Integrated approach for in vivo evaluation of respiratory muscles mechanics

The respiratory muscles constitute the respiratory pump, which determines the efficacy of ventilation. Any functional disorder in their performance may cause insufficient ventilation. This study was designed to quantitatively explore the relative contribution of major groups of respiratory muscles to global lung ventilation throughout a range of maneuvers in healthy subjects. A computerized experimental system was developed for simultaneous noninvasive measurement of inspired/expired airflow, mouth pressure and up to 8 channels of EMG surface signals from major respiratory muscles which are located near the skin (e.g., sternomastoid, external intercostal, rectus abdominis and external oblique) during various respiratory maneuvers. Lung volumes values were calculated by integration of airflow data. Hill's muscle model was utilized to calculate the forces generated by the muscles from the acquired EMG data. Analysis of EMG measurements and respiratory muscles forces revealed the following characteristics: (a) muscle activity increased with increased breathing effort, (b) inspiratory muscles contributed to inspiration even at relatively low flow rates, while expiratory muscles are recruited at higher flow rates, (c) the forces generated by the muscle depended on the muscle properties as well as on their EMG performance and (d) the pattern of the muscle's force curves varied between subjects, but were generally consistent for the same subject regardless of breathing effort.     

Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse

Sleep is associated with marked alterations in ventilatory control that lead to perturbations in respiratory timing, breathing pattern, ventilation, pharyngeal collapsibility, and sleep-related breathing disorders (SRBD). Mouse models offer powerful insight into the pathogenesis of SRBD; however, methods for obtaining the full complement of continuous, high-fidelity respiratory, electroencephalographic (EEG), and electromyographic (EMG) signals in unrestrained mice during sleep and wake have not been developed. We adapted whole body plethysmography to record EEG, EMG, and respiratory signals continuously in unrestrained, unanesthetized mice. Whole body plethysmography tidal volume and airflow signals and a novel noninvasive surrogate for respiratory effort (respiratory movement signal) were validated against simultaneously measured gold standard signals. Compared with the gold standard, we validated 1) tidal volume (correlation, R(2) = 0.87, P < 0.001; and agreement within 1%, P < 0.001); 2) inspiratory airflow (correlation, R(2) = 0.92, P < 0.001; agreement within 4%, P < 0.001); 3) expiratory airflow (correlation, R(2) = 0.83, P < 0.001); and 4) respiratory movement signal (correlation, R(2) = 0.79-0.84, P < 0.001). The expiratory airflow signal, however, demonstrated a decrease in amplitude compared with the gold standard. Integrating respiratory and EEG/EMG signals, we fully characterized sleep and breathing patterns in conscious, unrestrained mice and demonstrated inspiratory flow limitation in a New Zealand Obese mouse. Our approach will facilitate studies of SRBD mechanisms in inbred mouse strains and offer a powerful platform to investigate the effects of environmental and pharmacological exposures on breathing disturbances during sleep and wakefulness.     

Periodicities in respiration and heart rate in newborns

Periodic breathing is common in normal infants, but may be associated with prolonged apnea leading to crib death. The mechanisms of periodic breathing and its relation to normal breathing patterns are unclear. We recorded respiratory and heart rate (HR) patterns of 11 healthy newborn infants during quiet sleep, in both normal and periodic breathing. Spectral analysis of the respiratory pattern revealed a low-frequency (LF) periodicity in normal breathing approximately equal to the frequency of periodic breathing when this occurs. Periodic breathing thus appears to be an exaggeration of an underlying slow amplitude variation which is present in regular breathing. LF periodicity also appeared in the HR pattern in both normal and periodic breathing, suggesting an LF modulation of cardiovascular control as well. The lack of a definite phase relation between HR and ventilation at LF may indicate dominant peripheral, rather than central, interactions between HR and respiration at these frequencies.     

Modulation of upper airway collapsibility during sleep: influence of respiratory phase and flow regimen.

