Reproducibility of the multiple inert gas elimination technique

Although measurement errors in the multiple inert gas elimination technique have a coefficient of variation of approximately 3%, small biological fluctuations in ventilation, blood flow, or other variables must contribute additional variance to this method of assessing ventilation-perfusion (VA/Q) mismatch. To determine overall variance of computed indices of VA/Q mismatch, an analysis of variance was carried out using a total of 400 duplicate pairs of inert gas samples obtained from canine (N = 118) and human (N = 282) studies in the past 2 years. In both sets VA/Q mismatch ranged from minimal (2nd moment of ventilation and blood flow distributions, log SDV and log SDQ, respectively approximately equal to 0.3 each) to severe (log SDV and log SDQ approximately equal to 2.0). Differences between duplicate log SD values were computed and found to be a constant fraction of the mean log SD of each duplicate pair, averaging 13% for both canine and human ventilation and blood flow data. The resultant coefficient of variation for a single measurement of log SD about its mean averaged 8.6% for all data combined. This analysis demonstrates excellent reproducibility of these dispersion indices over a wide range of conditions, and if the mean of duplicate values is used, thus reducing variability by square root 2 to 6.1%, log SD can be estimated with an approximately 95% confidence limit of +/- 12%.     

Multiple inert gas elimination technique

The understanding of pulmonary gas exchange has undergone several major advances since the early 1900's. One of the most significant was the development of the multiple inert gas elimination technique for assessing the ventilation-perfusion (VA/Q) distribution in the lung. By measuring the mixed venous, arterial, and mixed expired concentrations of six infused inert gases, it is possible to distinguish shunt, dead space, and the general pattern of VA/Q distribution. As with all mathematical models of complex biological phenomena, there are limitations that can result in errors of interpretation if the technique is applied uncritically. In addition, methodological limitations also can lead to both experimental error and errors of interpretation. Despite these limitations, the multiple inert gas elimination technique remains the most powerful tool developed to date to analyze pulmonary gas exchange.     

A tidal breathing model for the multiple inert gas elimination technique.

The tidal breathing lung model described for the sine-wave technique (D. J. Gavaghan and C. E. W. Hahn. Respir. Physiol. 106: 209-221, 1996) is generalized to continuous ventilation-perfusion and ventilation-volume distributions. This tidal breathing model is then applied to the multiple inert gas elimination technique (P. D. Wagner, H. A. Saltzman, and J. B. West. J. Appl. Physiol. 36: 588-599, 1974). The conservation of mass equations are solved, and it is shown that 1) retentions vary considerably over the course of a breath, 2) the retentions are dependent on alveolar volume, and 3) the retentions depend only weakly on the width of the ventilation-volume distribution. Simulated experimental data with a unimodal ventilation-perfusion distribution are inserted into the parameter recovery model for a lung with 1 or 2 alveolar compartments and for a lung with 50 compartments. The parameters recovered using both models are dependent on the time interval over which the blood sample is taken. For best results, the blood sample should be drawn over several breath cycles.     

Effects of acetone in heparin on the multiple inert gas elimination technique

We have detected acetone in several brands of heparin. If uncorrected, this leads to errors in measuring acetone in blood collected in heparinized syringes, as in the multiple inert gas elimination technique for measuring ventilation-perfusion ratio (VA/Q) distributions. Error for acetone retention [R = arterial partial pressure-to-mixed venous partial pressure (P-V) ratio] is usually small, because R is normally near 1.0, and the error is similar in arterial and mixed venous samples. However, acetone excretion [E = mixed expired partial pressure (P-E)-to-P-V ratio] will appear erroneously low, because P-E is accurately measured in dry syringes, but P-V is overestimated. A physical model of a homogeneous alveolar lung at room temperature and without dead space shows: the magnitude of acetone E error depends upon the ratio of blood sample to heparinized saline volumes and acetone partial pressures, without correction, acetone E can be less than that of less soluble gases like ether, a situation incompatible with conventional gas exchange theory, and acetone R and E can be correctly calculated using the principle of mass balance if the acetone partial pressure in heparinized saline is known. Published data from multiple inert gas elimination experiments with acetone-free heparin, in our labs and others, are within the limits of experimental error. Thus the hypothesis that acetone E is anomalously low because of physiological mechanisms involving dead space tissue capacitance for acetone remains to be tested.     

