Bifurcation of the respiratory response to lung inflation in anesthetized dogs.

Numerous studies have demonstrated the effect of lung volume on prolongation of duration of expiration (TE) with limited understanding of the TE shortening and termination of expiration as observed in newborn. In 14 dogs, the effects of varied onset of lung inflation during expiration on the TE were evaluated. When lung inflation was applied in the first part of expiration (20-60% of TE) TE was lengthened. However, in the second portion (60-80% of TE) of expiration, lung inflation either terminated or prolonged TE; whereas in the last portion of expiration (80-90% of TE), lung inflation tended to terminate expiration prematurely. The effects were abolished after bilateral vagotomy. We postulate that prolongation of TE relates to the Breuer-Hering inflation reflex, which increases the time needed for a passive expiration; whereas the ability to shorten TE could relate to Head's paradoxical reflex acting to initiate inspiration or to activate inspiratory motor activity to brake expiratory flow as occurs in the newborn.

Computational analyses of CO-rebreathing methods for estimating haemoglobin mass in humans.

Measurement of haemoglobin mass (M(Hb)) is used to quantify alterations in oxygen delivery during exercise training or acclimatization to altitude. Uptake of carbon monoxide by haemoglobin is the basis of the common non-radioactive methods to determine M(Hb) in humans. This study used a validated mathematical model to simulate CO uptake during rebreathing protocols and to determine sources of errors in estimation of M(Hb). Our previously published model was validated using experimentally measured carboxyhaemoglobin levels (%HbCO) from arterial, capillary and venous blood sites of human subjects during CO-rebreathing protocols. This model was then used to simulate various CO-rebreathing protocols in 24 human subjects with known M(Hb). Using variables generated by the model, M(Hb) was estimated on the basis of assumptions typically made for calculating the volume of CO bound to myoglobin, the volume of CO exhaled and the volume of CO in the rebreathing system. It was found that inaccurate estimation of the volume of CO bound to myoglobin was the major source of error in determination of M(Hb). Additionally, the size of the error was found to depend on the site of blood sampling because of differences in %HbCO. Regression equations were developed to improve the estimation of volume of CO bound to myoglobin, and a new protocol that is less dependent on the site of blood sampling is proposed.

Coordination of respiratory muscles assessed by means of nonlinear forecasting of demodulated myographic signals.

Pulmonary diseases such as obstructive sleep apnea syndrome (OSAS) affect function of respiratory muscles. Individuals with OSAS suffer intermittent collapse of the upper airways during sleep due to unbalanced forces generated by the contraction of the diaphragm and upper airway dilator muscles. Respiratory rhythm and pattern generation can be described via nonlinear or coupled oscillators; therefore, the resulting activation of different respiratory muscles may be related to complex nonlinear interactions. The aims of this work were: to evaluate locally linear models for fitting and prediction of demodulated myographic signals from respiratory muscles; and to analyze quantitatively the influence of a pulmonary disease on this nonlinear forecasting related to low and moderate levels of respiratory effort. Electromyographic and mechanomyographic signals from three respiratory muscles (genioglossus, sternomastoid and diaphragm) were recorded in OSAS patients and controls while awake during an increased respiratory effort. Variables related to auto and cross prediction between muscles were calculated from the r(2) coefficient and the estimation of residuals, as functions of prediction horizon. In general, prediction improved linearly with higher levels of effort. A better prediction between muscle activities was obtained in OSAS patients when using genioglossus as the predictor signal. The prediction was significant for more than two respiratory cycles in OSAS patients compared to only a half cycle in controls. It could be concluded that nonlinear forecasting applied to genioglossus coupling with other muscles provides a promising assessment to monitor pulmonary diseases.

A mathematical modeling approach to risk assessment for normal and anemic women chronically exposed to carbon monoxide from biomass-fueled cookstoves.

