Multiple modes of periodic breathing during sleep.
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Humans↗
Biomedical subjects
M C Khoo
Publications and source records attributed to M C Khoo.
Change in the peripheral CO2 chemoreflex from rest to exercise.
A single-breath CO2 test of peripheral chemosensitivity has recently been described, and elaborated based on model simulations. This study was designed to measure the peripheral CO2 chemoreflex at rest and during heavy exercise to see if carotid chemosensitivity to CO2 increased. Ten healthy, adult males performed an incremental exercise test to determine their ventilatory anaerobic threshold (VAT), and 20 minutes of steady-state exercise at a pre-determined power output above VAT. Arterialized venous blood was obtained during each minute of incremental exercise to verify development of metabolic acidosis. Carotid chemosensitivity was tested repeatedly at rest and in steady-state exercise by the ventilatory response to a single breath of 13% CO2 in air. The peripheral chemoreflex for CO2 for the group of subjects doubled from rest to exercise (mean 0.096 l.s-1.kPa-1) with all subjects showing an increase. We conclude that the gain of the carotid CO2 chemoreflex increases from rest to exercise at work above the VAT.
Adult↗
Estimation of dynamic chemoresponsiveness in wakefulness and non-rapid-eye-movement sleep.
We developed a method for quantifying dynamic chemoresponsiveness on the basis of the ventilatory response to pseudorandom binary CO2 stimulation. The dynamic chemoreflex gain (GD) and effective time delay (TDeff) relating breath-to-breath fluctuations in alveolar PCO2 to ventilation were evaluated at frequencies between 0 and 0.05 Hz. Application of the method to simulated "data" showed that estimation errors in GD and TDeff were most likely to be minimized in the range of 0.01-0.03 Hz, corresponding to periodicities of 30-100 s. Estimation of TDeff was generally more susceptible to error than that of GD because of the limited time resolution of the breath-by-breath measurements. In eight awake normal adults, we compared estimates of GD derived from the pseudorandom binary CO2 stimulation test with peripheral and central hypercapnic sensitivities deduced from single-breath and Read rebreathing measurements in the same subject. GD at 0.02 Hz was highly correlated with peripheral hypercapnic sensitivity but poorly correlated with central hypercapnic sensitivity, underscoring the importance of the peripheral chemoreflexes in mediating ventilatory responses to phasic stimuli. Application of the procedure to a different group of 10 healthy volunteers during wakefulness and stage 2 sleep showed decreases in GD in 8 subjects but increases in 2 subjects. However, for the group as a whole, GD and TDeff did not change significantly between wakefulness and sleep. The proposed method may provide information more pertinent to periodic breathing than traditional CO2 response tests do, since the chemoreflex responses to phasic variations in blood gases are likely to be important in determining ventilatory control during sleep.
Adult↗
"Ventilatory stability to CO2 disturbances in wakefulness and quiet sleep".
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Carbon Dioxide↗
Ventilatory response to randomly modulated hypercapnia and hypoxia in humans.
We have developed a new method for characterizing the ventilatory response to combined hypercapnia and hypoxia (HCVR-HVR) based on the results of a single test procedure. The method is designed to evoke both hypercapnic and hypoxic responses simultaneously and to enable quantification of their static and dynamic features using an estimation algorithm based on the prediction error method. In six healthy subjects, we measured HCVR-HVR by modulating the CO2 and O2 content of the inhaled mixture in the form of two statistically independent random sequences. A two-component dynamic model was found to provide an adequate description of the stimulation-response data sets. The model consisted of a CO2 subsystem and a CO2-O2 subsystem in which a multiplicative interaction between hypercapnia and hypoxia was assumed. The steady-state gains were 2.08 +/- 0.68 (SD) 1.min-1.Torr-1 for the CO2 subsystem and 0.10 +/- 0.05 l.min-1.Torr-1 for the CO2-O2 subsystem, and the corresponding time constants were 116.7 +/- 32.3 and 19.0 +/- 4.4 s, respectively. Our results suggest that the hypercapnic component of HCVR-HVR is mediated primarily by the central chemoreceptors, whereas the interaction component is mediated largely by the peripheral chemoreceptors.
Adult↗
Optimal application of high-frequency ventilation in infants: a theoretical study.