Information content of multiple inert gas elimination measurements

The multiple inert gas elimination technique provides a fundamental assessment of the distribution of ventilation-perfusion (VA/Q) ratios in the lung. The resolution of the finer structure of this distribution is limited however. This study examines the theoretical basis of this limitation and presents an objective method for evaluating the independence of inert gas measurements. It demonstrates the linear dependence of the inert gas kernels and their filtering characteristics to be the factors most limiting information content. The limited number of gases available for measurement and experimental error are lesser limitations. At usual levels of experimental error, no more than seven different inert gases having partition coefficients between those of SF6 and acetone will provide independent information, and information content will be maximized by choosing gases with partition coefficients spaced equally on a logarithmic scale. A fivefold reduction in experimental error will not significantly alter the information content of the measurements. The analysis applies equally to other methods of multiple inert gas elimination data interpretation.     

Conducting airway gas exchange: diffusion-related differences in inert gas elimination.

We studied CO2 and inert gas elimination in the isolated in situ trachea as a model of conducting airway gas exchange. Six inert gases with various solubilities and molecular weights (MW) were infused into the left atria of six pentobarbital-anesthetized dogs (group 1). The unidirectionally ventilated trachea behaved as a high ventilation-perfusion unit (ratio = 60) with no appreciable dead space. Excretion of higher-MW gases appeared to be depressed, suggesting a MW dependence to inert gas exchange. This was further explored in another six dogs (group 2) with three gases of nearly equal solubility but widely divergent MWs (acetylene, 26; Freon-22, 86.5; isoflurane, 184.5). Isoflurane and Freon-22 excretions were depressed 47 and 30%, respectively, relative to acetylene. In a theoretical model of airway gas exchange, neither a tissue nor a gas phase diffusion resistance predicted our results better than the standard equation for steady-state alveolar inert gas elimination. However, addition of a simple ln (MW) term reduced the remaining residual sum of squares by 40% in group 1 and by 83% in group 2. Despite this significant MW influence on tracheal gas exchange, we calculate that the quantitative gas exchange capacity of the conducting airways in total can account for less than or equal to 16% of any MW-dependent differences observed in pulmonary inert gas elimination.     

Spectral analysis of inert gas elimination data: resolution limits

A new method of analyzing inert gas data for recovery of the pulmonary ventilation-perfusion ration (VA/Q) distribution is proposed. It is shown that the conventional inert gas elimination equation takes the form of a convolution integral, and the relationship between VA/Q distribution and inert gas elimination resembles that of a noncausal low-pass filter with infinite zero-frequency gain. With the use of this formulation, characteristic features of VA/Q distribution may be represented in the frequency domain in terms of the corresponding energy spectrum. It is shown that the lack of resolution associated with finite data samples and measurement error is caused by distortions in the high-frequency contents of the resulting VA/Q distribution. With six inert gases, the technique cannot resolve a log SD less than 0.21 decade and a modal separation less than 0.87 decade. In the presence of measurement error, the degree of resolution is even less. It is suggested that for maximum resolution the number of discrete and duplicate data samples should be chosen so that the resulting noise and sampling cutoff frequencies are approximately equal.     

Regional VA, Q, and VA/Q during PLV: effects of nitroprusside and inhaled nitric oxide.

Partial liquid ventilation (PLV) with high-specific-weight perfluorocarbon liquids has been shown to improve oxygenation in acute lung injury, possibly by redistributing perfusion from dependent, injured regions to nondependent, less injured regions of the lung. Our hypothesis was that during PLV in normal lungs, a shift in perfusion away from dependent lung zones might, in part, be due to vasoconstriction that could be reversed by infusing sodium nitroprusside (NTP). In addition, delivering inhaled NO during PLV should improve gas exchange by further redistributing blood flow to well-ventilated lung regions. To examine this, we used a single transverse-slice positron emission tomography camera to image regional ventilation and perfusion at the level of the heart apex in six supine mechanically ventilated sheep during five conditions: control, PLV, PLV + NTP, and PLV + NO at 10 and 80 ppm. We found that PLV shifted perfusion from dependent to middle regions, and the dependent region demonstrated marked hypoventilation. The vertical distribution of perfusion changed little when high-dose intravenous NTP was added during PLV, and inhaled NO tended to shift perfusion toward better ventilated middle regions. We conclude that PLV shifts perfusion to the middle regions of the lung because of the high specific weight of perflubron rather than vasoconstriction.     