We hypothesized that upper airway collapsibility is modulated dynamically throughout the respiratory cycle in sleeping humans by alterations in respiratory phase and/or airflow regimen. To test this hypothesis, critical pressures were derived from upper airway pressure-flow relationships in six tracheostomized patients with obstructive sleep apnea. Pressure-flow relationships were generated by varying the pressure at the trachea and nose during tracheostomy (inspiration and expiration) (comparison A) and nasal (inspiration only) breathing (comparison B), respectively. When a constant airflow regimen was maintained throughout the respiratory cycle (tracheostomy breathing), a small yet significant decrease in critical pressure was found at the inspiratory vs. end- and peak-expiratory time point [7.1 +/- 1.6 (SE) to 6.6 +/- 1.9 to 6.1 +/- 1.9 cmH(2)O, respectively; P < 0.05], indicating that phasic factors exerted only a modest influence on upper airway collapsibility. In contrast, we found that the inspiratory critical pressure fell markedly during nasal vs. tracheostomy breathing [1.1 +/- 1.5 (SE) vs. 6.1 +/- 1.9 cmH(2)O; P < 0.01], indicating that upper airway collapsibility is markedly influenced by differences in airflow regimen. Tracheostomy breathing was also associated with a reduction in both phasic and tonic genioglossal muscle activity during sleep. Our findings indicate that both phasic factors and airflow regimen modulate upper airway collapsibility dynamically and suggest that neuromuscular responses to alterations in airflow regimen can markedly lower upper airway collapsibility during inspiration.     

Robust Unidirectional Airflow through Avian Lungs: New Insights from a Piecewise Linear Mathematical Model

Avian lungs are remarkably different from mammalian lungs in that air flows unidirectionally through rigid tubes in which gas exchange occurs. Experimental observations have been able to determine the pattern of gas flow in the respiratory system, but understanding how the flow pattern is generated and determining the factors contributing to the observed dynamics remains elusive. It has been hypothesized that the unidirectional flow is due to aerodynamic valving during inspiration and expiration, resulting from the anatomical structure and the fluid dynamics involved, however, theoretical studies to back up this hypothesis are lacking. We have constructed a novel mathematical model of the airflow in the avian respiratory system that can produce unidirectional flow which is robust to changes in model parameters, breathing frequency and breathing amplitude. The model consists of two piecewise linear ordinary differential equations with lumped parameters and discontinuous, flow-dependent resistances that mimic the experimental observations. Using dynamical systems techniques and numerical analysis, we show that unidirectional flow can be produced by either effective inspiratory or effective expiratory valving, but that both inspiratory and expiratory valving are required to produce the high efficiencies of flows observed in avian lungs. We further show that the efficacy of the inspiratory and expiratory valving depends on airsac compliances and airflow resistances that may not be located in the immediate area of the valving. Our model provides additional novel insights; for example, we show that physiologically realistic resistance values lead to efficiencies that are close to maximum, and that when the relative lumped compliances of the caudal and cranial airsacs vary, it affects the timing of the airflow across the gas exchange area. These and other insights obtained by our study significantly enhance our understanding of the operation of the avian respiratory system.     

Monitoring respiratory function and sleep in the obese Vietnamese pot-bellied pig.

Development of drug treatments for obstructive sleep-disordered breathing has been impeded by the lack of animal models. The obese pig may be a suitable animal model, as it has been reported to experience sleep-disordered breathing resembling human obstructive sleep apnea. The purpose of this paper is to describe in detail techniques for chronic instrumentation of the obese Vietnamese pot-bellied pig and to study respiratory function during sleep. Under general anesthesia, four obese pigs were instrumented for long-term recording of intrapleural and tracheal pressures, genioglossal EMG, and bioelectric signals related to sleep. A custom-fitted face mask was used to record respiratory variables including airflow, snoring, and expired CO(2). Most chronic instrumentation provided robust signals for up to 6 wk after installation. All pigs displayed sleep-disordered breathing characterized by increased resistance to airflow, snoring, inspiratory flow limitation, and possible sleep disruption. Apneas and hypopneas were not a feature of breathing during sleep in these animals. Nonetheless, this animal preparation may be useful for exploring possible drug treatments for obstructive sleep-disordered breathing.     

