Respiratory system stability and abnormal carbon dioxide homeostasis.

We have tested the hypothesis that interactions among eight parameters of the respiratory and cardiovascular systems that determine the loop gain (LG) of the respiratory CO2 feedback control system might account for the degree of stability or instability of breathing patterns in healthy sleeping volunteers as well as in familial dysautonomia (FD) and congenital central hypoventilation syndrome (CCHS) patients. The predictability of cycle duration was tested as well. We measured the values of CO2 sensitivity, CO2 delivery capacity in the circulation, circulation delay, mean lung volume for CO2, and mixed venous PCO2 in 8 FD patients, 2 CCHS patients, and 19 healthy controls. The values of these parameters were used in a mathematical model to compute the LG of the respiratory control system during sleep for each epoch of respiration analyzed. The strength of the ventilatory oscillations (R) was quantified using power density spectra of the ventilation time series. All subjects were studied at inspiratory O2 concentrations (FIO2) of 0.21 and 0.15; CCHS patients and controls were also studied at 0.12 FIO2 to examine the effect of steady-state hypoxia on respiratory system stability. In 2 FD patients, LG was elevated at both levels of FIO2 and periodic breathing was observed; the values of R were elevated. Elevated mixed venous PCO2 and reduced CO2 delivery capacity were chiefly responsible for the abnormally high LG observed. In three healthy volunteers, high LG and unstable patterns were associated with high chemosensitivity. The CCHS patients, however, remained stable even at 0.12 FIO2 because LG remained equivalent to zero due to a lack of chemosensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

A minimal mathematical model of human periodic breathing

Numerous mathematical models of periodic breathing (PB) currently exist. These models suggest mechanisms that may underlie many known causes of PB. However, each model that has been shown to simulate PB under reasonable conditions contains greater than 15 physiological parameters. Because some parameters exhibit a wide range of values in a population, such simulations cannot test a model's ability to account for the breathing patterns of individuals. Furthermore it is impractical to perform a direct experimental validation study that would require the estimation of each of 15 or more parameters for each subject. A minimal model of PB is presented that is suitable for direct validation. Analytic expressions are given that define the conditions for PB in terms of the following: 1) CO2 sensitivity, 2) Cardiac output, 3) Mixed venous CO2, 4) Circulation time, and 5) Mean lung volume for CO2. This model is shown to be consistent with previous models and experimental data regarding the degree of hypoxia or congestive heart failure required to produce PB. A quantitative measure of relative stability is defined as a metric of comparison to the human studies described in the accompanying paper (J. Appl. Physiol. 65: 1389-1399, 1988).     

Induction of oscillatory ventilation pattern using dynamic modulation of heart rate through a pacemaker

For disease states characterized by oscillatory ventilation, an ideal dynamic therapy would apply a counteracting oscillation in ventilation. Modulating respiratory gas transport through the circulation might allow this. We explore the ability of repetitive alternations in heart rate, using a cardiac pacemaker, to elicit oscillations in respiratory variables and discuss the potential for therapeutic exploitation. By incorporating acute cardiac output manipulations into an integrated mathematical model, we observed that a rise in cardiac output should yield a gradual rise in end-tidal CO2 and, subsequently, ventilation. An alternating pattern of cardiac output might, therefore, create oscillations in CO2 and ventilation. We studied the effect of repeated alternations in heart rate of 30 beats/min with periodicity of 60 s, on cardiac output, respiratory gases, and ventilation in 22 subjects with implanted cardiac pacemakers and stable breathing patterns. End-tidal CO2 and ventilation developed consistent oscillations with a period of 60 s during the heart rate alternations, with mean peak-to-trough relative excursions of 8.4 +/- 5.0% (P < 0.0001) and 24.4 +/- 18.8% (P < 0.0001), respectively. Furthermore, we verified the mathematical prediction that the amplitude of these oscillations would depend on those in cardiac output (r = 0.59, P = 0.001). Repetitive alternations in heart rate can elicit reproducible oscillations in end-tidal CO2 and ventilation. The size of this effect depends on the magnitude of the cardiac output response. Harnessed and timed appropriately, this cardiorespiratory mechanism might be exploited to create an active dynamic responsive pacing algorithm to counteract spontaneous respiratory oscillations, such as those causing apneic breathing disorders.     

