Correction of inert gas washin or washout for gas solubility in blood

We show that when an inert gas is washed into the lungs its retention in the blood during any one breath is approximately proportional to its solubility. This relationship makes possible the correction of washin or washout data for blood uptake or release, provided that two gases of different solubility are used simultaneously. The method automatically allows for the characteristics of an individual washin or washout and for the occurrence of recirculation within a fairly short washin or washout period. It has been tested in models with nonuniform ventilation and perfusion and closely approximates the behavior of a truly insoluble gas. In the derived ventilation distribution, gas solubility appears as ventilation to units of low turnover. In the case of N2 this effect is small but causes appreciable overestimation of lung volume. The recovered dead space and main alveolar distribution are insignificantly affected.     

Effect of breath holding on ventilation maldistribution during tidal breathing in normal subjects

To test the hypothesis that during the course of a multiple-breath N2 washout (MBNW) diffusion-dependent ventilation maldistribution is more apparent in the early breaths, whereas convection-dependent maldistribution predominates in the later breaths, we performed MBNW with 0-, 1-, and 4-s end-inspiratory breath holds (BH0, BH1, BH4, respectively) in five normal subjects. Each subject breathed with a constant tidal volume of 1 liter, at 10-12 breaths/min and at constant flow rates. For each breath we computed the slope of the alveolar plateau normalized by the mean expired N2 concentration (Sn), the Bohr dead space (VDB), and an index analogous to the Fowler dead space (V50). In all five subjects, Sn, VDB, and V50 decreased with breath holding, indicating diffusion dependence of these indexes. Over the first five breaths the rate of increase of Sn as a function of cumulative expired volume (delta Sn/delta sigma VE) decreased by 29 and 54% during BH1 and BH4, respectively, compared with BH0. In contrast, from breath 5 to the end of the washout there was no significant change in delta Sn/delta sigma VE during BH1 and BH4 compared with BH0. Our results provide further experimental support for the hypothesis that the increase of Sn as a function of cumulative expired volume after the fifth breath constitutes a diffusion-independent index of ventilation inhomogeneity. It therefore reflects alveolar gas inequalities among larger units.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bolus technique for assessing distribution of inspired gas during tidal breathing

The washout of an insoluble tracer from the lung may be represented by a model with two ventilatory compartments representing poorly and better-ventilated regions. Using boli of a second insoluble gas delivered at a given point during inspirations of a multibreath washout test, the proportions of labeled inspired ventilation reaching the poorly and well-ventilated regions may be determined by analyzing the kinetics of the exhaled tracer. We studied eight normal subjects breathing through large-bore solenoid valves controlled to maintain tidal volume at 600 or 900 ml. Boli consisting of 15 ml of 80% He-20% O2 were delivered over 75 ms; this labeled approximately 125 ml of inspired gas. Boli were delivered after 50 ml had been inspired to mark early inspiration and after 300 ml had been inspired to mark midinspiration. Using 900-ml tidal breaths, late inspiration was marked by boli delivered at 600 ml. Subjects were studied in the seated and the supine positions. In both positions, significantly more of the early breath went to the poorly ventilated compartment. Several possible physiological mechanisms, singly or in combination, could account for these observations, but differences in dead space path length are most likely involved.     

Fast real-time moment-ratio analysis of multibreath nitrogen washout in children

To apply real-time moment-ratio analysis to multibreath N2-washout curves (MBNW) from children, a new processor-controlled device was constructed. Flow and fractional N2 concentration (FN2) were each sampled by 200 Hz. An electromagnetic triple-valve system, with an instrumental dead space of 36 ml and a valve resistance of 0.3 cmH2O . l-1 . s, was connected in series with a pneumotachograph and an N2 analyzer (Ohio 720) placed next to the mouthpiece. A FORTRAN/MACRO program on a PDP 11/23 computer enabled measurement of inspiratory and expiratory flow and FN2 sampling by a 12-bit analog-to-digital converter. The fast real-time digital processing of the N2 and flow signals incorporated filtering, delay compensation, and corrections for the effects of changes in gas composition and temperature. MBNW dynamics of the lungs were studied in 17 healthy and 28 asthmatic children and in 16 patients with cystic fibrosis, evaluating the moment ratios of the washout curves as indices of the ventilation characteristics. Intrasubject variability of the moment ratios (m1/m0, m2/m0) and determination of functional residual capacity (FRC) varied between 6.3 and 14.7% (depending on which parameter is considered) and was comparatively lower than other indices previously investigated in adults. In addition, the sensitivity of the moment ratios for discriminating different stages of ventilation inhomogeneity was superior to other indices. m2/m0 is closely related to the simultaneously measured airway resistance, and the ratio between cumulative expired volume and FRC is correlated with the ratio between residual volume and total lung capacity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of inspired CO2, hyperventilation, and time on VA/Q inequality in the dog.