In developing countries, the chronic exposure to carbon monoxide (CO) from biomass-fueled cookstoves may pose a significant health risk for women who use these stoves, especially for those with underlying clinical conditions that impair tissue oxygenation, e.g., anemia and coronary artery disease. CO concentrations measured in the vicinity of these cookstoves often exceed World Health Organization (WHO) indoor air guidelines for an 8-h average (9 ppm) and a 1-h maximum (26 ppm). Carboxyhemoglobin levels, reported infrequently because they are difficult to obtain, often exceed the WHO threshold of 2.5%. Despite this evidence, specific adverse effects have not yet been linked with chronic CO exposures in these women. Furthermore, anemia, which is prevalent in populations that use biomass fuels, could exacerbate the adverse effects of chronic CO exposure. Because of the difficulties inherent in conducting prospective studies to address this issue, we used a mathematical model to calculate the effects of reported CO levels and exercise on carboxyhemoglobin for women living in 1) Guatemalan villages at altitudes of 4,429-4,593 ft, and 2) coastal villages in Pakistan. In addition, we used the model to calculate the effects of CO exposures in women with moderate to severe anemia on specific physiological parameters (carboxyhemoglobin, carboxymyoglobin, cardiac output, and tissue Po(2)) at exercise levels representing the activities in which these women would be engaged. Our results demonstrate the efficacy of using a mathematical model to predict the physiologic responses to CO and also demonstrate that chronic anemia is a critically important determinant of CO toxicity in these women.

Mutual information analysis of EEG signals indicates age-related changes in cortical interdependence during sleep in middle-aged versus elderly women.

Elderly subjects exhibit declining sleep efficiency parameters with longer time spent awake at night and greater sleep fragmentation. In this article, we report on the changes in cortical interdependence during sleep stages between 15 middle-aged (range: 42-50 years) and 15 elderly (range: 71-86 years) women subjects. Cortical interdependence assessed from EEG signals typically exhibits increasing levels of correlation because human subjects progress from wake to deeper stages of sleep. EEG signals acquired from previously existing polysomnogram datasets were subjected to mutual information analysis to detect changes in information transmission associated with change in sleep stage and to understand how age affects the interdependence values. We observed a significant reduction in the interdependence between central EEG signals of elderly subjects in nonrapid eye movement and rapid eye movement stage sleep in comparison with middle-aged subjects (age group effect: elderly versus middle aged P < 0.001, sleep stage effect: P < 0.001, interaction effect between age group and sleep stage: P = 0.007). A narrowband analysis revealed that the reduction in mutual information was present in delta, theta, and sigma frequencies. These findings suggest that the lowered cortical interdependence in sleep of elderly subjects may indicate independently evolving dynamic neural activities at multiple cortical sites. The loss of synchronization between neural activities during sleep in the elderly may make these women more susceptible to localized disturbances that could lead to frequent arousals.

Transient decoupling of cortical EEGs following arousals during NREM sleep in middle-aged and elderly women.

Spontaneous cortical arousals in non-REM sleep increase with age and contribute to sleep fragmentation in the elderly. EEG spectral power in the faster frequencies exhibits well-described shifts during arousals. On the other hand, EEG activities also exhibit correlations, which are interpreted as an index of interdependence between distant cortical neural activities. The possibility of changes to the interdependence between cortical regions due to an arousal has not been considered. In this work, using previously recorded C3A2 and C4A1 EEG signals from two groups of adults, middle-aged (42-50 years) and elderly (71-86 years) women, we examined the effects of spontaneous arousals in NREM sleep on cortical interdependence. We quantified the auto- and cross-correlations in these signals using mutual information and characterized these correlations in periods before the onset and following the end of arousals. The pre-arousal period exhibited significantly higher interdependence between central regions than that following the arousal in both age groups (middle-aged: p=0.004, elderly: p<0.0001). Also, for both EEG signals the auto mutual information had a faster rate of decay, implying lower signal predictability, following the arousal than prior to it (both age groups, p<0.0001). These results indicate that the state of the cortex is different after, compared to before, the arousal even when the spectral power changes characteristic of an arousal are no longer visible. The findings suggest that the state following an arousal characterized by lower interdependence may resemble a more vigilant period during which the system may be vulnerable to more arousals.

Prediction of extravascular burden of carbon monoxide (CO) in the human heart.

