Sequential V(A)/Q distributions in the normal rabbit by micropore membrane inlet mass spectrometry.

We developed micropore membrane inlet mass spectrometer (MMIMS) probes to rapidly measure inert-gas partial pressures in small blood samples. The mass spectrometer output was linearly related to inert-gas partial pressure (r(2) of 0.996-1.000) and was nearly independent of large variations in inert-gas solubility in liquid samples. We infused six inert gases into five pentobarbital-anesthetized New Zealand rabbits and used the MMIMS system to measure inert-gas partial pressures in systemic and pulmonary arterial blood and in mixed expired gas samples. The retention and excretion data were transformed into distributions of ventilation-to-perfusion ratios (V(A)/Q) with the use of linear regression techniques. Distributions of V(A)/Q were unimodal and broad, consistent with prior reports in the normal rabbit. Total blood sample volume for each VA/Q distribution was 4 ml, and analysis time was 8 min. MMIMS provides a convenient method to perform the multiple inert-gas elimination technique rapidly and with small blood sample volumes.

Airway cross section strongly influences alveolar plateau slope of capnograms for smaller tidal volumes.

We compared the predictions of the single path convection-diffusion model (SPM) and the well-mixed single acinus model (SAM) with the normalized slopes (NS) of experimentally measured volumetric capnograms in which VT was varied in three healthy spontaneously breathing adults. For values of VT greater than 15 ml/kg, the tidal volume penetrates deep into the acinar airways, mixing by molecular diffusion is rapid and the predictions of the SAM and SPM both agree with the experiment. The SPM however shows much better agreement with the experimental NS data than does the SAM for values of VT less than 10 ml/kg. The explanation for the departure of the SAM from the observed experimental data, at small VT, is that it represents the limiting case (of well-mixed alveolar gas) for the SPM, only at large VT, where the assumption of rapid mixing is most accurate. We conclude that in general, gas phase diffusivity and total acinar airway cross sectional area variation with cumulative volume into the lung are essential to realistically model airway gas exchange between VT and FRC and to obtain agreement with experimental data under the widest range of breathing conditions.

Countercurrent extraction of sparingly soluble gases for membrane introduction mass spectrometry.

Membrane introduction mass spectrometry has been applied to inert gas measurements in blood and tissue, but gases with low blood solubility are associated with reduced sensitivity. Countercurrent extraction of inert gases from a blood sample into a water carrier phase has the potential to extract most of the gas sample while avoiding dependence of signal on blood solubility. We present the design of a membrane countercurrent exchange (CCE) device coupled with a conventional direct insertion membrane probe to measure partial pressure of low solubility inert gases in aqueous samples. A mathematical model of steady-state membrane CCB predicts that countercurrent extraction with appropriate selection of carrier and sample flow rates can provide a mass spectrometer signal nearly independent of variations in solubility over a specified range, while retaining a linear response to changes in gas partial pressure over several orders of magnitude. Experimental data are presented for sulfur hexafluoride and krypton in water samples. Optimal performance is dependent on adequate equilibration between the sample and carrier streams, and the large resistance to diffusion in the aqueous phase for insoluble gases presents a substantial challenge to the application of this principle.

EITS changes following oleic acid induced lung water.

We present the results of using electrical impedance tomographic spectroscopy (EITS) to follow the changes in lung water induced by oleic acid. Measurements were made on three goats before and after the injection of oleic acid. In addition to the EITs measurements, lung water was also measured using a double-indicator technique. Large falls in lung electrical impedance were seen as a result of the increase in lung water but the size of the fall was a function of the frequency at which the measurements were made. These changes have been modelled using the Cole equation. Four-electrode measurements were also made on two extracted porcine lungs and Cole equation modelling carried out following the introduction of saline into the lungs. Results were similar in the two sets of animal experiments.

The importance of a source term in modeling multibreath inert gas washout.

The single path model (SPM) of airway gas transport with a distributed blood source term was used to simulate multiple breath inert lung gas washout of N2, He, and SF6 after total body equilibration with these gases. Normalized phase III inert gas washout slopes were computed for each breath and compared with published experimental data obtained under similar conditions on human subjects. The model predicts a normalized slope asymptote which agrees with experimental results within two standard deviations or less of the mean, depending on the lengths and diameters assumed in the acinar airways of the SPM. In the model and in the human subject data, the asymptote represents the development of a quasi-steady state in which the volume of inert gas exhaled at the mouth is equal to the volume transported into the acinar airways by the pulmonary blood during each breath. The present study indicates that at least in the steady state, airway inhomogeneity is not essential to model lung washout data, and that a distributed blood source term in the SPM yields good agreement with experiment.