In a recent study by Tsukimoto et al. (J. Appl. Physiol. 68: 2488-2493, 1990), CO2 inhalation appeared to reduce the size of the high ventilation-perfusion ratio (VA/Q) mode commonly observed in anesthetized mechanically air-ventilated dogs. In that study, large tidal volumes (VT) were used during CO2 inhalation to preserve normocapnia. To separate the influences of CO2 and high VT on the VA/Q distribution in the present study, we examined the effect of inspired CO2 on the high VA/Q mode using eight mechanically ventilated dogs (4 given CO2, 4 controls). The VA/Q distribution was measured first with normal VT and then with increased VT. In the CO2 group at high VT, data were collected before, during, and after CO2 inhalation. With normal VT, there was no difference in the size of the high VA/Q mode between groups [10.5 +/- 3.5% (SE) of ventilation in the CO2 group, 11.8 +/- 5.2% in the control group]. Unexpectedly, the size of the high VA/Q mode decreased similarly in both groups over time, independently of the inspired PCO2, at a rate similar to the fall in cardiac output over time. The reduction in the high VA/Q mode together with a simultaneous increase in alveolar dead space (estimated by the difference between inert gas dead space and Fowler dead space) suggests that poorly perfused high VA/Q areas became unperfused over time. A possible mechanism is that elevated alveolar pressure and decreased cardiac output eliminate blood flow from corner vessels in nondependent high VA/Q regions.     

Numerical modelling and analysis of peripheral airway asymmetry and ventilation in the human adult lung

We present a new one-dimensional model of gas transport in the human adult lung. The model comprises asymmetrically branching airways, and heterogeneous interregional ventilation. Our model differs from previous models in that we consider the asymmetry in both the conducting and the acinar airways in detail. Another novelty of our model is that we use simple analytical relationships to produce physiologically realistic models of the conducting and acinar airway trees. With this new model, we investigate the effects of airway asymmetry and heterogeneous interregional ventilation on the phase III slope in multibreath washouts. The model predicts the experimental trend of the increase in the phase III slope with breath number in multibreath washout studies for nitrogen, SF(6) and helium. We confirm that asymmetrical branching in the acinus controls the magnitude of the first-breath phase III slope and find that heterogeneous interregional ventilation controls the way in which the slope changes with subsequent breaths. Asymmetry in the conducting airways appears to have little effect on the phase III slope. That the increase in slope appears to be largely controlled by interregional ventilation inhomogeneities should be of interest to those wishing to use multibreath washouts to detect the location of the structural abnormalities within the lung.     

Effects of embolus size on hemodynamics and gas exchange in canine embolic pulmonary hypertension

We examined the effects of different-sized glass-bead embolization on pulmonary hemodynamics and gas exchange in 12 intact anesthetized dogs. Pulmonary hemodynamics were evaluated by multipoint pulmonary arterial pressure (Ppa)/cardiac output (Q) plots before and 60 min after sufficient amounts of 100-microns (n = 6 dogs) or 1,000-microns (n = 6 dogs) glass beads to triple baseline Ppa were given and again 20 min after 5 mg/kg hydralazine in all the animals. Gas exchange was assessed using the multiple inert gas elimination technique in each of these experimental conditions. Embolization increased both the extrapolated pressure intercepts (by 6 mmHg) and the slopes (by 5 mmHg.l-1.min.m2) of the linear Ppa/Q plots, together with an 80% angiographic pulmonary vascular obstruction. These changes were not significantly different in the two subgroups of dogs. However, arterial PO2 was most decreased after the 100-microns beads, and arterial PCO2 was most increased after the 1,000-microns beads. Both bead sizes deteriorated the distribution of ventilation (VA)/perfusion (Q) ratios, with development of lung units with higher as well as with lower than normal VA/Q. Only 100-microns beads generated a shunt. Only 1,000-microns beads generated a high VA/Q mode and increased inert gas dead space. Hydralazine increased the shunt and decreased the slope of the Ppa/Q plots after 100-microns beads and had no effect after 1,000-microns beads. We conclude that in embolic pulmonary hypertension, Ppa/Q characteristics are unaffected by embolus size up to 1,000 microns.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantification of regional V/Q ratios in humans by use of PET. I. Theory