Periodic breathing in the mouse.

The hypothesis was that unstable breathing might be triggered by a brief hypoxia challenge in C57BL/6J (B6) mice, which in contrast to A/J mice are known not to exhibit short-term potentiation; as a consequence, instability of ventilatory behavior could be inherited through genetic mechanisms. Recordings of ventilatory behavior by the plethsmography method were made when unanesthetized B6 or A/J animals were reoxygenated with 100% O(2) or air after exposure to 8% O(2) or 3% CO(2)-10% O(2) gas mixtures. Second, we examined the ventilatory behavior after termination of poikilocapnic hypoxia stimuli in recombinant inbred strains derived from B6 and A/J animals. Periodic breathing (PB) was defined as clustered breathing with either waxing and waning of ventilation or recurrent end-expiratory pauses (apnea) of > or = 2 average breath durations, each pattern being repeated with a cycle number > or = 3. With the abrupt return to room air from 8% O(2), 100% of the 10 B6 mice exhibited PB. Among them, five showed breathing oscillations with apnea, but none of the 10 A/J mice exhibited cyclic oscillations of breathing. When the animals were reoxygenated after 3% CO(2)-10% O(2) challenge, no PB was observed in A/J mice, whereas conditions still induced PB in B6 mice. (During 100% O(2) reoxygenation, all 10 B6 mice had PB with apnea.) Expression of PB occurred in some but not all recombinant mice and was not associated with the pattern of breathing at rest. We conclude that differences in expression of PB between these strains indicate that genetic influences strongly affect the stability of ventilation in the mouse.     

Effect of paced breathing on ventilatory and cardiovascular variability parameters during short-term investigations of autonomic function

Paced breathing (PB) around 0.25 Hz has been advocated as a means to avoid confounding and to standardize measurements in short-term investigations of autonomic cardiovascular regulation. Controversy remains, however, as to whether it causes any alteration in autonomic control. We addressed this issue in 40 supine, middle-aged, healthy volunteers by assessing the changes induced by PB (0.25 Hz for 8 min) on 1) ventilatory parameters, 2) the indexes of autonomic control of cardiovascular function, and 3) the spectral indexes of cardiovascular variability. Subjects were grouped into group 1 (n = 31), if spontaneous breathing was regular and within the high-frequency (HF) band (0.15-0.45 Hz), or group 2 (n = 9), if it was irregular or slow (< 0.15 Hz). In both groups, PB was accompanied by an increase in minute ventilation (both groups, P < 0.01), whereas tidal volume increased only in group 1 (P = 0.0003). End-tidal CO2 decreased by [median (lower quartile, upper quartile)] -0.2 (-0.5, -0.1)% (group 1, P < 0.0001) and -0.6 (-0.8, -0.5)% (group 2, P = 0.008). Mean R-R interval and systolic and diastolic pressure remained remarkably stable (all P > or = 0.13, both groups). No significant changes were observed in spectral indexes of R-R and pressure variability (all P > or = 0.12, measured only in group 1 to avoid confounding), except in the HF power of pressure signals, which significantly increased (all P < 0.05) in association with increased tidal volume. In conclusion, PB at 0.25 Hz causes a slight hyperventilation and does not affect traditional indexes of autonomic control or, in subjects with spontaneous breathing in the HF band, most relevant spectral indexes of cardiovascular variability. These findings support the notion that PB does not alter cardiovascular autonomic regulation compared with spontaneous breathing.     