Volumetric capnography in children. Influence of growth on the alveolar plateau slope.

BACKGROUND: Lung growth in children is associated with dramatic increases in the number and surface area of alveolated airways. Modelling studies have shown the slope of the alveolar plateau (phase III) is sensitive to the total cross-sectional area of these airways. Therefore, the influence of age and body size on the phase III slope of the volumetric capnogram was investigated. METHODS: Phase III slope (alveolar dcCO2/dv) and airway deadspace (VDaw) were derived from repeated single-breath carbon dioxide expirograms collected on 44 healthy mechanically ventilated children (aged 5 months-18 yr) undergoing minor surgery. Ventilatory support was standardized (VT = 8.5 and 12.5 ml/kg, f = 8-15 breaths/min, inspiratory time = 1 s, end-tidal partial pressure of carbon dioxide = 30-45 mmHg), and measurements were recorded by computerized integration of output from a heated pneumotachometer and mainstream infrared carbon dioxide analyzer inserted between the endotracheal tube and anesthesia circuit. Experimental data were compared to simulated breath data generated from a numeric pediatric lung model. RESULTS: An increased VDaw, a smaller VDaw/VT, and flatter phase III slope were found at the larger tidal volume (P < 0.01). Strong relationships were seen at VT = 12.5 ml/kg between airway deadspace and age (R2 = 0.77), weight (R2 = 0.93), height (R2 = 0.78), and body surface area (R2 = 0.89). The normalized phase III slopes of infants were markedly steeper than that of adolescents and were reduced at both tidal volumes with increasing age, weight, height, and body surface area. Phase III slopes and VDaw generated from modelled carbon dioxide washout simulations closely matched the experimental data collected in children. CONCLUSIONS: Morphometric increases in the alveolated airway cross-section with lung growth is associated with a decrease of the phase III slope. During adolescence, normalized phase III slopes approximate those of healthy adults. The change in slope with lung growth may reflect a decrease in diffusional resistance for carbon dioxide transport within the alveolated airway resulting in diminished acinar carbon dioxide gradients.

Noninvasive recovery of acinar anatomic information from CO2 expirograms.

A numerical single path model of respiratory gas exchange with distributed alveolar gas sources was used to estimate the anatomical changes in small peripheral airways such as occur in chronic obstructive pulmonary diseases (COPD). A previous sensitivity analysis of the single path model showed that decreasing total acinar airway cross-sectional area by an area reduction factor, R, results in computed gas expirograms with Phase III steepening similar to that observed in COPD patients. From experimental steady state CO2 washout data recorded from six healthy subjects and six COPD patients, optimized area reduction factors for the single path model were found that characterize peripheral airway anatomy for each subject. Area reduction factors were then combined with measured functional residual capacity data to calculate the normalized peripheral airspace diameters in a given subject, relative to the airspace diameters in the generations of an idealized standard lung. Mean area reduction factors for the patient subgroup were 63% of those for the healthy subgroup, which is related to the gas transport limitation observed in disease. Mean airspace sizes for the patient subgroup were 235% of the healthy subgroup, which characterizes the increase in size and reduction in number of peripheral airspaces due to tissue erosion in emphysema. From these results, the air-phase diffusive conductance in COPD patients was calculated to be 32% of the mean value in the healthy subjects. These findings correlated well with standard pulmonary function test data for the patients and yield the recovery of acinar airway information from gas washout by combining the single path model with experimental measurements.

Pulmonary uptake of propofol in cats. Effect of fentanyl and halothane.