With positron emission tomography, quantitative measurements of regional alveolar and mixed venous concentrations of positron-emitting radioisotopes can be made within a transaxial section through the thorax. This allows the calculation of regional ventilation-to-perfusion (V/Q) ratios by use of established tracer dilution theory and the constant intravenous infusion of 13N. This paper considers the effect of the inspiration of dead-space gas on regional V/Q and investigates the relationship between the measured V/Q, physiological V/Q, and V/Q defined conventionally in terms of bulk gas flow (VA/Q). Ventilation has been described in terms of net gas transport, and the term effective ventilation has been introduced. A simple two-compartment model has been constructed to allow for the reinspiration of regional (or personal) and common dead-space gas. By use of this model, with parameters representative of normal lung the effective V/Q ratio for 13N [(VA/Q)eff(13N)] is shown to overestimate VA/Q by 18% when VA/Q = 0.1 but underestimate VA/Q by 68% when VA/Q = 10. For physiological gases, the model predicts that the behavior of O2 should be similar to that of 13N, so that, in terms of gas transport, V/Q ratios obtained using the infusion of 13N closely follow those for O2. Values of the effective V/Q ratio for CO2 [(VA/Q)eff(CO2)] lie approximately halfway between (VA/Q)eff(13N) and VA/Q. These results indicate that dead-space ventilation is far less a confounding issue when V/Q is considered in terms of net gas transport (VAeff), rather than bulk flow (VA).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Convection- and diffusion-dependent ventilation maldistribution in normal subjects

We performed multiple-breath N2 washouts (MBNW) with tidal volumes of 1 liter at 8-16 breaths/min and constant flow rates in six normal subjects. For each breath we computed the slope of the alveolar plateau, normalized by the mean expired N2 concentration (Sn), the Bohr dead space (VDB), an index analogous to the Fowler dead space (V50), and the normalized slope of phase II (S2). In four subjects helium (He) and sulfur hexafluoride (SF6) were washed out after equilibration with a 5% gas mixture of each tracer. The Sn for He and SF6 increased in consecutive breaths, but the difference (delta Sn) increased only over the first five breaths, remaining constant thereafter. In all six subjects Sn, VDB, and V50 increased progressively in consecutive breaths of the MBNW, the increase in Sn being the greatest, approximately 290% from the first to the 23-25th breath. In contrast, S2 was unchanged initially and decreased after the sixth breath. The results indicate that after the fifth breath the increase in Sn during a MBNW is diffusion independent and may constitute a sensitive index of convection-dependent inhomogeneity (CDI). Subtraction of this component from the first breath suggests that Sn in a single-breath washout is largely due to a diffusion-dependent mechanism. The latter may reflect an interaction of convection and diffusion within the lung periphery, whereas CDI may comprise ventilation inequality among larger units, subtended by more centrally located branch points.     

Model simulations of gas mixing and ventilation distribution in the human lung

A new lung model that incorporates intra-acinar diffusion- and convection-dependent inhomogeneities (DCDI) and interregional and intraregional convection-dependent inhomogeneities (CDI) is described. The model is divided into two regions, each containing two subunits. Each of the four subunits in the model consists of a multi-branch-point structure, based on the anatomic data from Haefeli-Bleuer and Weibel (Anat. Record 220: 401-414, 1988). The subunit turnover (TO), i.e., the ratio of subunit tidal to resting volume, and the flow sequences (FS) between the subunits are used as model parameters. The model simulates the normalized alveolar slope (Sn), Fowler and Bohr dead space (VDF and VDB), and alveolar mixing efficiency (AME) as a function of breath number (n) during a multiple-breath N2 washout (MBNW). For the first breath of the MBNW, these indexes are poorly sensitive to the TO distribution or FS between the subunits. However, as the washout proceeds, the n dependence of both Sn and VDB becomes markedly distinct for simulations with different TO and FS. VDF increases only slightly with n during the MBNW for a large range of TO and FS combinations, and AME is independent of FS. Comparison of published experimental observations with model simulations gave a consistent picture of ventilation maldistribution in the human lung. MBNW simulations in conditions of weightlessness, which will be performed shortly in Spacelab, suggest that it will be possible to evaluate quantitatively the intraregional elastic inhomogeneities in the human lung.     

Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans.

