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Biomedical subjects

G M Saidel

Publications and source records attributed to G M Saidel.

At least 55 records · Page 3Linked to original sources

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).

Carbon Dioxide↗

Simulation of the diffusion of acetylcholine in the neuroeffector junctions of the sinus node.

Traditionally, the diffusion of acetylcholine (ACh) from a neuron to cardiac muscle in a neuroeffector junction has been modeled as radial diffusion from a nerve ending into a spherical homogeneous medium. Various microscopic structures in the heart may or may not influence the spatial distribution of ACh within neuroeffector junctions. To determine the effect of microscopic anatomy on the diffusion of ACh in neuroeffector junctions, we simulated the diffusion of ACh in a two-dimensional inhomogeneous geometry that was based on micrographs of neuroeffector junctions in the sinus node. ACh was released at sites adjacent to a neuron. Simulations showed that the times of peak concentration after release and the peak concentrations per se were distributed symmetrically above and below and to the right and left of the neuron, but not radially about the neuron. We conclude that the diffusion of ACh in the neuroeffector junctions of the sinus node cannot be predicted well by a mathematical model that assumes radial diffusion in a spherical and homogeneous medium.

Acetylcholine↗

Chest wall mechanics: effects of acute and chronic lung disease.

Data from the literature show that lung tissue properties affect the chest wall compliance, Ccw, which is the change in lung volume, Vl, with respect to the pleural pressure, Ppl. to analyze the difference between acute and chronic lung tissue changes, we used a mathematical model that describes the static, nonlinear mechanics of the ventilatory system in terms of its major elements: rib cage; abdomen; diaphragm and lung. With this model we derived the relationship between chest wall, rib-cage and diaphragm compliances. Although the Vl-Ppl relation is independent of lung mechanics, the volume operating point (FRC) of the ventilatory system depends on lung tissue properties. This accounts for the effect of acute lung abnormalities. In the presence of chronic lung abnormalities, the properties of the rib-cage are changed which shifts the entire Vl-Ppl curve. In general, valid comparisons of (extra-pulmonary) chest wall mechanics can only be made using the entire Vl-Ppl relation, or at least a sufficiently large part of the relation about FRC. Differentiation of the rib-cage and diaphragm mechanics requires additional measurements of the rib-cage A-P distance and the relative position of the diaphragm.

Abdominal Muscles↗

Mathematical model of dependence of heart rate on tissue concentration of acetylcholine.

The change in sinus period elicited by vagal stimulation depends on the rate of acetylcholine (ACh) release from the nerve endings, the rate of ACh degradation in the nodal tissue, and the responsiveness of the sinus node to ACh. Vagal stimulation in anesthetized dogs prolonged sinus period. After cessation of vagal stimulation, the sinus period returned to the prestimulation period. We developed a mathematical model to analyze the dynamics of ACh degradation in the neuroeffector junction and the dependence of sinus period on the concentration of ACh. From the in vitro reaction kinetics of acetylcholinesterase, we derived an analytical expression for the rate of ACh degradation in the intact animal. Our model represents the electrical behavior of the sinus node by the electrical activity of one pacemaker cell with six membrane ionic currents. This model predicts the decline in sinus period of the intact anesthetized dog as acetylcholinesterase degrades ACh in the neuroeffector junction. The half-life of ACh after cessation of vagal stimulation was estimated to be 2.7 s. We conclude that following termination of vagal stimulation, the sinus node of the intact animal responds to ACh as if the sinus node were one oscillator.

Acetylcholine↗

Mechanical analysis of extrapulmonary volume displacements in the thorax and abdomen.

Currently, the effect of intrathoracoabdominal, extrapulmonary volume displacements (Vep) are not well understood. Various clinical conditions can lead to volume displacements caused by gas or liquid accumulations. To analyze the pressure and volume changes that occur by Vep, we used a mathematical model of chest wall and lung mechanics that accounts for static changes associated with rib cage, diaphragm, abdomen, and lungs. By solving the model equations, we obtained simulations of the pleural and abdominal displacements that clearly differentiate the mechanisms involved. When abdominal displacement occurs, the reduction in lung volume is less than that caused by an equal displacement in pleural space. Abdominal displacement produces an increased pressure that expands the rib cage significantly, whereas pleural displacement does not produce a comparable action. Furthermore, our model predicts the conditions under which the work of inspiration is expected to increase as a consequence of these displacements. Finally, an important distinction is predicted between abdominal displacements caused by gas or liquid accumulation. Although an abdominal gas displacement tends to decrease the resting lung volume, the weight effect of a liquid displacement tends to increase the resting lung volume by pulling down the diaphragm.

Abdomen↗

CO2 control of the respiratory system: plant dynamics and stability analysis.