Stability analysis of CO2 control of ventilation

A theoretical analysis of the CO2 control of the respiratory system is presented using both analytic and simulation techniques. A stability index (SI) is obtained by linearizing a dynamic first-order model with a time delay. Analytically, SI values greater than unity predict an unstable response to a disturbance. Because the first-order model is reduced from a higher-order physiological model, SI can be algebraically related to physiological parameters. This relationship shows that SI increases with a decrease in system tissue volume, metabolic rate, or inspired CO2 partial pressure; SI decreases with a decrease in time delay, cardiac output, controller gain, or controller intercept. Analytically, SI distinguishes stable from unstable domains. By simulations of the nonlinear first-order model, three domains are obtained: an unstable domain (sustained oscillations, SI greater than 1.1), an underdamped stable domain (transient oscillations, 0.3 less than SI less than 1.1), and an overdamped stable domain (no oscillations, 0 less than SI less than 0.3). With this classification, disturbances such as change of state (e.g., from awake to asleep) or sigh may produce transient oscillations if the system becomes underdamped even though stable. Potential applications of this work include quantitative distinction of the physiological factors in control disorders associated with short-term periodicities (e.g., Cheyne-Stokes breathing, sleep apnea, breathing at altitude).     

Periodic breathing in heart failure patients: testing the hypothesis of instability of the chemoreflex loop.

In this study, we applied time- and frequency-domain signal processing techniques to the analysis of respiratory and arterial O(2) saturation (Sa(O(2))) oscillations during nonapneic periodic breathing (PB) in 37 supine awake chronic heart failure patients. O(2) was administered to eight of them at 3 l/min. Instantaneous tidal volume and instantaneous minute ventilation (IMV) signals were obtained from the lung volume signal. The main objectives were to verify 1) whether the timing relationship between IMV and Sa(O(2)) was consistent with modeling predictions derived from the instability hypothesis of PB and 2) whether O(2) administration, by decreasing loop gain and increasing O(2) stores, would have increased system stability reducing or abolishing the ventilatory oscillation. PB was centered around 0.021 Hz, whereas respiratory rate was centered around 0.33 Hz and was almost stable between hyperventilation and hypopnea. The average phase shift between IMV and Sa(O(2)) at the PB frequency was 205 degrees (95% confidence interval 198-212 degrees). In 12 of 37 patients in whom we measured the pure circulatory delay, the predicted lung-to-ear delay was 28.8 +/- 5.2 s and the corresponding observed delay was 30.9 +/- 8.8 s (P = 0.13). In seven of eight patients, O(2) administration abolished PB (in the eighth patient, Sa(O(2)) did not increase). These results show a remarkable consistency between theoretical expectations derived from the instability hypothesis and experimental observations and clearly indicate that a condition of loss of stability in the chemical feedback control of ventilation might play a determinant role in the genesis of PB in awake chronic heart failure patients.     

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

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

Changes in lung volume and breathing pattern during exercise and CO2 inhalation in humans

Lung volume changes during CO2 inhalation and exercise were compared in seven human subjects. Expiratory reserve volume (ERV) normalized by vital capacity (VC) was used as an index of end-expiratory lung volume (EELV). Work loads tried were 30, 60, and 90 W and inspired CO2 concentrations were 3.5 and 5.0%. Exercise at 30 W led to a significant decrease in EELV, by 7% VC (P less than 0.005), with no further change at higher levels of exercise (P greater than 0.1). Both 3.5 and 5.0% CO2 inhalation resulted in an increase in EELV that was not statistically significant (3% VC, P greater than 0.1). A possible linkage of this different EELV behavior to breathing pattern was tested. The tidal volume-inspiratory duration curve shifted to a higher volume region during exercise compared with CO2 inhalation. Consequently, the volume-time threshold characteristic was better described by an end-inspiratory lung volume-inspiratory duration plot, resulting in a common relationship under these two different stimuli. These results suggest that the depth and rate of breathing in humans can be affected by not only phasic but also tonic components. A decrease in functional residual capacity or EELV was peculiar to exercise and should be associated with increased mechanical efficiency compared with CO2 inhalation. Theoretical predictions based on work of breathing optimization via a decreased EELV seemed to be capable of explaining isocapnic exercise hyperpnea in conjunction with proportional control of arterial CO2 tension.     