Using positron emission tomography (PET) and intravenously injected (13)N(2), we assessed the topographical distribution of pulmonary perfusion (Q) and ventilation (V) in six healthy, spontaneously breathing subjects in the supine and prone position. In this technique, the intrapulmonary distribution of (13)N(2), measured during a short apnea, is proportional to regional Q. After resumption of breathing, regional specific alveolar V (sVA, ventilation per unit of alveolar gas volume) can be calculated from the tracer washout rate. The PET scanner imaged 15 contiguous, 6-mm-thick, slices of lung. Vertical gradients of Q and sVA were computed by linear regression, and spatial heterogeneity was assessed from the squared coefficient of variation (CV(2)). Both CV and CV were corrected for the estimated contribution of random imaging noise. We found that 1) both Q and V had vertical gradients favoring dependent lung regions, 2) vertical gradients were similar in the supine and prone position and explained, on average, 24% of Q heterogeneity and 8% of V heterogeneity, 3) CV was similar in the supine and prone position, and 4) CV was lower in the prone position. We conclude that, in recumbent, spontaneously breathing humans, 1) vertical gradients favoring dependent lung regions explain a significant fraction of heterogeneity, especially of Q, and 2) although Q does not seem to be systematically more homogeneous in the prone position, differences in individual behaviors may make the prone position advantageous, in terms of V-to-Q matching, in selected subjects.     

A visual aid for teaching ventilation-perfusion relationships

To help students understand the concept of the ventilation-perfusion ratio (VA/Q) and the effects that VA/Q mismatching has on pulmonary gas exchange, a "sliding rectangles" visual aid was developed to teach VA/Q relationships. Adjacent rectangles representing "ventilation" and "perfusion" are slid past one another so that portions of the ventilation and perfusion rectangles are not touching, illustrating the concepts of dead-space ventilation (VD) and shunt flow (QS). The portion of the ventilation bar representing VD is further subdivided into anatomical and alveolar VD and used to show the effects of alveolar dead space on the PO2 (PAO2) and PCO2 of alveolar air (PACO2); movement away from the "ideal" point). Similarly, the portion of the perfusion bar representing QS is used to define anatomical and physiological shunts and the effect of shunts on the PO2 (PaO2) and PCO2 of arterial blood (PaCO2). The genesis of the PAO2-PaO2 (A-a) PO2 difference as well as the effects of VA/Q mismatching and diffusion abnormalities can all be discussed with this visual aid. This approach has greatly assisted some students in mastering this traditionally difficult area of respiratory physiology.     

Ventilation-perfusion relationships in isolated blood-free perfused rabbit lungs.

The multiple inert gas elimination technique (MIGET) was applied to blood-free perfused isolated rabbit lungs. Commonly accepted criteria for reliability of the method were found to be fulfilled in this model. Ventilation-perfusion (VA/Q) distributions in isolated control lungs corresponded to those repeatedly detected under physiological conditions. In particular, a narrow unimodal dispersion of perfusate flow was observed: perfusion of low-VA/Q areas ranged below 1% and shunt flow approximately 2-3%; perfusion of high-VA/Q regions was not detected. Gas flow was characterized by narrow dispersion in the midrange-VA/Q areas. Application of a low level of PEEP (1 cmH2O) reduced shunt flow to less than 1%, and low-VA/Q areas were no longer noted. By using this PEEP-level, stable gas exchange conditions were maintained for greater than 5 h of extracorporeal perfusion. Graded embolization with small air bubbles caused a typical rightward shift (to higher VA/Q ratios) of mean ventilation, associated with the appearance of high-VA/Q regions and an increase in dead space ventilation. Mean perfusion was shifted leftward, and shunt flow was approximately doubled. Whole lung lavage with saline for washout of surfactant evoked a progressive manifold increase in shunt flow, accompanied by a moderate rise of perfusate flow to low-VA/Q areas. We conclude that the MIGET can be applied to isolated blood-free perfused rabbit lungs for assessment of gas exchange and that typical patterns of VA/Q mismatch are reproduced in this model.     

Effects of mean airway pressure on gas transport during high-frequency ventilation in dogs

In 10 anesthetized, paralyzed, supine dogs, arterial blood gases and CO2 production (VCO2) were measured after 10-min runs of high-frequency ventilation (HFV) at three levels of mean airway pressure (Paw) (0, 5, and 10 cmH2O). HFV was delivered at frequencies (f) of 3, 6, and 9 Hz with a ventilator that generated known tidal volumes (VT) independent of respiratory system impedance. At each f, VT was adjusted at Paw of 0 cmH2O to obtain a eucapnia. As Paw was increased to 5 and 10 cmH2O, arterial PCO2 (PaCO2) increased and arterial PO2 (PaO2) decreased monotonically and significantly. The effect of Paw on PaCO2 and PaO2 was the same at 3, 6, and 9 Hz. Alveolar ventilation (VA), calculated from VCO2 and PaCO2, significantly decreased by 22.7 +/- 2.6 and 40.1 +/- 2.6% after Paw was increased to 5 and 10 cmH2O, respectively. By taking into account the changes in anatomic dead space (VD) with lung volume, VA at different levels of Paw fits the gas transport relationship for HFV derived previously: VA = 0.13 (VT/VD)1.2 VTf (J. Appl. Physiol. 60: 1025-1030, 1986). We conclude that increasing Paw and lung volume significantly decreases gas transport during HFV and that this effect is due to the concomitant increase of the volume of conducting airways.     

