that "normal" control respiratory behaviour in awake cats is better described by the range and pattern of breathing than by average values.     

Ventilatory response during CO2 inhalation after airway anesthesia with lidocaine

Airway anesthesia with inhaled aerosolized lidocaine has been associated with increases in minute ventilation (VE) and mean inspiratory flow rate (VT/TI) during CO2 inhalation. However, it is unclear whether these increases are local effects of the anesthesia or systemic effects of absorbed and circulating lidocaine. To evaluate this 20 normal subjects were treated on separate days with aerosolized lidocaine, intravenous lidocaine, aerosolized control solution, or intravenous control solution, and the effects of each treatment on VE and VT/TI were determined and compared during room-air breathing and inhalation of 5% CO2-95% O2. None of the treatments altered VE or VT/TI during room-air breathing. Aerosolized lidocaine produced small (5.9-6.0%) increases in VE and VT/TI during CO2 inhalation, but these effects were not present after intravenous lidocaine despite equivalent lidocaine blood levels. We concluded that the increases in VE and VT/TI after aerosolized lidocaine were local effects of airway anesthesia rather than systemic effects of absorbed and circulating lidocaine.     

Angiotensin stimulates respiration in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system. We hypothesized 1) that ventilation (V) would be greater in conscious SHR than in control Wistar-Kyoto (WKY) rats and 2) that intravenous infusion of the ANG II-receptor blocker saralasin would depress respiration in SHR, but not in WKY. Respiration and oxygen consumption (VO(2)) were measured in conscious aged-matched groups (n = 16) of adult female SHR and WKY. For protocol 1, rats were habituated to a plethysmograph and measurements obtained over 60-75 min. After installation of chronic intravenous catheters, protocol 2 consisted of 30 min of saline infusion ( approximately 14 microliter. kg(-1). min(-1)) followed by 40 min of saralasin (1.3 microgram. kg(-1). min(-1)). V, tidal volume (VT), inspiratory flow [VT/inspiratory time (TI)], breath expiratory time, and VO(2) were higher, and breath TI was lower in "continuously quiet" SHR. In SHR, but not in WKY rats, ANG II-receptor block decreased V, VT, and VT/TI and increased breath TI. During ANG II-receptor block, an average decrease in VO(2) in SHR was not significant. About one-half of the higher V in SHR appears to be accounted for by an ANG II mechanism acting either via peripheral arterial receptors or circumventricular organs.     

Inspiratory timing of heart-lung transplant recipients during progressive hypercapnia.

The relationship between tidal volume (VT) and inspiratory duration (TI) displays biphasic characteristics during progressive hypercapnia in humans: an initial phase in which VT increases while TI remains constant (region I) and a subsequent phase with reciprocal decreases of TI as VT continues to increase (region II). Region II behavior is generally attributed, albeit inferentially, to lung volume-mediated inflation inhibition (Breuer-Hering reflex). To investigate this phenomenon, we compared CO2 responses of 10 heart-lung transplant recipients (HL) with normal pulmonary function tests and 13 normal controls. Despite pulmonary denervation, the HL exhibited region II behavior identical to controls. In four additional HL with pulmonary restriction, there were comparative decreases of the region II slope (P less than 0.05), but the absolute VT where the phase change between regions occurred was indistinguishable from the other groups. We conclude that TI shortening in humans during progressive hypercapnia occurs in the absence of pulmonary reflexes. The consistency of the VT associated with phase changes, despite pulmonary denervation, suggests that the stimulus for this behavior is volume displacement of extra-pulmonary respiratory structures.     

Short-term potentiation of breathing in humans.

