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Biomedical subjects

M C Khoo

Publications and source records attributed to M C Khoo.

At least 19 recordsLinked to original sources
PubMed1998

Fuzzy assessment of sleep-disordered breathing during continuous positive airway pressure therapy.

We propose a new method of quantifying sleep-disordered breathing (SDB) for the purpose of automating continuous positive airway pressure (CPAP) titration. Our algorithm, based on fuzzy logic, emulates the less-than-crisp kind of decision-making generally employed at the human level. Three input variables were first derived on a breath-by-breath basis from respiratory airflow measurements. These were: (1) the relative duration of inspiratory flow limitation in each breath; (2) the degree of hypopnea relative to the past 15 breaths; and (3) the intensity of snoring. Using these descriptors as inputs, our fuzzy inference algorithm produced a "severity index" (SI) quantifying the degree of SDB. Severity index was determined in CPAP titration procedures conducted on one normal snorer and 12 patients with moderate-to-severe obstructive sleep apnea. SI computed over the last 6 minutes of each CPAP level was compared against other more-conventional indices of SDB, such as total pulmonary resistance (RL), the number of apneas and hypopneas (NAH), and the number of arousals (NAr). In all but one of the subjects, the correlation coefficients for SI vs each of RL, NAH, and NAr were significantly different from zero, but not different from each other. The group correlation coefficients for SI vs RL, NAH, and NAr were 0.89, 0.86, and 0.87, respectively, demonstrating that SI accurately quantifies SDB. SI collapses multiple features of the airflow pattern into a single index and, therefore, may be useful as a "feedback" variable for the automatic control of CPAP therapy.

Adult↗
PubMed1998

Ventilatory dynamics of transient arousal in patients with obstructive sleep apnea.

The hyperpnea that accompanies arousal at the end of obstructive apnea is believed to be due to the progressive build-up in chemical drive during the apnea and a state-related decrease in upper airway resistance. We postulated the existence of a third component: a state-related transient increase in neural drive to the ventilatory pump muscles. To quantify this contribution, we measured the ventilatory response to arousal (VRA) in eight patients with obstructive sleep apnea (OSA) during continuous positive airway pressure (CPAP) therapy, applied at individually titrated levels. CPAP application reduced total pulmonary resistance (RL) to approximately normal levels, stabilizing ventilation and sleep state. Transient arousal from stage 2 sleep was induced using 5-sec tones (60-90 dB). Mean inspiratory flow increased above control on the second and third post-arousal breaths (P < 0.05), with a peak increase of 7.8 +/- 2.9 L/min while the accompanying changes in RL were significant. The time-course of VRA measured in three normal subjects under CPAP was similar to that observed in the OSA patients. However, elimination of CPAP prolonged the VRA time-course. Taken together, these findings demonstrate that: (1) during arousal, the increase in state-related neural respiratory drive is short-lived but not substantial; and (2) the resulting VRA time-course is shaped by the dynamics of the upper airway response to arousal.

Acoustic Stimulation↗
PubMed1998

Within-night variation in respiratory effort preceding apnea termination and EEG delta power in sleep apnea.

We studied the within-night variability of the maximum esophageal pressure deflection before apnea termination (DPmax) in nine patients with severe obstructive sleep apnea as an index of the arousal threshold and the mean electroencephalogram (EEG) delta power for each 30 s as an index of the timing of sleep cycles. Periodicity in the time variation of delta power and DPmax was analyzed by determining their power spectral density and their relationship determined by cross correlation. DPmax and delta power varied cyclically and in phase with a major periodicity (major peak in power spectral density) of 117.6 +/- 8.8 (SE) min. The correlation between the values of DPmax and delta power was significant (P < 0.001) in each subject (mean r = 0.47 +/- 0.03), and the coherence between DPmax and delta power at their dominant frequency was high. Within cycles of non-rapid-eye-movement sleep, DPmax and delta power increased, reaching peak values on average at or after midcycle. These findings suggest that the arousal threshold to airway occlusion in patients with obstructive sleep apnea varies cyclically during the night synchronous to the underlying cycles of sleep.

Activity Cycles↗
PubMed1997

Estimation of chemoreflex loop gain using pseudorandom binary CO2 stimulation.

We have developed a method for deriving estimates of the chemoreflex control loop gain (LG) from the ventilatory response to inhaled CO2, modulated between 0% and 5% in the form of a pseudorandom binary sequence. The corresponding changes in alveolar (and thus, arterial) CO2 result from two components: 1) the direct effect of breath-to-breath changes in inhaled CO2 and 2) the chemoreflex-mediated changes in ventilation. LG between 0.01 and 0.03 Hz, the frequency range pertinent to periodic breathing, was estimated by computationally delineating the first component from the overall ventilatory response. The method was tested against simulated and experimental data. In both cases, we found strong correlations between our predictions and LG magnitude estimates derived by other methods. However, LG phase estimates were considerably more variable when compared to model predictions based on small-signal analysis. We propose that our method, which uses data from a single test procedure lasting < 10 min, may be more useful than traditional tests of chemoresponsiveness for the quantitative assessment of respiratory control stability during changes in sleep-wake state.