Adenosine infusion and periodic breathing during sleep.

Intravenously administered adenosine may increase ventilation (VI) and the ventilatory response to CO2 (HCVR). Inasmuch as we have previously hypothesized that those with higher HCVR may be more prone to periodic breathing during sleep, we measured VI and HCVR and monitored ventilatory pattern in seven healthy subjects before and during an infusion of adenosine (80 micrograms.kg-1.min-1) during uninterrupted sleep. Adenosine increased the mean sleeping VI (7.6 +/- 0.4 vs. 6.5 +/- 0.4 l/min, P less than 0.05) and decreased mean end-tidal CO2 values (42.4 +/- 1.2 vs. 43.7 +/- 1.0 Torr, P = 0.06, paired t test) during stable breathing. In six of seven subjects, periodic breathing occurred during this infusion. The amplitude (maximum VI--mean VI) and period length of this periodic breathing was variable among subjects and not predicted by baseline HCVR [correlation coefficients (r) = 0.64, P = 0.17 and r = -0.1, P = 0.9, respectively]. Attempts to measure HCVR during adenosine infusion were unsuccessful because of frequent arousals and continued periodic breathing despite hyperoxic hypercapnia. We conclude that adenosine infusion increases VI and produces periodic breathing during sleep in most normal subjects studied.     

Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats.

The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO(2)/H(+) chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats (n = 13), and breathing at rest (awake and asleep), breathing during exercise, as well as CO(2) sensitivity were assessed repeatedly before and after sequential injections of the neurotoxins saporin conjugated to substance P [SP-SAP; neurokinin-1 receptor (NK1R) specific] and ibotenic acid (IA; nonspecific glutamate receptor excitotoxin). In all goats, microtubule implantation alone resulted in altered breathing periods, manifested as central or obstructive apneas, and fractionated breathing. The frequency and characteristics of the altered breathing periods were not subsequently affected by injections of the neurotoxins (P > 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO(2) sensitivity was reduced (P < 0.05) by 23.8 and 26.8%, respectively, but CO(2) sensitivity returned to preinjection control values >7 days postinjection. However, there was no hypoventilation at rest (awake, non-rapid eye movement sleep, or rapid eye movement sleep) or during exercise after these injections (P > 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced (P < 0.05) both tryptophan hydroxylase-expressing (36%) and NK1R-expressing (35%) neurons at the site of injection. We conclude that both NK1R- and glutamate receptor-expressing neurons in the medullary raphe nuclei influence CO(2) sensitivity apparently through CO(2)/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO(2) chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms.     

Cardiovascular regulation during long-duration spaceflights to the International Space Station

Early evidence from long-duration flights indicates general cardiovascular deconditioning, including reduced arterial baroreflex gain. The current study investigated the spontaneous baroreflex and markers of cardiovascular control in six male astronauts living for 2-6 mo on the International Space Station. Measurements were made from the finger arterial pressure waves during spontaneous breathing (SB) in the supine posture pre- and postflight and during SB and paced breathing (PB, 0.1 Hz) in a seated posture pre- and postflight, as well as early and late in the missions. There were no changes in preflight measurements of heart rate (HR), blood pressure (BP), or spontaneous baroreflex compared with in-flight measurements. There were, however, increases in the estimate of left ventricular ejection time index and a late in-flight increase in cardiac output (CO). The high-frequency component of RR interval spectral power, arterial pulse pressure, and stroke volume were reduced in-flight. Postflight there was a small increase compared with preflight in HR (60.0 ± 9.4 vs. 54.9 ± 9.6 beats/min in the seated posture, P < 0.05) and CO (5.6 ± 0.8 vs. 5.0 ± 1.0 l/min, P < 0.01). Arterial baroreflex response slope was not changed during spaceflight, while a 34% reduction from preflight in baroreflex slope during postflight PB was significant (7.1 ± 2.4 vs. 13.4 ± 6.8 ms/mmHg), but a smaller average reduction (25%) during SB (8.0 ± 2.1 vs. 13.6 ± 7.4 ms/mmHg) was not significant. Overall, these data show no change in markers of cardiovascular stability during long-duration spaceflight and only relatively small changes postflight at rest in the seated position. The current program routine of countermeasures on the International Space Station provided sufficient stimulus to maintain cardiovascular stability under resting conditions during long-duration spaceflight.     