Clinically significant myocardial abnormalities (e.g., arrhythmias, S-T elevation) occur in patients with mild-to-severe carbon monoxide (CO) poisoning. We enhanced our previous whole body model [Bruce, E. N., M. C. Bruce, and K. Erupaka. Prediction of the rate of uptake of carbon monoxide from blood by extravascular tissues. Respir. Physiol. Neurobiol. 161(2):142-159, 2008] by adding a cardiac compartment (containing three vascular and two tissue subcompartments differing in capillary density) to predict myocardial carboxymyoglobin (MbCO) and oxygen tensions (P(c)O2) for several CO exposure regimens at rest and during exercise. Model predictions were validated with experimental data in normoxia, hypoxia, and hyperoxia. We simulated exposure at rest to 6462 ppm CO (10 min) and to 265 ppm CO (480 min), and during three levels of exercise at 20% HbCO. We compared responses of carboxyhemoglobin (HbCO), MbCO and P(c)O2 to estimate the potential for myocardial injury due to CO hypoxia. Simulation results predict that during CO exposures and subsequent therapies, cardiac tissue has higher MbCO levels and lower P(c)O2's than skeletal muscle. CO exposure during exercise further decreases P(c)O2 from resting levels. We conclude that in rest and moderate exercise, the myocardium is at greater risk for hypoxic injury than skeletal muscle during the course of CO exposure and washout. Because the model can predict CO uptake and distribution in human myocardium, it could be a tool to estimate the potential for hypoxic myocardial injury and facilitate therapeutic intervention.

Sample entropy tracks changes in electroencephalogram power spectrum with sleep state and aging.

The regularity of electroencephalogram signals was compared between middle-aged (47.2 +/- 2.0 years) and elderly (78.4 +/- 3.8 years) female subjects in wake, nonrapid eye movement stages 2 and 3 (S-2, S-3), and rapid eye movement sleep. Signals from C3A2 leads of healthy subjects, acquired from polysomnograms obtained from the Sleep Heart Health Study, were analyzed using both sample entropy (SaEn) and power spectral analysis (delta, theta, alpha, and beta frequency band powers). SaEn changed systematically and significantly (P < 0.001) with sleep state in both age groups, following the relationships wake > rapid eye movement > S-2 > S-3. SaEn was found to be negatively correlated with delta power and positively correlated with beta power. Small changes in SaEn seem to reflect changes in spectral content rather than changes in regularity of the signal. A better predictor of SaEn than the frequency band powers was the logarithm of the power ratio (alpha + beta)/(delta + theta). Thus, SaEn seems to reflect the balance between sleep-promoting and alertness-promoting mechanisms. SaEn of the elderly was larger than that of middle-aged subjects in S-2 (P = 0.029) and rapid eye movement (P = 0.001), suggesting that cortical state is shifted toward alertness in elderly subjects in these sleep states compared with the middle-aged subjects.

Prediction of the rate of uptake of carbon monoxide from blood by extravascular tissues.

Uptake of environmental carbon monoxide (CO) via the lungs raises the CO content of blood and of myoglobin (Mb)-containing tissues, but the blood-to-tissue diffusion coefficient for CO (DmCO) and tissue CO content are not easily measurable in humans. We used a multicompartment mathematical model to predict the effects of different values of DmCO on the time courses and magnitudes of CO content of blood and Mb-containing tissues when various published experimental studies were simulated. The model enhances our earlier model by adding mass balance equations for oxygen and by dividing the muscle compartment into two subcompartments. We found that several published experimental findings are compatible with either fast or slow rates of blood-tissue transfer of CO, whereas others are only compatible with slow rates of tissue uptake of CO. We conclude that slow uptake is most consistent with all of the experimental data. Slow uptake of CO by tissue is primarily due to the very small blood-to-tissue partial pressure gradients for CO.

Evaluation of respiratory muscles activity by means of cross mutual information function at different levels of ventilatory effort.

Analysis of respiratory muscles activity is an effective technique for the study of pulmonary diseases such as obstructive sleep apnea syndrome (OSAS). Respiratory diseases, especially those associated with changes in the mechanical properties of the respiratory apparatus, are often associated with disruptions of the normally highly coordinated contractions of respiratory muscles. Due to the complexity of the respiratory control, the assessment of OSAS related dysfunctions by linear methods are not sufficient. Therefore, the objective of this study was the detection of diagnostically relevant nonlinear complex respiratory mechanisms. Two aims of this work were: (1) to assess coordination of respiratory muscles contractions through evaluation of interactions between respiratory signals and myographic signals through nonlinear analysis by means of cross mutual information function (CMIF); (2) to differentiate between functioning of respiratory muscles in patients with OSAS and in normal subjects. Electromyographic (EMG) and mechanomyographic (MMG) signals were recorded from three respiratory muscles: genioglossus, sternomastoid and diaphragm. Inspiratory pressure and flow were also acquired. All signals were measured in eight patients with OSAS and eight healthy subjects during an increased respiratory effort while awake. Several variables were defined and calculated from CMIF in order to describe correlation between signals. The results indicate different nonlinear couplings of respiratory muscles in both populations. This effect is progressively more evident at higher levels of respiratory effort.