A stability analysis of respiratory chemical control is developed using a mathematical model of CO2 mass transport dynamics. Starting with a 3-compartment model of CO2 stores that distinguishes alveolar, muscle, and other tissue, model reduction techniques are applied to obtain a first-order representation of the respiratory plant. This model contains an effective tissue volume for CO2, whose derived value is much smaller than previously predicted. To investigate oscillatory instabilities, a controller which incorporates only peripheral chemoreceptor responses was added to the first-order plant model. An explicit stability index (SI) is obtained analytically from a linearized version of this model. SI varies directly with the controller gain and circulation delay time and inversely with the effective tissue volume and inspired CO2 concentration. Numerical simulations using the first-order nonlinear model show that SI is a good predictor of system stability. According to the linearized model, the system is stable for SI less than 1; from the nonlinear model, the system is stable for SI less than 1.1. For typical normal adults, the SI value is well within the stable region.

Adult↗

Water vapour and temperature dynamics in the upper airways of normal and CF subjects.

Water vapour partial pressure (PH2O) and temperature (T) were measured together, continuously, at the airway opening (either lips or nares) and at the oropharynx of human subjects with normal lungs or with cystic fibrosis (CF). No apparent differences in PH2O or T were found between normal and CF groups breathing ambient air (22 +/- 2 degrees C). During inspiration the relative humidity at the pharynx for nose breathing (95%) was higher than for mouth breathing (75%). For hot air breathing (48 +/- 2 degrees C), the PH2O and relative humidity of inspired gas at the pharynx was lower for the CF group than for the normal group. Also, the CF group had a higher airway surface temperature at the airway openings on inspiration. These data suggest that when the rate of evaporation is sufficiently high, the rate-limiting step may be water transport through the mucosal tissue and/or secretions. At least for the upper airways, this rate limitation is more evident for CF patients than for normal subjects.

Adult↗

Estimation of the determinants of transcutaneous oxygen tension using a dynamic computer model.

A dynamic model for oxygen transport within the outer layers of the skin and a tcPO2 sensor has been developed. By comparing model simulations with clinical measurements from adults, it is possible to analyze some of the physiologic and physical determinants of the tcPO2 measurement. The results indicate that the permeability of the epidermis is a significant parameter when using a microcathode sensor. Using this model, the values obtained for normalized stratum papillare blood flow and metabolic oxygen consumption of the dermis are higher than those seen for other models.

Adult↗

Pulmonary diffusing capacity in the presence of ventilation inhomogeneity.

A model has been developed to quantify the effectiveness of alveolar-capillary transport in the presence of ventilation inhomogeneity. The exhalation dynamics of carbon monoxide (CO), argon (Ar), and lung volume from a single-breath experiment are analyzed simultaneously. A membrane transport coefficient (MTCO) that does not vary with lung volume is evaluated by a two-stage optimization procedure and related to diffusing capacity. Also, the model allows for a decrease in membrane transport rate associated with reduced lung volume. The model is tested by simulation studies and experiments with human subjects having normal or diseased (mainly obstructed) lungs. The MTCO provides a clear distinction between normal and obstructed lungs with respect to alveolar-capillary transport, whereas the semilog slope of the Ar alveolar plateau characterizes the ventilation inhomogeneity. Only when the diffusing capacity is corrected by the Ar slope, DLCO(Ar), do the breathing maneuvers performed from different preinflation volumes (residual volume or functional residual capacity) yield the same results for lungs with ventilation inhomogeneity. The uncorrected DLCO overestimates the effectiveness of alveolar-capillary transport in the presence of ventilation inhomogeneity.

Adult↗

Transport abnormalities from single-breath dynamics of Ar, CO2 and O2.

A model framework is developed for analyzing non-invasive measurements of Ar, CO2, O2, and lung volume during a single exhalation from healthy and diseased lungs. The objective is to distinguish ventilation inhomogeneity from gas-exchange limitations associated with alveolar-capillary transport and processes within the blood. Several practical, quantitative indices are compared to provide distinction and physiological interpretation in terms of rate-determining transport processes. Some indices arise from a model in which the composition in the alveolar space differs from that of the exhaled gas. Other indices are computed from the effective dead-space volumes for Ar, CO2, and O2. Ventilation inhomogeneity is accounted for by the Ar dynamics. Values of these indices were computed from experiments with human subjects having normal lungs, restrictive pulmonary disease, or chronic obstructive pulmonary disease. These three groups are clearly distinguished by a pair of indices: one reflects ventilation inhomogeneity, while the other reflects dysfunction associated with the alveolar-capillary transport and capillary blood flow and distribution.

Airway Obstruction↗

Parameter estimation and sensitivity analysis of a nonlinearly elastic static lung model.