BACKGROUND: Many drugs are removed by the lung. The pulmonary uptake of one drug can be inhibited when a second, highly accumulated drug is administered parenterally or as a chronic oral treatment. The effect of inhalational anesthetics on pulmonary drug uptake has not been extensively studied and may alter pharmacokinetics of intravenously administered drugs. METHODS: The uptake of propofol by the lung during a single passage through the pulmonary circulation was studied in four groups of anesthetized cats: spontaneously breathing cats (control group, n = 6), cats whose lungs were mechanically ventilated (n = 6), and cats whose lungs were mechanically ventilated and that were anesthetized with 1% (n = 6) or 1.5% (n = 6) halothane. In an additional group, the single-pass pulmonary uptake of propofol was studied in six spontaneously breathing cats pretreated with fentanyl. The amount of propofol taken up by the lung during the first pass was measured from double indicator-dilution outflow curves using indocyanine green (ICG) as the intravascular reference indicator. RESULTS: The first-pass uptake of propofol (mean +/- SEM) was 61.3 +/- 4.9% and 60 +/- 3.7% of the injected dose in control cats and in cats whose lungs were mechanically ventilated, respectively. Although exposure of the animals to 1% halothane had no significant effect on pulmonary extraction of propofol, the first-pass uptake decreased significantly to 38.8 +/- 6.9% in cats exposed to 1.5% halothane compared with control cats and to cats undergoing mechanical ventilation of the lungs without exposure to halothane. Also, in animals pretreated with fentanyl, propofol uptake was reduced to 40 +/- 5% compared with the control group. CONCLUSIONS: The results demonstrate a substantial extraction of propofol by the lung that is not affected by mechanical ventilation. Inhibition of propofol uptake by 1.5% halothane and by fentanyl provides a potential mechanism of drug-drug interaction that may interfere with the pharmacokinetic profile of propofol, and may alter the amount of propofol needed to achieve or supplement a given depth of anesthesia.

Microemboli reduce phase III slopes of CO2 and invert phase III slopes of infused SF6.

We investigated the effect of increasing doses of intravenously infused glass microspheres (mean diameter 125 microns) on gas exchange in anesthetized, heparinized, mechanically ventilated goats (VT = 16-18 ml/kg). Breath-by-breath CO2 expirograms were collected using a computerized system (Study A) during the infusion of a total of 15 g of microspheres. We found a 50% decrease in extravascular lung water by indicator dilution with a corresponding doubling of alveolar dead space (VDalv). Airways deadspace (VDaw) decreased by 13 ml (10%) and mean normalized phase III slope for CO2 decreased from 0.23 to -0.08 L-1 becoming negative in 3 of 5 animals. In a second study (Study B), simultaneous breath-by-breath CO2 and infused SF6 expirograms were collected using an infrared CO2 analyzer and a mass spectrometer. Under baseline conditions VDaw for CO2 was smaller than for SF6 and the ratio of the phase III slope for SF6 to the phase III slope for CO2 was 1.39. Following embolization there were no differences in VDaw between the two gases, however, the phase III slope for CO2 became either slightly negative or extremely flat, while the phase III slope for SF6 became negative in 73% of the breaths (-0.17 L-1, P < 0.05). Negative phase III slopes have been predicted by a single path model when blood flow is confined to the most mouthward generations of the acinus (Schwardt et al., Ann. Biomed. Engin, 19: 679-697, 1991). The agreement between the numerical model and the experimental data is consistent with a serial distribution of blood flow within the acinus.

Modelling steady state pulmonary elimination of He, SF6 and CO2: effect of morphometry.

We studied the influence of acinar morphometry on the shape of simulated expirograms computed from a single path convection-diffusion model that includes a source term for gas evolution from the blood (Scherer et al., J. Appl. Physiol. 64: 1022-1029, 1988). Acinar structure was obtained from published data of 3 different lung morphometries. The simulations were performed over a range of tidal volumes (VT) and breathing frequencies (f) comparable to those observed in a previously reported human study. Airways dead space (VDaw) increased with VT in all the morphometric models tested and in the experimental data. The increase in VDaw with VT was inversely related to the diffusivity of the evolving gas and to the rate of increase in airway cross-section of the most mouthward (proximal) alveolated generations of the models. Normalized phase III slope for all the gases decreased with increasing VT in all the models as was previously reported for healthy human subjects. In the model simulations, the greatest sensitivity of phase III slope to VT was seen with the least diffusible gas using the airway morphometry with the smallest cross-sectional areas in the proximal alveolated generations. We conclude that both VDaw and phase III slope of an evolving gas are sensitive to the geometry of the proximal acinar airways and that this is manifest by their dependence on tidal volume, breathing frequency, molecular diffusivity and alveolar/blood source emission rate. The model simulations indicate that heterogeneity of gas washout is not required to explain the magnitude of the phase III slope in healthy human subjects.

Diffusivity, respiratory rate and tidal volume influence inert gas expirograms.

