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.     

The physiological factors which govern inert gas exchange

The decay constants (k _j ) of the equation of inert gas exchanges are the roots of an algebraic equation of degreen+1, wheren is the number of distinct absorbing tissues. The coefficients of this equation can be obtained numerically by certain independent experiments to measure the tissue parameters. Graphical solution of this equation yields theoretical values of thek _j . Combining these constants with the numerical values for the partial derivatives of thek _j then gives the per cent rate of change of thek _j as any one tissue parameter varies by a given fraction of its normal range. A numerical example of these calculations shows good conformity with experiment, and permits a quantitative estimate of variations in the speed of gas exchange from a knowledge of changes in the physiological state. The opinions expressed in this article are the private ones of the writers, and are not to be construed as reflecting the policies of the Navy Department or the Naval Service at large.     

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%.     

Simultaneous measurement of acetylene reduction and respiratory gas exchange of attached root nodules

A method was developed for the simultaneous measurement of acetylene reduction, carbon dioxide evolution and oxygen uptake by individual root nodules of intact nitrogen-fixing plants (Alnus rubra Bong.). The nodules were enclosed in a temperature-controlled leak-tight cuvette. Assay gas mixtures were passed through the cuvette at a constant, known flow rate and gas exchange was measured by the difference between inlet and outlet gas compositions. Gas concentrations were assayed by a combination of an automated gas chromatograph and a programmable electronic integrator. Carbon dioxide and ethylene evolution were determined with a coefficient of variation which was less than 2%, whereas the coefficient of variation for oxygen uptake measurements was less than 5%. Nodules subjected to repeated removal from and reinsertion into the cuvette and to long exposures of 10% v/v acetylene showed no irreversible decline in respiration or acetylene reduction. This system offers long-term stability and freedom from disturbance artifacts plus the ability to monitor continuously, rapidly and specifically the changes in root nodule activity caused by environmental perturbation.     

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.     

Automated detection of the phase III slope during inert gas washout testing

We describe a method to determine the phase III slope for the purpose of calculating indexes of ventilation heterogeneity, S(acin) and S(cond), from the multiple breath nitrogen washout test (MBNW). Our automated method applies a recursive, segmented linear regression technique to each breath of the MBNW test and determines the best point of transition, or breakpoint, between each phase of the washout. A sample set of 50 MBNW tests (controls, asthma, and COPD) was used to establish the conditions in which the phase III slope obtained from the automated technique best matched that obtained by two manual interpreters. We then applied our technique to a test set of 30 subjects (with an even number of subjects in each of the above groups) and compared these results against the manual analysis of a third independent manual interpreter. Indexes of ventilation heterogeneity were determined using both methods and compared. The phase III slopes determined by the automatic technique best matched the manual interpreter when the phase III slope was calculated from the phase II-III transition point plus the addition of 50% of the phase II volume to the end of the expiration. Calculation of the indexes S(acin) and S(cond) showed no overall difference between analysis methods in either S(acin) (P = 0.14) or S(cond) (P = 0.59) when the set threshold was applied to our automated analysis. Our analysis method provides an alternate means for rapid quantification of the MBNW test, removing operator dependence without alteration in either S(acin) or S(cond).     

Estimation of cardiac output by analysis of respiratory gas exchange.

Cardiac output is estimated by least squares fitting of a model of pulmonary gas exchange to measurements of respiratory gas composition obtained with a mass spectrometer during a rebreathing maneuver. This new technique estimates cardiac output on spontaneously breathing subjects at rest and requires neither central venous nor arterial blood samples. Principal features of the technique are the use of multiple gases simultaneously in the analysis, the use of a mathematical model for breath-to-breath evaluation of gas exchange, and simultaneous estimation of gas exchange and alveolar gas tensions with the same instrumentation. The technique is compared with thermal dilution estimates in dogs before and during hemorrhagic shock. Two-thirds of these estimates were within 20% of one another. The standard deviation of replication was 15%. Shortcomings, possibilities for improvement, and possible applications are discussed.     

Measurement of respiratory gas exchange during artificial respiration

This paper reports a new system for the continuous measurements of respiratory gas exchange in ventilated subjects. It involves mixing some of the inspired gas with all of the expired gas and withdrawing the mixture at a constant rate through a dry gas meter that measures the flow. The inspired gas and expired gas mixtures are sampled and O2 and CO2 concentrations measured with a paramagnetic gas analyzer and a capnograph, respectively, to an accuracy of 0.01%. Evidence is presented to confirm the necessary stability and sensitivity of these instruments. It is possible to use the system with high inspired O2 concentrations, with ventilators where there is incomplete separation of inspired and expired gas, and in the presence of intermittent mandatory ventilation, positive end-expiratory pressure, and continuous airway pressure. The system was compared with the N2-dilution method and with the collection of expired gas in a Douglas bag in dog experiments and with patients in the intensive therapy unit. Excellent correlation between these methods was found in all circumstances.