The purpose of this study was to determine if the increase in ventilation induced by hypoxic stimulation of the carotid bodies (CB) persists after cessation of the stimulus in humans. I reasoned that a short-term potentiation (STP) of breathing, sometimes called an "afterdischarge," could be unmasked by combining hypoxia with exercise, because ventilation increases synergistically under these conditions. Seven young healthy men performed mild bicycle exercise (30% peak power) while breathing O2 for 1.5 min ("control" state), and their CB were then stimulated by 1.5 min of hypoxic exercise (10% O2--balance N2). CB stimulation was then terminated by changing the inspirate back to O2 as exercise continued. Inspiratory and expiratory duration (TI and TE) and inspiratory flow and its time integral [tidal volume (VT)] were measured with a pneumotachometer. Inspired minute ventilation (VI) and mean inspiratory flow (VT/TI) declined exponentially after the cessation of CB stimulation, with first-order time constants of 28.6 +/- 6.7 and 24.6 +/- 1.6 (SD) s, respectively. The slow decay of VI was due primarily to potentiation of both TI and TE, although the effect on the latter predominated. Additional experiments in six subjects showed that brief intense CB stimulation with four to five breaths of N2 during mild exercise induced STP of similar magnitude to that observed in the hypoxic exercise experiments. Finally, the imposition of hyperoxia during air breathing exercise at a level of respiratory drive similar to that induced by the hypoxic exercise did not change VI significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of vagal afferents in determining ventilation in newborn rats

We studied the effect of acute bilateral vagotomy on ventilation and ventilatory pattern in rats. In 1- to 6-day-old unanesthetized rats, vagotomy resulted in a substantial decrease (38%) in ventilation during air breathing. After vagotomy there was a threefold increase in tidal volume (VT), inspiratory time (TI) doubled, and expiratory time (TE) was six times longer. When studied under isoflurane anesthesia, newborn rats showed decreases in ventilation similar to that observed without anesthesia, whereas anesthetized adult rats had no consistent changes in ventilation. Adult and newborn rats had nearly identical proportionate increases in VT and TI after vagotomy, but TE lengthened to a greater extent in the newborns. Additionally, we demonstrated a significant decrease in ventilation when 100% O2 rather than air was supplied to nonvagotomized unanesthetized newborn rats. Ventilation decreased by 19% after vagotomy under hyperoxic conditions. We conclude that vagal afferent input, probably of pulmonary mechanoreceptor origin, provides positive feedback to respiration in newborn rats and that newborn rats greater than 24 h old also have a degree of peripheral chemoreceptor drive during air breathing.     

Control of depth and frequency of breathing during baroreceptor stimulation in cats.

In 10 tracheotomized anesthetized cats during steady-state inhalation of various concentrations of CO2 and O2, the acute respiratory response to baroreceptor stimulation produced by transient inflation of a balloon placed in the descending aorta was studied. The latter induced a sudden rise in mean arterial pressure, ranging from 62 to 95 mmHg. At all PACO2 levels above 30 mmHg, elevation in arterial pressure was accompanied by an immediate drop in tidal volume (VT) and prolongation of the durations of inspiration (Ti) and total breath (Ttot). Breaths obtained during baroreceptor stimulation fell along the same VT vs. Ti and VT vs. Ttot relationships obtained in the normotensive state, suggesting that the lung volume-related vagal control of Ti and Ttot is unaffected by changes in arterial pressure. Since, for a given change in arterial pressure, a constant reduction in VT was obtained at all PACO2 levels above 30 mmHg, it can be concluded that the interaction between PACO2 and arterial pressure is additive. In three cats, at PACO2 levels below 30 mmHg, aortic obstruction resulted in brief periods of apnea. Following apnea, the control of Ti and Ttot was transiently offset, describing hysteresis pathways on the VT vs. Ti and VT vs. Ttot relationships.     