A recent multicenter study of preterm infants concluded that high-frequency ventilation (HFV) applied at 15 Hz, in comparison with conventional mechanical ventilation (CMV), did not lead to reduced incidence of barotrauma, contrary to previous expectations. The primary goal of the present theoretical study was to determine whether computed estimates of lung pressures during HFV and CMV are consistent with these findings. An existing theoretical model of lung mechanics and gas transport in HFV was modified for applicability to neonates. New features, such as expiratory flow limitation and pulmonary air leak, were also incorporated. Simulations with the model were conducted assuming combinations of frequency and tidal volume that maintained a constant level of eucapnia. We found that peak alveolar pressures and the magnitude of alveolar pressure swings resulting from HFV at 15 Hz were in general comparable to those produced by CMV in healthy neonates and infants with bronchopulmonary dysplasia; peak alveolar pressures in the latter group tended to be higher with HFV than in CMV. Application of HFV at 15 Hz was even less advantageous than CMV when pulmonary air leak was also present in the infants with bronchopulmonary dysplasia. However, the model predicted the existence of an optimal range of frequencies between 2 and 4 Hz in which alveolar pressure swings and peak alveolar pressures could be minimized, and in some cases, reduced below the levels produced by CMV.
Bronchial Fistula↗
Sleep-induced periodic breathing and apnea: a theoretical study.
To elucidate the mechanisms that lead to sleep-disordered breathing, we have developed a mathematical model that allows for dynamic interactions among the chemical control of respiration, changes in sleep-waking state, and changes in upper airway patency. The increase in steady-state arterial PCO2 accompanying sleep is shown to be inversely related to the ventilatory response to CO2. Chemical control of respiration becomes less stable during the light stage of sleep, despite a reduction in chemoresponsiveness, due to a concomitant increase in "plant gain" (i.e., responsiveness of blood gases to ventilatory changes). The withdrawal of the "wakefulness drive" during sleep onset represents a strong perturbation to respiratory control: higher magnitudes and rates of withdrawal of this drive favor instability. These results may account for the higher incidence of periodic breathing observed during light sleep and sleep onset. Periodic ventilation can also result from repetitive alternations between sleep onset and arousal. The potential for instability is further compounded if the possibility of upper airway occlusion is also included. In systems with high controller gains, instability is mediated primarily through chemoreflex overcompensation. However, in systems with depressed chemoresponsiveness, rapid sleep onset and large blood gas fluctuations trigger repetitive episodes of arousal and hyperpnea alternating with apneas that may or may not be obstructive. Between these extremes, more complex patterns can arise from the interaction between chemoreflex-mediated oscillations of shorter-cycle-duration (approximately 36 s) and longer-wavelength (approximately 60-80 s) state-driven oscillations.
Airway Obstruction↗
A model-based evaluation of the single-breath CO2 ventilatory response test.
The accuracy of the single-breath CO2 inhalation test as a method for determining peripheral chemoreflex gain (Gp) is evaluated through computer simulations using a mathematical model of the closed-loop respiratory control system. Estimates of Gp (G'p) are based on "corrected" changes in end-tidal PCO2, because the uncorrected end-tidal values do not accurately reflect changes in alveolar PCO2. The influence of the central chemoreflex on G'p is generally less than 10% but can become disproportionally more significant as the relative contribution of the peripheral chemoreflex diminishes. G'p tends to overestimate Gp with the inclusion of peripheral chemoreceptor rate sensitivity, but this effect is offset by the time constant for adaptation. The spontaneous variability of breathing can seriously impair the resolution of G'p. Averaging of G'p deduced from individual single-breath tests can lead to erroneous estimates of Gp even when a large number of repetitions are performed. This problem can be minimized by first ensemble averaging the data from individual single-breath tests and, then, computing G'p from the resulting mean changes.
Carbon Dioxide↗
Estimation of peripheral chemoreflex gain from spontaneous sigh responses.
A method is proposed for quantifying the responsiveness of the peripheral chemoreflex loop to CO2 by utilizing the natural fluctuations in ventilation and end-tidal PCO2 which occur subsequent to the appearance of spontaneous sighs. The advantage of this method lies in its simplicity and noninvasiveness: the need for administering inhaled mixtures with high CO2 content is eliminated. Using autoregressive moving-average (ARMA) analysis, we demonstrate that post-sigh responses can be adequately described by a simple chemoreflex model that contains first-order dynamics and a pure time delay. The effective gain of this model is shown to reflect peripheral chemosensitivity closely when the estimation procedure is applied to 'data' obtained from computer simulations of the respiratory control system. Although central chemosensitivity affects the absolute values of effective gain, the slope of the linear correlation between effective and peripheral gains remains unchanged. Application of the procedure to spontaneously breathing anesthetized dogs shows that, in every case, effective gain increased with the induction of hypoxia, which is known to enhance peripheral chemosensitivity.
Animals↗
Non-invasive tracking of peripheral ventilatory response to carbon dioxide.