Analysis of factors that influence rates of carbon monoxide uptake, distribution, and washout from blood and extravascular tissues using a multicompartment model.

To better understand factors that influence carbon monoxide (CO) washout rates, we utilized a multicompartment mathematical model to predict rates of CO uptake, distribution in vascular and extravascular (muscle vs. other soft tissue) compartments, and washout over a range of exposure and washout conditions with varied subject-specific parameters. We fitted this model to experimental data from 15 human subjects, for whom subject-specific parameters were known, multiple washout carboxyhemoglobin (COHb) levels were available, and CO exposure conditions were identical, to investigate the contributions of exposure conditions and individual variability to CO washout from blood. We found that CO washout from venous blood was biphasic and that postexposure times at which COHb samples were obtained significantly influenced the calculated CO half times (P < 0.0001). The first, more rapid, phase of CO washout from the blood reflected the loss of CO to the expired air and to a slow uptake by the muscle compartment, whereas the second, slower washout phase was attributable to CO flow from the muscle compartment back to the blood and removal from blood via the expired air. When the model was used to predict the effects of varying exposure conditions for these subjects, the CO exposure duration, concentration, peak COHb levels, and subject-specific parameters each influenced washout half times. Blood volume divided by ventilation correlated better with half-time predictions than did cardiac output, muscle mass, or ventilation, but it explained only approximately 50% of half-time variability. Thus exposure conditions, COHb sampling times, and individual parameters should be considered when estimating CO washout rates for poisoning victims.

A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to inhalation of carbon monoxide.

We have developed a model that predicts the distribution of carbon monoxide (CO) in the body resulting from acute inhalation exposures to CO. The model includes a lung compartment, arterial and venous blood compartments, and muscle and nonmuscle soft tissues with both vascular and nonvascular subcompartments. In the model, CO is allowed to diffuse between the vascular and nonvascular subcompartments of the tissues and to combine with myoglobin in the nonvascular subcompartment of muscle tissue. The oxyhemoglobin dissociation curve is represented by a modified Hill equation whose parameters are functions of the carboxyhemoglobin (HbCO) level. Values for skeletal muscle mass and cardiac output are calculated from prediction formulas based on age, weight, and height of individual subjects. We demonstrate that the model fits data from CO rebreathing studies when diffusion of CO into the muscle compartment is considered. The model also fits responses of HbCO to single or multiple exposures to CO lasting for a few minutes each. In addition, the model reproduces reported differences between arterial and venous HbCO levels and replicates predictions from the Coburn-Forster-Kane equation for CO exposures of a 1- to 83-h duration. In contrast to approaches based on the Coburn-Forster-Kane equation, the present model predicts uptake and distribution of CO in both vascular and tissue compartments during inhalation of either constant or variable levels of CO.

Dexamethasone-induced changes in lung function are not prevented by concomitant treatment with retinoic acid.

Alveolarization is impaired in rats treated with dexamethasone (Dex) on postnatal days 4-13, but concomitant treatment with all-trans retinoic acid (RA) increases alveolar number. To determine whether morphological changes induced by Dex and/or RA predict changes in lung function at 1 mo, we assessed resting breathing parameters, dynamic compliance, ventilation required to maintain O(2) saturation at > or = 90%, and pressure-volume curves of air-filled lungs. During resting breathing, mean tidal volume per gram was greater in Dex + RA-treated rats than in controls (P < 0.05). Dynamic compliance was also greater in Dex- and Dex + RA-treated rats than in controls or RA-treated rats (P < 0.02). In Dex- and Dex + RA-treated rats, we observed increased hysteresis ratios (P < or = 0.006), air trapping (P < 0.05), and lung volumes at 5 and 13.5 cmH(2)O pressure (P < 0.001) and decreased elastic recoil (P < 0.007). The effect of Dex on elastic recoil was greater in female than in male rats (P = 0.006). Despite impaired septation, O(2) saturation was not compromised in Dex- or Dex + RA-treated rats. Thus lung function changes induced by Dex treatment during alveolarization were not prevented by concomitant treatment with RA.