We modified, and developed software for, a computer-controlled quadrupole mass spectrometer to measure complete breath-by-breath expirograms of helium (He) and sulfur hexafluoride (SF6) exhaled during the infusion of saline saturated with the inert gases. He and SF6 have similar blood solubilities but very different gas phase diffusivities allowing examination of the influence of gas phase diffusivity on steady state inert gas expirograms. We studied six normal human volunteers in nine separate studies and examined the influence of tidal volume (VT) and breathing frequency (f) on the airways dead space (VDaw) and alveolar plateau slope (phase III) for the inert gases and CO2. The experimental data showed a reduction in VDaw with rapid shallow breathing, while phase III slope increased by a factor of two to three. We critically evaluated the data and methodology of these and previously reported studies of continuous and single breath washout of He and SF6. In general the 15 to 20 ml differences in VDaw between He and SF6 were in keeping with previous studies by others. The ratio of phase III slopes of SF6 to He reported by us previously (Scherer et al., J. Appl. Physiol. 64: 1022-1029, 1988) was 3.13. In the current study, which includes the analysis of more than 400 He and SF6 breaths, the ratio of SF6 to He slope was 1.85. The difference between the two studies was largely related to the improved methodology of the current study, particularly for the measurement of He. The results support the conclusion that diffusivity is an important component of both phase II and phase III of the expirogram. However, the difference in phase III between He and SF6 is somewhat less than previously reported.

Sensitivity of CO2 washout to changes in acinar structure in a single-path model of lung airways.

A numerical solution of the convection-diffusion equation with an alveolar source term in a single-path model (SPM) of the lung airways simulates steady state CO2 washout. The SPM is used to examine the effects of independent changes in physiologic and acinar structure parameters on the slope and height of Phase III of the single-breath CO2 washout curve. The parameters investigated include tidal volume, breathing frequency, total cardiac output, pulmonary arterial CO2 tension, functional residual capacity, pulmonary bloodflow distribution, alveolar volume, total acinar airway cross sectional area, and gas-phase molecular diffusivity. Reduced tidal volume causes significant steepening of Phase III, which agrees well with experimental data. Simulations with a fixed frequency and tidal volume show that changes in blood-flow distribution, model airway cross section, and gas diffusivity strongly affect the slope of Phase III while changes in cardiac output and in pulmonary arterial CO2 tension strongly affect the height of Phase III. The paper also discusses differing explanations for the slope of Phase III, including sequential emptying, stratified inhomogeneity, and the issue of asymmetry, in the context of the SPM.

Commercial double-indicator-dilution densitometer using heavy water: evaluation in oleic-acid pulmonary edema.

We evaluated a commercially available, double-indicator-dilution densitometric system for the estimation of pulmonary extravascular water volume in oleic acid-induced pulmonary edema. Indocyanine green and heavy water were used as the nondiffusible and diffusible tracers, respectively. Pulmonary extravascular water volume, measured with this system, was 67% of the gravimetric value (r = 0.91), which was consistent with values obtained from the radioisotope methods. The measured volume was not influenced by changes in cardiac index over a range of 1 to 4 L.min.m2. This system is less invasive than the thermal-dye technique and has potential for repeated clinical measurements of pulmonary extravascular lung water and cardiac output.

Evaluation of heavy water for indicator dilution cardiac output measurement.

We evaluated deuterium oxide (D2O) as a tracer for cardiac output measurements. Cardiac output measurements made by thermodilution were compared with those made by indicator dilution with D2O and indocyanine green as tracers. Five triplicate measurements for each method were made at intervals of 30 minutes in each of 9 anesthetized, mechanically ventilated goats. Cardiac output ranged between 0.68 and 3.79 L/min. The 45 data points yielded a correlation coefficient of 0.948 for the comparison of D2O indicator dilution cardiac output measurements with thermodilution measurements and a linear regression slope of 1.046. D2O indicator dilution measurements were biased by -0.11 +/- 0.22 L/min compared with thermodilution measurements and had a standard deviation of +/- 0.12 L/min for triplicate measurements. Hematocrits ranging between 20 and 50 vol% had no effect on optical density for D2O. D2O is more stable than indocyanine green and approximately one-tenth the price (40 cents per injection compared with $4). The basic instrumentation cost of approximately $9,000 is an additional initial expense, but provides the ability to perform pulmonary extravascular water measurements with a double-indicator dilution technique. D2O has potential as a tracer for the clinical determination of indicator dilution cardiac output measurements and pulmonary extravascular water measurements.

Permeation of inert gases through human skin: modeling the effect of skin blood flow.