A model for the static pressure-volume behavior of the lung parenchyma based on a pseudo-elastic strain energy function was tested. Values of the model parameters and their variances were estimated by an optimal least-squares fit of the model-predicted pressures to the corresponding data from excised, saline-filled dog lungs. Although the model fit data from twelve lungs very well, the coefficients of variation for parameter values differed greatly. To analyze the sensitivity of the model output to its parameters, we examined an approximate Hessian, H, of the least-squares objective function. Based on the determinant and condition number of H, we were able to set formal criteria for choosing the most reliable estimates of parameter values and their variances. This in turn allowed us to specify a normal range of parameter values for these dog lungs. Thus the model not only describes static pressure-volume data, but also uses the data to estimate parameters from a fundamental constitutive equation. The optimal parameter estimation and sensitivity analysis developed here can be widely applied to other physiologic systems.

Animals↗

Multiple-objective criteria for optimal experimental design: application to ferrokinetics.

Optimal experimental design is used to predict the experimental conditions that will allow the "best" estimates of model parameters. A variety of criteria must be considered before an optimal design is chosen. Maximizing the determinant of the information matrix (D optimality), which tends to produce the most precise simultaneous estimates of all parameters, is commonly considered as the primary criterion. To complement this criterion, we present another whose effect is to reduce the interaction among the parameter estimates so that changes in any one parameter can be more distinct. This new criterion consists of maximizing the determinant of an appropriately scaled information matrix (M optimality). These criteria are applied jointly in a multiple-objective function. To illustrate the use of these concepts, we develop an optimal experimental design of blood sampling schedules using a detailed ferrokinetic model.

Humans↗

Role of inner medullary collecting duct NaCl transport in urinary concentration.

Mathematical modeling and simulation techniques were used to analyze the role of medullary collecting duct NaCl transport in the urinary concentrating process. The mathematical model incorporated experimentally determined epithelial transport parameters and anatomical parameters obtained chiefly from experiments in rabbit kidneys. The simulations predict that solute concentration profiles along the medullary collecting ducts are highly sensitive to the rate and pattern of active NaCl absorption along the length of the collecting duct system. When active NaCl absorption was assumed to be zero in the outer medullary collecting duct and to increase along the inner medulla to a very high value at the papillary tip, the simulated solute concentration profiles in the medullary collecting ducts as well as relative concentrations between different inner medullary structures agreed well with experimental data. However, despite optimal choice of collecting duct transport parameters and the use of experimentally determined permeability coefficients, only modest total solute gradients could be generated axially in the inner medullary interstitium, and passive luminal dilution did not occur in the thin ascending limb. We conclude: 1) Axial heterogeneity of transport properties along the inner medullary collecting duct must be assumed to explain in vivo findings from micropuncture and microcatheterization studies. 2) Active NaCl transport from the inner medullary collecting ducts is important chiefly for efficient conservation of NaCl rather than for concentration of solutes in the renal inner medulla. 3) Important inconsistencies exist between several previously reported experimental observations and the theoretical requirements for passive luminal dilution in the thin ascending limb of Henle's loop.

Animals↗

Ventilatory inhomogeneity associated with acute bronchoconstriction in asthmatic patients.

Ventilation inhomogeneity was assessed in asthmatic subjects before and after antigen-induced bronchoconstriction and bronchodilator administration. As an index of inhomogeneous distribution of inspired air, the mean dilution number (the ratio of the first to zero moments) was calculated from each multibreath nitrogen washout during spontaneous breathing. This index was compared to plethysmographic, spirometric, and lung volume indices. In the baseline state, a weak relationship existed between the mean dilution number (MDN) and indices of mechanical abnormality, FEV1/FVC and SRAW. Antigen-induced bronchoconstriction led to increases in the MDN, SRAW, and RV/TLC, and a decrease in FEV1/FVC. The reverse effects were found by administering bronchodilators. No statistically significant correlations were found between changes in MDN and changes in the other indices of pulmonary function. Thus, the maldistribution of inspired air resulting from acute bronchoconstriction cannot be quantified from common indices of pulmonary function.

Adult↗

Helium-oxygen breathing in severe chronic obstructive pulmonary disease.

The effect of breathing helium-oxygen (He-O2) mixtures was evaluated in 15 patients with severe chronic obstructive pulmonary disease (COPD). Gas exchange was assessed during quiet breathing at rest before and after 15 minutes of breathing 80 percent He-20 percent O2 mixtures in all patients. Functional residual capacity (FRC) determined during argon (Ar) washing studies fell significantly while breathing He-O2, but we did not find significant changes in minute ventilation, tidal volume, respiratory frequency, or inspiratory or expiratory timing. Eleven patients showed decreases in arterial PCO2 and CO2 excretion during resting breathing on He-O2. Expiratory flows were increased at a given lung volume during He-O2 breathing as expected. Apparently, mechanical work of breathing was decreased in patients with severe COPD while breathing He-O2, leading to a reduction in VCO2 and improvement in overall alveolar ventilation. These findings lend support to the therapeutic use of He-O2 under some conditions in patients with severe COPD.

Aged↗