Lung impedance in healthy humans measured by forced oscillations from 0.01 to 0.1 Hz

Lung impedance was measured from 0.01 to 0.1 Hz in six healthy adults by superimposing small-amplitude forced oscillations on spontaneous breathing. Measurements were made with an almost constant-volume input (160-180 ml) or with an almost constant-flow input (20-30 ml.s-1). No significant difference was found between the two conditions. Lung resistance (RL) sharply decreased from 0.97 kPa.l-1.s at 0.01 Hz to 0.27 kPa.l-1.s at 0.03 Hz and then mildly to 0.23 kPa.l-1.s at 0.1 Hz. Lung effective compliance (CL) decreased slightly and regularly from 0.01 Hz (2.38 l.kPa-1) to 0.1 Hz (1.93 l.kPa-1). The data were analyzed using a linear viscoelastic model adapted from Hildebrandt (J. Appl. Physiol. 28:365-372, 1970) and complemented by a Newtonian resistance (R): RL = R + B/(9.2f); CL = 1/(A + 0.25B + B.log2 pi f), where f is the frequency and B/A is an index of lung tissue viscoelasticity. A good fit was generally obtained, with an average difference of 10% between the observed and predicted values. The ratio B/A was not affected by the breathing and was 10.6 and 13.6% in the constant-volume and constant-flow conditions, respectively, which agrees with Hildebrandt's observations in isolated cat lungs. R was systematically larger than the plethysmographic airway resistance, suggesting that lung tissue resistance might also include a Newtonian component.     

Effort sensation, chemoresponsiveness, and breathing pattern during inspiratory resistive loading.

Although inspiratory resistive loading (IRL) reduces the ventilatory response to CO2 (VE/PCO2) and increases the sensation of inspiratory effort (IES), there are few data about the converse situation: whether CO2 responsiveness influences sustained load compensation and whether awareness of respiratory effort modifies this behavior. We studied 12 normal men during CO2 rebreathing while free breathing and with a 10-cmH2O.l-1.s IRL and compared these data with 5 min of resting breathing with and without the IRL. Breathing pattern, end-tidal PCO2, IES, and mouth occlusion pressure (P0.1) were recorded. Free-breathing VE/PCO2 was inversely related to an index of effort perception (IES/VE; r = -0.63, P less than 0.05), and the reduction in VE/PCO2 produced by IRL was related to the initial free-breathing VE/PCO2 (r = 0.87, P less than 0.01). IRL produced variable increases in inspiratory duration (TI), IES, and P0.1 at rest, and the change in tidal volume correlated with both VE/PCO2 (r = 0.63, P less than 0.05) and IES/VE (r = -0.69, P less than 0.05), this latter index also predicting the changes in TI with loading (r = -0.83, P less than 0.01). These data suggest that in normal subjects perception of inspiratory effort can modify free-breathing CO2 responsiveness and is as important as CO2 sensitivity in determining the response to short-term resistive loading. Individuals with good perception choose a small-tidal volume and short-TI breathing pattern during loading, possibly to minimize the discomfort of breathing.     

Glucose formation in human skeletal muscle. Influence of glycogen content.