We present an analytic method for determining the effects of skin perfusion--vasculature and flow rates--on the flux of inert gases through human skin. We systematically specify the underlying blood flow and examine the resulting fluxes of several gases, allowing for the appropriate tissue resistances. For physiological flows, the stratum corneum has an effect equivalent to a series resistance. Helium flux at low total flow depends primarily on subdermal perfusion, but at higher flow, middermal and subpapillary effects become important. The fluxes of less permeable gases, such as argon and xenon, depend on middermal and subpapillary flow at lower total flows. From any single measurement of gas flux, it is difficult to establish an unambiguous value for the underlying blood flow, but the simultaneous measurement of different gases narrows the range of plausible conditions.

The use of quantitative perfusion fluorometry to measure relative tumor and liver blood flow after transient microembolization.

Optimal chemotherapy delivery to the tumor depends on regional drug concentration, tumor perfusion, tissue drug uptake, and metabolism. Modulation of tumor blood flow has been used to improve tumor response to treatment. Transient microembolization is one method to alter regional blood flow, but its effects on relative changes in tumor and liver blood flow have not been previously measured. This study used quantitative perfusion fluorometry (QPF) to evaluate blood flow distribution in liver and tumor before and after hepatic arterial infusion of degradable starch microspheres (DSMs) in 10 New Zealand white rabbits. QPF was compared with radioactive xenon-133 washout, an established method for measuring blood flow. Xenon-133 was injected intraparenchymally and the clearance rate was measured allowing calculation of relative blood flow. QPF was then used to measure liver and tumor blood flow in a hepatic VX-2 tumor model after hepatic artery injection of DSMs. Initial tumor blood flow was 55% of liver flow. DSMs produced a significant and transient decrease in hepatic blood flow that was decreased to 40% of baseline after 25 min. Changes in relative hepatic blood flow after DSMs as measured by QPF correlated strongly with results obtained by xenon-133 washout (R = 0.97, P less than 0.01). Fluorometry's simplicity and reliability may be clinically useful to evaluate tumor blood flow characteristics.

Skin blood flow from gas transport: helium xenon and laser Doppler compared.

A study was designed to compare three independent measures of cutaneous blood flow in normal healthy volunteers: xenon-133 washout, helium flux, and laser velocimetry. All measurements were confined to the volar aspect of the forearm. In a large group of subjects we found that helium flux through intact skin changes nonlinearly with the controlled local skin temperature whereas helium flux through stripped skin, which is directly proportional to skin blood flow, changes linearly with cutaneous temperature over the range 33 degrees to 42 degrees. In a second group of six volunteers we compared helium flux through stripped skin to xenon-133 washout (intact skin) at a skin temperature of 33 degrees, and we found an essentially linear relationship between helium flux and xenon measured blood flow. In a third group of subjects we compared helium flux blood flow (stripped skin) to laser doppler velocimetric (LDV) measurements (intact skin) at adjacent skin sites and found a nonlinear increase in the LDV skin blood flow compared to that determined by helium over the same temperature range. A possible explanation for the nonlinear increases of helium flux through intact skin and of LDV output with increasing local skin temperature is that they reflect more than a change in blood flow. They may also reflect physical changes in the stratum corneum, which alters its diffusional resistance to gas flux and its optical characteristics.

Numerical and experimental study of steady-state CO2 and inert gas washout.

The predictions of a single-path trumpet-bell numerical model of steady-state CO2 and infused He and sulfur hexafluoride (SF6) washout were compared with experimental measurements on healthy human volunteers. The mathematical model used was a numerical solution of the classic airway convention-diffusion equation with the addition of a distributed source term at the alveolar end. In the human studies, a static sampling technique was used to measure the exhaled concentrations and phase III slopes of CO2, He, and SF6 during the intravenous infusion of saline saturated with a mixture of the two inert gases. We found good agreement between the experimentally determined normalized slopes (phase III slope divided by mixed expired concentration) and the numerically determined normalized slopes in the model with no free parameters other than the physiological ones of upper airway dead space, tidal volume, breathing frequency, and breathing pattern (sinusoidal). We conclude 1) that the single-path (Weibel) trumpet-bell anatomic model used in conjunction with the airway convection-diffusion equation with a distributed source term is adequate to describe the steady-state lung washout of CO2 and infused He and SF6 in normal lungs and 2) that the interfacial area separating the tidal volume fron from the functional residual capacity gas, through which gas diffusion into the moving tidal volume occurs, exerts a major effect on the normalized slopes of phase III.