Carbon Dioxide↗
PubMed1997

Estimation of cardiorespiratory transfer under spontaneous breathing conditions: a theoretical study.

Using simulated noisy sequences of respiration and heart rate, we assessed the accuracy of the respiratory sinus arrhythmia transfer function (RSATF) estimation under three kinds of spontaneous breathing patterns: regular or tidal breathing, periodic breathing with apnea, and broadband breathing. Estimation employing the cross-power and autopower spectra of the simulated data produced RSATF estimates that were generally more variable than those computed with an autoregressive modeling approach. Variability and bias errors in the RSATF estimates became larger as respiratory bandwidth decreased when the breathing pattern changed from broadband to periodic to regular breathing. However, between frequencies of 0.1 and 0.3 Hz, these errors fell within 12% in all breathing patterns. Error in the RSATF estimates was only slightly increased, with reductions in data length to as low as 90 s. The results suggest the feasibility of obtaining accurate estimates of RSATF between 0.1 and 0.8 Hz from a wide variety of conditions, such as in different sleep-wake states where voluntary control of breathing is not possible and the ventilatory pattern may vary substantially.

Arrhythmia, Sinus↗
PubMed1996

Dynamics of periodic breathing and arousal during sleep at extreme altitude.

To determine whether nocturnal periodic breathing (PB) at altitude is due primarily to unstable control of ventilation or the inability to maintain stable sleep states, we performed visual and computer analyses of the electroencephalographic and respiratory records of healthy volunteers at simulated altitudes of 4572, 6100 and 7620 m. Transient arousals were associated with < 52% of the apneas identified; thus, the PB cycle was not always associated with transient arousal. Following the termination of oxygen breathing, the reinitiation of PB was not dependent on the occurrence of arousal as the primary event. The transition from apnea to breathing preceded the appearance of arousal by approximately 1 to 4 sec. Ventilatory drive in the breaths immediately following arousal was significantly larger than corresponding control breaths, matched for SaO2. Our findings suggest that altitude-induced PB is unlikely to result from primary fluctuations in state. Arousals promote the development of PB with apnea and help to sustain these episodes, but are not necessary for their initiation.

Altitude↗
PubMed1996

Transduction dynamics of intrapulmonary CO2 receptors.

We have developed a functional model for quantitatively characterizing the transduction dynamics of the intrapulmonary CO2 receptors (IPC) in the snake lung. The model was based on experiments in which the neural discharges of several IPCs were recorded in response to abrupt step changes in CO2 concentration. Initial attempts to model the transduction dynamics linearly proved inadequate, although the linear model captured gross features such as rate sensitivity and the existence of two time constants in the adaptation time-course. However, with the incorporation of two static nonlinear features, namely, thresholding and preferential directionality of the rate-sensitive component, it was possible to account for over 80% of the total variation in the data. The model produced accurate predictions of IPC responses to other inputs, such as pseudorandom binary changes in CO2. The model also allows the prediction of IPC discharge in spontaneous breathing given measurements of lung CO2 concentration, and may serve as a starting point for further studies of transduction mechanisms at the cellular level.

Animals↗
PubMed1996

Modeling the interaction between arousal and chemical drive in sleep-disordered breathing.

We have measured the ventilatory response to acoustically induced arousal in normal subjects and patients with obstructive sleep apnea syndrome (OSAS). The arousal responses are similar in magnitude and time-course over the first 3 breaths, but in OSAS the subsequent response declines much more rapidly. Incorporation of these empirical findings into an existing model of sleep-disordered breathing allows an improved characterization of state-chemoreflex interactions. The shorter time-course of the arousal response in OSAS promotes greater ventilatory and state instability at low-to-intermediate levels of CO2 gain.

Adolescent↗
PubMed1996

Ventilatory dynamics during transient arousal from NREM sleep: implications for respiratory control stability.

The polysomnographic and ventilatory patterns of nine normal adults were measured during non-rapid-eye-movement (NREM) stage 2 sleep before and after repeated administrations of a tone (40-72 dB) lasting 5 s. The ventilatory response to arousal (VRA) was determined in data sections showing electrocortical arousal following the start of the tone. Mean inspiratory flow and tidal volume increased significantly above control levels in the first seven breaths after the start of arousal, with peak increases (64.2% > control) occurring on the second breath. Breath-to-breath occlusion pressure 100 ms after the start of inspiration showed significant increases only on the second and third postarousal breaths, whereas upper airway resistance declined immediately and remained below control for > or = 7 consecutive breaths. These results suggest that the first breath and latter portion of the VRA are determined more by upper airway dynamics than by changes in the neural drive to breathe. Computer model simulations comparing different VRA time courses show that sustained periodic apnea is more likely to occur when the fall in the postarousal increase in ventilation is more abrupt.

Adult↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1994

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↗
PubMed1993

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↗
PubMed1991

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↗
PubMed1990

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↗