We propose a new method for quantifying the ventilatory sensitivity of the peripheral chemoreceptors to changes in CO2 through analysis of the natural breath-to-breath variations in ventilation (y) and alveolar PCO2 (x). This technique is truly non-invasive in that the need for administering CO2-enriched mixtures is circumvented, and peripheral chemosensitivity is assessed while the respiratory control system operates in its normal eucapnic state, unperturbed by external interventions. The method is based on solution of the inverse problem relating the cross-correlation between alveolar PCO2 and ventilation changes, and the autocorrelation of changes in alveolar PCO2. Tests are performed using simulated data generated by a closed-loop respiratory control model. The impulse response of the controller and the convective delay between lungs and chemoreceptors are estimated from the data. Subsequently, the best exponential fit to the estimated impulse response yields values for the effective controller gain (G) and the associated time constant of the response. The estimates of G contain a small contribution from the control chemoreflex gain; however, the relation between changes in G and changes in peripheral gain remains unaltered. The effects of other details in the computation procedure, such as length of data sequence, maximum number of correlation lags and starting lag number, are also investigated.
Carbon Dioxide↗
Lung pressures and gas transport during high-frequency airway and chest wall oscillation.
The major goal of this study was to compare gas exchange, tidal volume (VT), and dynamic lung pressures resulting from high-frequency airway oscillation (HFAO) with the corresponding effects in high-frequency chest wall oscillation (HFCWO). Eight anesthetized paralyzed dogs were maintained eucapnic with HFAO and HFCWO at frequencies ranging from 1 to 16 Hz in the former and 0.5 to 8 Hz in the latter. Tracheal (delta Ptr) and esophageal (delta Pes) pressure swings, VT, and arterial blood gases were measured in addition to respiratory impedance and static pressure-volume curves. Mean positive pressure (25-30 cmH2O) in the chest cuff associated with HFCWO generation decreased lung volume by approximately 200 ml and increased pulmonary impedance significantly. Aside from this decrease in functional residual capacity (FRC), no change in lung volume occurred as a result of dynamic factors during the course of HFCWO application. With HFAO, a small degree of hyperinflation occurred only at 16 Hz. Arterial PO2 decreased by 5 Torr on average during HFCWO. VT decreased with increasing frequency in both cases, but VT during HFCWO was smaller over the range of frequencies compared with HFAO. delta Pes and delta Ptr between 1 and 8 Hz were lower than the corresponding pressure swings obtained with conventional mechanical ventilation (CMV) applied at 0.25 Hz. delta Pes was minimized at 1 Hz during HFCWO; however, delta Ptr decreased continuously with decreasing frequency and, below 2 Hz, became progressively smaller than the corresponding values obtained with HFAO and CMV.
Animals↗
Minimization of lung pressure swings during high-frequency ventilation: a model.
The goal of this theoretical study was to develop a simple computational model for determining the lung pressure excursions that accompany the maintenance of adequate gas transport through high-frequency airway oscillations applied via the trachea (HFAO) and by transthoracic means (HFTO). Respiratory mechanics and gas transport parameters estimated from the preceding companion study (J. Appl. Physiol. 67: 985-992, 1989) were used in the model for computing tracheal, alveolar, pleural, and transpulmonary pressure swings. Comparison of model predictions with corresponding data obtained in dogs showed close agreement. The specification of eucapnia as a constraint led to results that were significantly different from previous findings which had assumed constant airflow. We used the model to identify "quasi-optimal" strategies for HFAO and HFTO application in which all pressure excursions were kept below the corresponding levels produced by conventional mechanical ventilation operating at 15 breaths/min. The model suggests the application of both HFAO and HFTO at frequencies substantially lower than the settings commonly employed in high-frequency ventilation. Application of HFAO at frequencies ranging from 1 to 4 Hz is recommended, whereas for HFTO the quasi-optimal range lies between 1 and 1.7 Hz. In patients with chronic obstructive pulmonary disease, pressure costs during HFAO or HFTO are minimized in the vicinity of 1 Hz.
Airway Resistance↗
Effects of high-frequency chest wall oscillation on respiratory control in humans.
We studied the spontaneous breathing patterns of 10 normal adult volunteers during high-frequency chest wall oscillation (HFCWO), accomplished by inflating and deflating a vest worn around each subject's thorax at 2.5 Hz. Tidal volumes generated by HFCWO averaged 100 ml. Mean vest pressure was maintained at approximately 35 cm H2O throughout each experiment, even when HFCWO was not applied. During HFCWO, subjects were instructed occasionally to exhale deeply to obtain end-tidal samples representative of PACO2. HFCWO increased the breath-to-breath variability of spontaneous respiration in all subjects, prolonging expiratory pauses and producing short apneas in some cases. PACO2 decreased significantly (p less than 0.05). The effects on minute ventilation, tidal volume, and inspiratory and expiratory durations remained variable across subjects, even when differences in PACO2 between control and HFCWO states were reduced through inhalation of a low CO2 mixture. None of the changes were statistically significant, although average expiratory duration increased by 29%. Ventilatory responses to CO2 with and without HFCWO were also measured. Normocapnic (PACO2 = 40 mm Hg) ventilatory drive increased significantly (p less than 0.05) in six subjects (Type 1 response) and decreased substantially in the others (Type 2 response); with hypercapnia, the changes in drive were attenuated in both groups. Consequently, CO2 sensitivity decreased in Type 1 subjects and increased in Type 2 subjects. A simple analysis based on this result shows that with HFCWO, Type 2 subjects breathing air will tend to have a lower spontaneous minute ventilation and become hypercapnic. Type 1 subjects will become hypocapnic, but minute ventilation may be higher or lower than control.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Simulation of gas transport due to cardiogenic oscillations.