How much does nasal cavity morphology matter? Patterns and rates of olfactory airflow in phyllostomid bats

The morphology of the nasal cavity in mammals with a good sense of smell includes features that are thought to improve olfactory airflow, such as a dorsal conduit that delivers odours quickly to the olfactory mucosa, an enlarged olfactory recess at the back of the airway, and a clear separation of the olfactory and respiratory regions of the nose. The link between these features and having a good sense of smell has been established by functional examinations of a handful of distantly related mammalian species. In this paper, we provide the first detailed examination of olfactory airflow in a group of closely related species that nevertheless vary in their sense of smell. We study six species of phyllostomid bats that have different airway morphologies and foraging ecologies, which have been linked to differences in olfactory ability or reliance. We hypothesize that differences in morphology correlate with differences in the patterns and rates of airflow, which in turn are consistent with dietary differences. To compare species, we make qualitative and quantitative comparisons of the patterns and rates of airflow through the olfactory region during both inhalation and exhalation across the six species. Contrary to our expectations, we find no clear differences among species in either the patterns of airflow through the airway or in rates of flow through the olfactory region. By and large, olfactory airflow seems to be conserved across species, suggesting that morphological differences appear to be driven by other mechanical demands on the snout, such as breathing and feeding. Olfactory ability may depend on other aspects of the system, such as the neurobiological processing of odours that work within the existing morphology imposed by other functional demands on the nasal cavity.     

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.     

A Simple Dynamic Model of Respiratory Pump

To study the interaction of forces that produce chest wall motion, we propose a model based on the lever system of Hillman and Finucane (J Appl Physiol 63(3):951–961, 1987) and introduce some dynamic properties of the respiratory system. The passive elements (rib cage and abdomen) are considered as elastic compartments linked to the open air via a resistive tube, an image of airways. The respiratory muscles (active) force is applied to both compartments. Parameters of the model are identified in using experimental data of airflow signal measured by pneumotachography and rib cage and abdomen signals measured by respiratory inductive plethysmography on eleven healthy volunteers in five conditions: at rest and with four level of added loads. A breath by breath analysis showed, whatever the individual and the condition are, that there are several breaths on which the airflow simulated by our model is well fitted to the airflow measured by pneumotachography as estimated by a determination coefficient R ² ≥ 0.70. This very simple model may well represent the behaviour of the chest wall and thus may be useful to interpret the relative motion of rib cage and abdomen during quiet breathing.     

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.     

Neural Mechanisms Underlying Breathing Complexity

Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.     

Posterior cricoarytenoid and diaphragm activities during tidal breathing in neonates

To investigate airflow regulation in newborn infants, we recorded airflow, volume, diaphragm (Di), and laryngeal electromyogram (EMG) during spontaneous breathing in eight supine unsedated sleeping full-term neonates. Using an esophageal catheter electrode, we recorded phasic respiratory activity consistent with that of the principal laryngeal abductors, the posterior cricoarytenoids (PCA). Sequential activation of PCA and Di preceded inspiration. PCA activity typically peaked early in inspiration followed by either a decrescendo or tonic EMG activity of variable amplitude during expiration. Expiratory airflow retardation, or braking, accompanied by expiratory prolongation and reduced ventilation, was commonly observed. In some subjects we observed a time interval between PCA onset and a sudden increase in expiratory airflow just before inspiration, suggesting that release of the brake involved an abrupt loss of antagonistic adductor activity. Our findings suggest that airflow in newborn infants is controlled throughout the breathing cycle by the coordinated action of the Di and the reciprocal action of PCA and laryngeal adductor activities. We conclude that braking mechanisms in infants interact with vagal reflex mechanisms that modulate respiratory cycle timing to influence both the dynamic maintenance of end-expiratory lung volume and ventilation.     