Gas density dependence of regional VA/V and VA/Q inequality during constant-flow ventilation

Constant-flow ventilation (CFV) is achieved by delivering a constant stream of inspiratory gas through cannulas aimed down the main stem bronchi at flow rates totaling 1-3 l.kg-1.min-1 in the absence of tidal lung motion. Previous studies have shown that CFV can maintain a normal arterial PCO2, although significant ventilation-perfusion (VA/Q) inequality appears. This VA/Q mismatch could be due to regional differences in lung inflation that occur during CFV secondary to momentum transfer from the inflowing stream to resident gas in the lung. We tested the hypothesis that substitution of a gas with lower density might attenuate regional differences in alveolar pressure and reduce the VA/Q inequality during CFV. Gas exchange was studied in seven anesthetized dogs by the multiple inert gas elimination technique during ventilation with intermittent positive-pressure ventilation, CFV with O2-enriched nitrogen (CFV-N2), or CFV with O2-enriched helium (CFV-He). As an index of VA/Q inequality independent of shunt, the log SD blood flow increased from 0.757 +/- 0.272 during intermittent positive-pressure ventilation to 1.54 +/- 0.36 (P less than 0.001) during CFV-N2. Switching from CFV-N2 to CFV-He at the same flow rate did not improve log SD blood flow (1.45 +/- 0.21) (P greater than 0.05) but tended to increase arterial PCO2. In excised lungs with alveolar capsules attached to the pleural surface, CFV-He significantly reduced alveolar pressure differences among lobes compared with CFV-N2 as predicted. Regional alveolar washout of Ar after a stap change of inspired concentration was slower during CFV--He than during CFV-N2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Linear programming analysis of VA/Q distributions: average distribution

The defining equations of the multiple inert gas elimination technique are underdetermined, and an infinite number of VA/Q ratio distributions exists that fit the same inert gas data. Conventional least-squares analysis with enforced smoothing chooses a single member of this infinite family whose features are assumed to be representative of the family as a whole. To test this assumption, the average of all ventilation-perfusion ratio (VA/Q) distributions that are compatible with given data was calculated using a linear program. The average distribution so obtained was then compared with that recovered using enforced smoothing. Six typical sets of inert gas data were studied. In all sets but one, the distribution recovered with conventional enforced smoothing closely matched the structure of the average distribution. The single exception was associated with the broad log-normal VA/Q distribution, which is rarely observed using the technique. We conclude that the VA/Q distribution conventionally recovered approximates a simple average of all compatible distributions. It therefore displays average features and only that degree of fine structural detail that is typical of the family as a whole.     

Determination of the distribution of ventilation-perfusion ratios: technic of elimination of multiple inert gases

The multiple inert gas elimination technique (MIGT) facilitates the estimation of the distributions of ventilation-perfusion (VA/Q) ratios in the experimental and clinical setting. The most relevant technical aspects and equipment and operational requirements needed to measure a mixture of inert gases in both the gas phase and the blood phase using gas chromatography are overviewed with detail. Results obtained in 3 dogs and 4 syringe-homogeneous lung models were entirely consistent with data formerly reported in the literature. Particular attention is paid to the linearity of the gas chromatograph detectors, reproducibility of inert gases sampling, and analysis of brands of heparin to detect acetone content. The errors of measurement (coefficients of variation) in blood were: 1.4 for sulfur hexafluoride; 1.8% for ethane; 2% for cyclopropane and halothane, each; 2.4% for diethyl ether; and, 3.6% for acetone. Important practical points are also emphasized in order to draw attention to potential problems and issues that should be concentrated upon to minimize the error in the measurements. It is concluded that the setting up of the MIGT is well established and validated.