We simulated gas transport due to cardiogenic oscillations (CO) using a model developed to quantify the gas mixing due to high-frequency ventilation (16). The basic components of the model are 1) gas mixing by augmented transport, 2) symmetrical lung morphometry, and 3) a Lagrangian (moving) reference frame. The theoretical predictions of the model are in general agreement with published experimental studies that have examined the effect of CO on the nitrogen concentration obtained by intrapulmonary gas sampling and the effect of CO on regional and total anatomical dead space. Further, the model predicts that augmentation of gas transport due to CO is less, nearer to the alveolar regions of the lung, and that the effect of CO during normal tidal breathing is negligible, but that CO may contribute up to approximately 10% of the alveolar ventilation in patients with severe hypoventilation. The agreement between experimental and theoretical results suggests that it may not be necessary to invoke gas transport mechanisms specific to an asymmetrical bronchial tree to explain the major proportion of gas transport due to CO.
Carbon Monoxide↗
Intra-airway gas mixing during high-frequency ventilation.
We examined the intra-airway gas transport mediated by high-frequency oscillations (HFO) in 10 nonintubated healthy volunteers using a method based on comparisons of single-breath N2-washout curves obtained after various durations of breath hold or high-frequency oscillations. With a mathematical analysis based on Fick's law of diffusion we computed the local transport parameter, effective diffusivity, during oscillations of frequency 2-24 Hz and tidal volume 10-120 ml and during breath hold alone. Local effective diffusivity increased with both oscillatory frequency and tidal volume at all levels in the tracheobronchial tree; the enhancing effect of tidal volume on local effective diffusivity was more pronounced than that of frequency so that effective diffusivity was greater with larger tidal volume at fixed frequency-tidal volume product (f . VT). The greatest enhancement of gas mixing within the lung during HFO (over breath hold) was seen in the central airways. In previous studies examining CO2 removal rate during HFO (J. Clin. Invest. 68: 1475, 1981), we found that CO2 output was also greater with larger tidal volume at fixed f . VT, and we attributed this to an end constraint imposed by a fresh gas bias flow. Results of the current study, performed without a bias flow, indicate that bias flow end constraint does not solely account for the observed dependence of CO2 output on frequency and tidal volume.
Adult↗
Gas mixing during high-frequency ventilation: an improved model.
A model for gas transport during high-frequency ventilation incorporating recently derived empirical forms for the effective diffusivity in oscillatory gas flow through a symmetrical branching network is proposed. The model accounts for the movement of gas among airways with changing cross-sectional area by using a moving-reference-frame analysis. The analysis technique incorporates the convective purging of the bias flow at the airway opening. The model predicts that although the cycle-averaged CO2 elimination rate (VCO2) depends most strongly on the product of frequency and tidal volume (VT), VT has an effect on its own, a finding consistent with published observations. This "VT effect" is due primarily to the oscillatory movement of gas from more central regions into peripheral regions where large cross-sectional areas promote efficient CO2 transport by molecular diffusion. Although the VT effect exists independent of the presence of a bias flow, placing the bias flow near the main carina can enhance the VT effect substantially. As VT is increased to values in the range of ordinary tidal breaths, VCO2 predicted by the model achieves close agreement with VCO2 deduced from conventional gas exchange theory.
Biological Transport↗
Factors inducing periodic breathing in humans: a general model.
A general model is developed to account for all kinds of periodic breathing (PB) resulting from instability in respiratory control: in normals during sleep and on acute exposure to high altitude, in sleeping infants, and in patients with cardiovascular or neurologic lesions. It is found that in almost every case the ventilatory oscillation is mediated predominantly by the peripheral controller. System stability is decreased by hypoxia, hypercapnia, increased lung washout times, prolonged lung-chemoreceptor delays, and high controller sensitivity. Stability is enhanced by large lung CO2 and O2 storage volumes but little affected by body tissue stores. Using our own measurements of lung-ear delays, the model predicts that the mean cycle time of PB decreases from about 30 s at sea level to 20 s at 14,000 ft, in excellent agreement with data from other studies. Allometric scaling of the relevant parameters also shows close agreement between model predictions and data obtained on infants.
Adult↗
Visibility of chromatic flicker upon spectrally mixed adapting fields.
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Adaptation, Ocular↗