Effect of ozone on breathing in dogs: vagal and nonvagal mechanisms

We exposed two awake dogs with a chronic tracheostomy and the cervical vagus nerves exteriorized in skin loops to 1.0 ppm of ozone (O3) for 2 h at intervals of 4 wk. We measured ventilatory variables before and after O3 exposure during rest and exercise before and after vagal block. We compared the effects of vagal blockade, exercise, and O3 on the primary determinants of breathing pattern (VT/TI, VT/TE, TI, and TE) in each of three conditions: base line (steady state), during hypercapnia, and after inhalation of 1% histamine. Under base-line conditions, O3 increased respiratory rate and decreased tidal volume (VT) by shortening time of expiration (TE) and time of inspiration (TI) without affecting VT/TI, an indicator of the neural drive to breathing. During progressive hypercapnia, O3 shortened TE and TI by effects both on tonic (nonvolume-related) and on phasic (volume-related) vagal inputs, and only the latter were prevented completely by cooling of the vagus nerves. Histamine-induced tachypnea was increased by O3 and was totally blocked by cooling the vagus nerves. We conclude that O3 shortens the timing of respiration without increasing ventilatory drive, shortens TI and TE through vagal and nonvagal pathways, increases tonic nonvagal and phasic vagal inputs, and stimulates more than one vagal fiber type.     

Pattern of breathing in the rat.

The basic ventilation values - tidal volume (VT), breathing frequency (f), minute ventilation (VE) and the duration of inspiration (TI) and expiration (TE) -- were determined in adult male rats. The range of these values is given and the pattern of breathing is defined as the relationship between VE and VT, which in the rat is linear throughout its entire range. The role of TI and TE in changing f in the rat were evaluated. The breathing pattern of the rat was compared with data for the rabbit and man, using percentual expression of the basic values. A shift of the breathing pattern to higher f values was observed in rats with experimental lung diseases. In these rats, the inhalation of 100% O2 shifted the pattern of breathing markedly to lower VE values, though not to values comparable with the controls. Bilateral cervical vagotomy was followed by a pronouced decrease in f, an increase in VT and T1 persisted even after vagotomy, however; it can be assumed that this relationship is effected either by means of receptors in the chest muscles, or by the direct action of CO2 which is used to stimulate breathing, on the bulbopontine pacemaker.     

Effects of hypercapnia on Breuer-Hering threshold for inspiratory termination

The effects of CO2 concentration on the timing of inspiratory duration (TI) and expiratory duration (TE) and the responses to lung inflation were studied in decerebrate paralyzed cats. With lung volume held at functional residual capacity during the breath cycle, hypercapnia (fractional concentration of inspired CO2 = 0.04) caused variable changes in TI and significant increases in TE. To obtain the Breuer-Hering threshold relationship [tidal volume (VT) vs. TI] and the timing relationship between TE and the preceding TI (TE vs. TI), ramp inflations of various sizes were used to terminate inspiration at different times in the breath cycle. Hypercapnia caused the VT vs. TI curves to shift in an upward direction so that at higher lung volumes TI was lengthened. Also, the slope of the TE vs. TI relationship was increased. The results suggest that hypercapnia diminished the sensitivity of the Breuer-Hering reflex to the lung volume, thus allowing volume to increase with little effect on TI. In addition, TE appears to become more sensitive to changes in the preceding TI. A model is presented which provides a possible neural mechanism for these responses.     

Control of breathing at elevated lung volumes in anesthetized cats

We monitored the steady-state ventilatory responses of anesthetized cats to increases in lung volume produced by expiratory threshold loads (ETL) to study the roles of peripheral and central neural mechanisms in controlling respiration at elevated lung volumes. Application of an ETL of 5 cmH2O produced a significant decrease in respiratory frequency (-18%) but no change in minute ventilation (VE) due to a significant increase in tidal volume (VT) (19.3%). The drop in frequency was due solely to an increase in expiratory duration. ETL of 10 cmH2O significantly reduced VE (-17.5%) for the same reason. VT was maintained or increased at elevated lung volumes due to both an increase in the rate of rise of phrenic activity and a maintenance of inspiratory duration (TI) despite increases in both chemical drive and pulmonary stretch receptor (PSR) activity. No PSR adapted completely to the maintained change in lung volume. The sensitivity of the inspiratory off-switch mechanism to increases in lung volume, given by the reciprocal of the VT-TI relationship, decreased significantly during breathing on ETL. The results are consistent with the hypothesis that central habituation, not just peripheral adaptation of PSR, determines breathing pattern at elevated lung volumes.     