Eight men exercised at 66% of their maximal isometric force to fatigue after prior decrease in the glycogen store in one leg (low-glycogen, LG). The exercise was repeated with the contralateral leg (control) at the same relative intensity and for the same duration. Muscle (quadriceps femoris) glycogen content decreased in the LG leg from 199 +/- 17 (mean +/- S.E.M.) to 163 +/- 16 mmol of glucosyl units/kg dry wt. (P less than 0.05), and in the control leg from 311 +/- 23 to 270 +/- 18 mmol/kg (P less than 0.05). The decrease in glycogen corresponded to a similar accumulation of glycolytic intermediates. Muscle glucose increased in the LG leg during the contraction, from 1.8 +/- 0.1 to 4.3 +/- 0.6 mmol/kg dry wt. (P less than 0.01), whereas no significant increase occurred in the control leg (P greater than 0.05). It is concluded that during exercise glucose is formed from glycogen through the debranching enzyme when muscle glycogen is decreased to values below about 200 mmol/kg dry wt.     

Stability of the human respiratory control system I. Analysis of a two-dimensional delay state-space model

A number of mathematical models of the human respiratory control system have been developed since 1940 to study a wide range of features of this complex system. Among them, periodic breathing (including Cheyne-Stokes respiration and apneustic breathing) is a collection of regular but involuntary breathing patterns that have important medical implications. The hypothesis that periodic breathing is the result of delay in the feedback signals to the respiratory control system has been studied since the work of Grodins et al. in the early 1950's [12]. The purpose of this paper is to study the stability characteristics of a feedback control system of five differential equations with delays in both the state and control variables presented by Khoo et al. [17] in 1991 for modeling human respiration. The paper is divided in two parts. Part I studies a simplified mathematical model of two nonlinear state equations modeling arterial partial pressures of O2 and CO2 and a peripheral controller. Analysis was done on this model to illuminate the effect of delay on the stability. It shows that delay dependent stability is affected by the controller gain, compartmental volumes and the manner in which changes in the ventilation rate is produced (i.e., by deeper breathing or faster breathing). In addition, numerical simulations were performed to validate analytical results. Part II extends the model in Part I to include both peripheral and central controllers. This, however, necessitates the introduction of a third state equation modeling CO2 levels in the brain. In addition to analytical studies on delay dependent stability, it shows that the decreased cardiac output (and hence increased delay) resulting from the congestive heart condition can induce instability at certain control gain levels. These analytical results were also confirmed by numerical simulations.     

Effect of reducing anatomic dead space on arterial PCO2 during CO2 inhalation

Carotid body-denervated (CBD) ponies have a less than normal increase in arterial PCO2 (PaCO2) when inspired CO2 (PICO2) is increased, even when pulmonary ventilation (VE) and breathing frequency (f) are normal. We studied six tracheostomized ponies to determine whether this change 1) might be due to increased alveolar ventilation (VA) secondary to a reduction in upper airway dead space (VD) or 2) is dependent on an upper airway sensory mechanism. Three normal and three chronic CBD ponies were studied while they were breathing room air and at 14, 28, and 42 Torr PICO2. While the ponies were breathing room air, physiological VD was 483 and 255 ml during nares breathing (NBr) and tracheostomy breathing (TBr), respectively. However, at elevated PICO2, mixed expired PCO2 often exceeded PaCO2; thus we were unable to calculate physiological VD using the Bohr equation. At all PICO2 in normal ponies, PaCO2 was approximately 0.3 Torr greater during NBr than during TBr (P less than 0.05). In CBD ponies this NBr-TBr difference was only evident while breathing room air and at 28 Torr PICO2. At each elevated PICO2 during both NBr and TBr, the increase in PaCO2 above control was always less in CBD ponies than in normal ponies (P less than 0.01). The VE-PaCO2, f-PaCO2, and tidal volume-PaCO2 relationships did not differ between NBr and TBr (P greater than 0.10) nor did they differ between normal and CBD ponies (P greater than 0.10). We conclude that the attenuated increase in PaCO2 during CO2 inhalation after CBD is not due to a relative increase in VA secondary to reducing upper airway VD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stability of the human respiratory control system II. Analysis of a three-dimensional delay state-space model