Function of brainstem neurons in optimal control of respiratory mechanics

An optimization control procedure is developed to describe the function of the human respiratory controller in determination of the respiratory frequency, the expiratory reserve volume, and the physiological dead space volume at all levels of human activity. The required level of alveolar ventilation is considered to have been determined based on the inputs from the peripheral and central chemoreceptors. The proposed procedure describes the mechanical control of breathing in which the excitation signals are adjusted and transferred from the neuron pools in the brainstem to the respiratory muscles to control the rate and depth of breathing. The criterion of minimum average respiratory work rate is used to find the optimal characteristics of respiration. The respiratory frequency, physiologic dead space volume, and expiratory reserve volume are used simultaneously as the optimization variables to minimize the average respiratory work rate. The optimization procedure has been applied by using different airflow patterns at various levels of ventilation. The theoretical results of the study have been compared with the experimental data in exercise taken from the literature. The results show a close agreement between the experimentally measured data and the theoretical values found by the optimization control procedure. The findings attest to the validity of the minimum average work rate criterion and the proposed multivariable optimization procedure compared with other procedures suggested in the literature in control of respiratory mechanics.     

Modeling the bifurcating flow in an asymmetric human lung airway

In a former paper, the inspiratory flow characteristics in a three-generation symmetric bifurcation airway have been numerically investigated using a control volume method to solve the fully three-dimensional laminar Navier-Stokes equations. The present paper extends the work to deal with asymmetric airway extracted from the 5th-11th branches of the model of Weibel (Morphometry of the Human Lung. New York Academic Press, Verlag, 1963) in order to more appropriately model human air passage. Computations are carried out in the Reynolds number range 200-1600, corresponding to mouth-air breathing rates ranging from 0.27 to 2.16l/s, representative for an averaged height man breathing from quiet to vigorous state. Particular attentions are paid to establishing relations between the Reynolds number and the overall flow characteristics, including flow patterns and pressure drop. The study shows that the ratios of airflow rate through the medial branches to that of their mother branches are the same, and this is also true for the ratios of airflow rate through the lateral branches. This partially explains why regular human breathing is not affected by airways of different sizes.     

IL-6 increases airway resistance in the rat

The end-inspiratory occlusion method was applied in anesthetized, paralyzed, positive pressure-ventilated rats to assess the possible effects of interleukin IL-6 on respiratory mechanics in normal rats. Measurements were made in control rats and in experimental animals before and after IL-6 intraperitoneal administration (15 ng/100 g), including static respiratory system elastance, the resistance to airflow and to the movement of respiratory system tissues, and the resistance due to lung stress–relaxation and mechanical inhomogeneity. Respiratory system hysteresis was also measured, and total mechanical breathing work rate and its elastic and resistive components calculated.Control rats did not exhibit alteration in respiratory mechanics during the observation period (30 min), while the experimental animals showed an increase in resistive pressure dissipations starting 15 min after IL-6 administration. Dose-dependent effects were also investigated.In a rather delayed effect, IL-6 increased the resistance to airflow and to the movement of respiratory system tissues, the resistance due to lung stress–relaxation and mechanical inhomogeneity, and the related resistive mechanical breathing work rate, and left the elastic pressure dissipation unaltered. The mechanisms by which IL-6 may contribute to the airways resistance increase which is seen in different respiratory diseases are likewise discussed.     

Breathing strategy of the adult horse (Equus caballus) at rest

To investigate the mechanism underlying the polyphasic airflow pattern of the equine species, we recorded airflow, tidal volum, rib cage and abdominal motion, and the sequence of activation of the diaphragm, intercostal, and abdominal muscles during quiet breathing in nine adult horses standing at rest. In addition, esophageal, abdominal, and transdiaphragmatic pressures were simultaneously recorded using balloon-tipped catheters. Analysis of tidal flow-volume loops showed that, unlike humans, the horse at rest breathes around, rather than from, the relaxed volume of the respiratory system (Vrx). Analysis of the pattern of electromyographic activities and changes in generated pressures during the breathing cycle indicate that the first part of expiration is passive, as in humans, with deflation toward Vrx, but subsequent abdominal activity is responsible for a second phase of expiration: active deflation to below Vrx. From this end-expiratory volume, passive inflation occurs toward Vrx, followed by a second phase of inspiration: active inflation to above Vrx, brought about by inspiratory muscle contraction. Under these conditions the abdominal muscles appear to share the principal pumping duties with the diaphragm. Adoption of this breathing strategy by the horse may relate to its peculiar thoracoabdominal anatomic arrangement and to its very low passive chest wall compliance. We conclude that there is a passive and active phase to both inspiration and expiration due to the coordinated action of the respiratory pump muscles responsible for the resting adult horse's biphasic inspiratory and expiratory airflow pattern. This unique breathing pattern perhaps represents a strategy of minimizing the high elastic work of breathing in this species, at least at resting breathing frequencies.     