Ventilatory response to high-frequency airway oscillation in humans

To investigate respiratory control during high-frequency oscillation (HFO), ventilation was monitored in conscious humans by respiratory inductive plethysmography during application at the mouth of high-frequency pressure oscillations. Studies were conducted before and after airway and pharyngeal anesthesia. During HFO, breathing became slow and deep with an increase in tidal volume (VT) of 37% (P less than 0.01) and inspiratory duration (TI) of 34% (P less than 0.01). Timing ratio (TI/TT) increased 14% (P less than 0.05) and respiratory frequency (f) decreased 12% (P less than 0.01). Mean inspiratory flow (VT/TI) did not change during HFO. Following airway anesthesia, VT increased only 26% during HFO (P less than 0.01), whereas significant changes in TI, TI/TT, and f were not observed. Pharyngeal anesthesia failed to diminish the effect of HFO on TI, TT, or f, although the increase in VT was reduced. These results indicate that 1) HFO presented in this manner alters inspiratory timing without affecting the level of inspiratory activity, and 2) receptors in the larynx and/or lower airways may in part mediate the response.     

Breathing patterns during varied activities.

The level of ventilation attained and breathing patterns adopted during activity have important implications for the distribution and deposition of particles that are inhaled. However, breathing patterns and levels of ventilation adopted during specific physical activities are unknown. We used a noninvasive means of measuring ventilation in subjects performing a variety of activities (bicycling, arm ergometry, lifting, and pulling) during unencumbered (no mouthpiece) breathing and while breathing through a mouthpiece. Minute ventilation (VE), tidal volume (VT), inspiratory time (TI), and total breathing cycle time (TT) were measured initially both spirometrically and from body surface displacements. When a mouthpiece was used, VE and breathing patterns were significantly altered during all activities such that VE, VT, and TT increased by 16, 34, and 20%, respectively. This mouthpiece effect was attenuated at the higher levels of VE. A task dependency of breathing pattern was also noted such that there was much greater variability of VT and TI for a given VE during the lifting activity compared with bicycling (coefficient of variation for VT of 0.39 +/- 0.09 vs. 0.20 +/- 0.07, P less than 0.01; and for TI of 0.38 +/- 0.08 vs. 0.21 +/- 0.08, P less than 0.01). We conclude that a mouthpiece significantly alters breathing pattern during varied types and intensities of activities, and breathing patterns may differ significantly from one activity to another. When the total dose of particulates inhaled in the lung are assessed, the mouthpiece effect and activity effect on breathing pattern must be considered.     

Effects of inspiratory resistive load on respiratory control in hypercapnia and exercise

Eight healthy young men underwent two separate steady-state incremental exercise runs within the aerobic range on a treadmill with alternating periods of breathing with no load (NL) and with an inspiratory resistive load (IRL) of approximately 12 cmH2O.1-1.s. End-tidal PCO2 was maintained constant throughout each run at the eucapnic or a constant hypercapnic level by adding 0-5% CO2 to the inspired O2. Hypercapnia caused a steepening, as well as upward shift, relative to the corresponding eucapnic ventilation-CO2 output (VE - VCO2) relationship in NL and IRL. Compared with NL, the VE - VCO2 slope was depressed by IRL, more so in hypercapnic [-19.0 +/- 3.4 (SE) %] than in eucapnic exercise (-6.0 +/- 2.0%), despite a similar increase in the slope of the occlusion pressure at 100 ms - VCO2 (P100 - VCO2) relationship under both conditions. The steady-state hypercapnic ventilatory response at rest was markedly depressed by IRL (-22.6 +/- 7.5%), with little increase in P100 response. For a given inspiratory load, breathing pattern responses to separate or combined hypercapnia and exercise were similar. During IRL, VE was achieved by a greater tidal volume (VT) and inspiratory duty cycle (TI/TT) along with a lower mean inspiratory flow (VT/TI). The increase in TI/TT was solely because of a prolongation of inspiratory time (TI) with little change in expiratory duration for any given VT. The ventilatory and breathing pattern responses to IRL during CO2 inhalation and exercise are in favor of conservation of respiratory work.(ABSTRACT TRUNCATED AT 250 WORDS)