A number of mathematical models of the human respiratory control system have been developed since 1940 to study a wide range of features of this complex system. Among them, periodic breathing (including Cheyne-Stokes respiration and apneustic breathing) is a collection of regular but involuntary breathing patterns that have important medical implications. The hypothesis that periodic breathing is the result of delay in the feedback signals to the respiratory control system has been studied since the work of Grodins et al. in the early 1950's [1]. The purpose of this paper is to study the stability characteristics of a feedback control system of five differential equations with delays in both the state and control variables presented by Khoo et al. [4] in 1991 for modeling human respiration. The paper is divided in two parts. Part I studies a simplified mathematical model of two nonlinear state equations modeling arterial partial pressures of O2 and CO2 and a peripheral controller. Analysis was done on this model to illuminate the effect of delay on the stability. It shows that delay dependent stability is affected by the controller gain, compartmental volumes and the manner in which changes in the ventilation rate is produced (i.e., by deeper breathing or faster breathing). In addition, numerical simulations were performed to validate analytical results. Part II extends the model in Part I to include both peripheral and central controllers. This, however, necessitates the introduction of a third state equation modeling CO2 levels in the brain. In addition to analytical studies on delay dependent stability, it shows that the decreased cardiac output (and hence increased delay) resulting from the congestive heart condition can induce instability at certain control gain levels. These analytical results were also confirmed by numerical simulations.     

Avian ventilatory responses to dynamic CO2 signals.

This study uses an awake unidirectionally ventilated avian preparation to examine the effects of dynamic CO2 signals on the respiratory drive. Results show that minute ventilation is affected by both 1) mean CO2 level and 2) amplitude of CO2 oscillations at the frequency of breathing. An increase in mean CO2 level increased minute ventilation. Comparisons of the effects of CO2 oscillations at the same mean CO2 level, however, showed minute ventilation to be less with the larger amplitudes of oscillations than with smaller ones. Graphs of minute ventilation (V) versus mean CO2 for families of oscillation sizes (0.5%, 1% and 2%) showed that the ventilatory sensitivity (slop) was least for the 2% oscillations and greatest for the 0.5% oscillations. Therefore, a static model for the respiratory regulator is not adequate. However, the apneic level of CO2 (V = O intercept) was independent of the size of the CO2 oscillations.     

The effects of the continuous administration of N,N-dimethyl-4-phenylazoaniline (DAB) on the activities and the inducibilities of some drug-metabolizing enzymes in rat liver.

(1) The effect of feeding a relatively low-protein diet containing 0.06% DAB for 29 weeks on the activity of DAB-azoreductase, nitroreductase (p-nitrobenzoic acid), N-oxidase (N,N-dimethylaniline), N-demethylase (DAB), cytochrome P-450, NADPH-cytochrome c reductase, beta-glucuronidase and arylsulphatase A were studied. Rapid decreases occurred in the activities of the first six enzymes, reaching minimal values at between 4 and 8 weeks. Activities then increased in all cases to control or nearly control levels. This rate of increase was least for cytochrome P-450. At 4 weeks azoreductase activity with the chemotherapeutic agent CB10-252 (I) as substrate was significantly higher than in control rats. Early increases occurred in the activities of beta-glucuronidase and arylsulphatase A and the activity of the latter never dropped below the control level. (2) An investigation was made of the differential effects of dye feeding on some of the enzyme activities in the two major liver lobes and differences were found. (3) The effect of phenobarbital (PB) pretreatment on the DAB-fed rats was studied at 4-week intervals. The activities of DAB-azoreductase and of nitroreductase increased throughout the whole period, while the activities of the lysosomal enzymes were decreased. (4) After feeding DAB for 4 weeks the effect of PB and 3-methylcholanthrene (MC) on the activities of DAB-azoreductase, CB10-252-azoreductase and components of the azoreductases-cytochrome P-450, NADPH-cytochrome c reductase, the CO-CB10-252-azoreductase was not induced by PB or MC, and CO did not inhibit its reduction. Its reduction depended only slightly on NADH. CO caused a greater relative decrease in the activity of DAB-azoreductase in dye-fed animals and also in animals following PB and MC pretreatment, implying a greater role of cytochrome P-450 in dye-fed animals.