Consequences of postural changes and removal of vestibular inputs on the movement of air in and out of the lungs of conscious felines.

A variety of experimental approaches in human subjects and animal models established that the vestibular system contributes to regulation of respiration. In cats, the surgical elimination of labyrinthine signals produced changes in the spontaneous activity and posturally related responses of a number of respiratory muscles. However, these effects were complex and sometimes varied between muscle compartments, such that the physiological role of vestibulo-respiratory responses is unclear. The present study determined the functional significance of vestibulo-respiratory influences by examining the consequences of a bilateral labyrinthectomy on breathing rate and the pressure, volume, and flow rate of air exchanged during inspiration and expiration as body orientation with respect to gravity was altered. Data were collected from conscious adult cats acclimated to breathing through a facemask connected to a pneuomotach during 60 degrees head-up pitch and ear-down roll body rotations. Removal of vestibular inputs resulted in a 15% reduction in breathing rate, a 13% decrease in minute ventilation, a 16% decrease in maximal inspiratory airflow rate, and a 14% decrease in the maximal expiratory airflow rate measured when the animals were in the prone position. However, the lesions did not appreciably affect phasic changes in airflow parameters related to alterations in posture. These results suggest that the role of the vestibular system in the control of breathing is to modify baseline respiratory parameters in proportion to the general intensity of ongoing movements, and not to rapidly alter ventilation in accordance with body position.     

Regional deposition of particles in the lung during cigarette smoking in humans

Studies were carried out on 11 habitual cigarette smokers to ascertain whether there was a difference in the regional deposition of particles during cigarette smoking compared with tidal breathing and also to investigate whether the ventilatory maneuvers associated with smoking influence the deposition site. A cigarette holder was constructed that permitted cigarette smoke to mix with a radioaerosol. An added resistance simulated the airflow resistance present in a filter-tipped cigarette. Respiratory patterns for the control period of tidal breathing and during smoking were monitored with a respiratory inductance plethysmograph. Smoking resulted in greater apical and central deposition than expected from the distribution of resting ventilation. The changes in the site of deposition during smoking are probably influenced mainly by the properties of the particles concerned, namely, its size, reactivity, and hygroscopicity. Changes in respiratory patterns that occur during inhalation of cigarette smoke may also have an effect but are difficult to quantify and show marked intersubject variation. In selected subjects smoking caused apical deposition to exceed that of the lower zones.     

Individuality of breathing patterns during hypoxia and exercise.

Breathing was recorded via a pulsed ultrasonic flowmeter in 11 healthy subjects, at rest and during steady-state exercise (at 50% of their maximal O2 consumption) at both sea level (200 m) and simulated altitude (4,500 m in a hypobaric chamber). The pattern of breathing was quantified breath by breath in terms of classical respiratory variables (tidal volume and inspiratory and expiratory times), and the shape of the entire airflow profile was quantified by harmonic analysis. Statistical tests were used to compare the within-individual with the between-individual variations. In comparing the sea level vs. altitude rest (16% increase in ventilation) and sea level vs. altitude exercise (40% increase in ventilation) airflow profiles, we found a significantly greater resemblance within the individual than between individuals. Comparisons of sea level rest and exercise (295% increase in ventilation) and altitude rest and exercise (375% increase in ventilation) revealed no similarity within individuals. Despite airflow profile changes between rest and exercise, it is still possible to attest to a diversity of flow profile between individuals during exercise. Hypoxia at rest or during exercise does not alter the phenomenon of the individuality of breathing patterns.