Model of gas transport during high-frequency ventilation

We analyze gas exchange during high-frequency ventilation (HFV) by a stochastic model that divides the dead space into N compartments in series where each compartment has a volume equal to tidal volume (V). We then divide each of these compartments into alpha subcompartments in series, where each subcompartment receives a well-mixed concentration from one compartment and passes a well-mixed concentration to another in the direction of flow. The number of subcompartments is chosen on the basis that 1/alpha = (sigma t/-t)2, where -t is mean transit time across a compartment of volume, and sigma t is standard deviation of transit times. If (sigma t/-t)D applies to the transit times of the entire dead space, the magnitude of gas exchange is proportional to (sigma t/-t)D, frequency, and V raised to some power greater than unity in the range where V is close to VD. When V is very small in relation to VD, gas exchange is proportional to (sigma t/-t)2D, frequency, and V raised to a power equal to either one or two depending on whether the flow is turbulent or streamline, respectively. (sigma t/-t)D can be determined by the relation between the concentration of alveolar gas at the air outlet and volume expired as in a Fowler measurement of the volume of the dead space.     

Estimation of blood flow distribution in skeletal muscle from inert gas washout

A new method is evaluated for the estimation of blood flow-to-volume distribution in skeletal muscle from inert gas washout kinetics. Acetylene washout from the isolated, blood-perfused canine gracilis muscle was measured continuously with a blood gas catheter in combination with a mass spectrometer. The washout curves were transformed to flow-to-volume ratio distributions by means of a 50-compartment model. The algorithm fits the expression for the washout curve derived from the model by a least-squares method with enforced smoothing. The algorithm was evaluated using computer simulations in which artificial washout curves were generated by a multicompartment model with a known flow distribution. A wide range of given flow distributions could be recovered from the simulated data. The data were also analyzed using a linear programming technique. Analysis of the experimental data with the least-squares method showed that there is considerable heterogeneity in the distribution of perfusion in resting gracilis muscle. The distribution is characterized by at least two modes and a single compartment with a very low perfusion-to-volume ratio. Experimental noise made it impossible to obtain feasible flow distributions by means of linear programming.     

Respiratory impedance and multibreath N2 washout in healthy, asthmatic, and cystic fibrosis subjects

We measured forced expiratory volume in 1 s (FEV1), respiratory impedance (Zrs) from 4 to 60 Hz, and a multibreath N2 washout (MBNW) in 6 normal, 10 asthmatic, and 5 cystic fibrosis (CF) subjects. The MBNW were characterized by the mean dilution number (MDN) derived by a moment analysis. The Zrs spectra were characterized by the minimum resistance (Rmin), the drop in resistance (Rdrop) from 4 Hz to Rmin, and the first resonance frequency (Fr1). Measurements were repeated after bronchodilation in three normal and all asthmatic subjects. Before bronchodilation, six of the asthmatic subjects showed close to normal FEV1. The Zrs in the normal subjects showed low Rmin (1.9 +/- 0.7 cmH2O.l-1.s), Rdrop (0.4 +/- 0.4), and Fr1 (10 +/- 2 Hz). Four of the mildly obstructed asthmatic subjects had normal Zrs but elevated MDNs (i.e., abnormal ventilation distribution). The other six asthmatic subjects had significantly elevated Rmin (4.1 +/- 0.8), Rdrop (6.3 +/- 5.8), and Fr1 (34 +/- 0.4 Hz) and elevated MDNs. The CF patients had elevated Zrs features and MDNs. After bronchodilation, no changes in FEV1, MDN, or Zrs occurred in the normal subjects. All asthmatic subjects showed increased FEV1 and decreased MDN, but the Zrs was unaltered in the four asthmatic subjects whose base-line Zrs was normal. For the other six asthmatic subjects, there were large decreases in the Rmin, Rdrop, and Fr1. Finally, there was a poor correlation between the MDN and the Zrs features but high correlation between the Zrs features alone. These results imply that significant nonuniform peripheral airway obstruction can exist such that ventilation distribution is abnormal but Zrs from 4 to 60 Hz is not. Abnormalities in Zrs from 4 to 60 Hz occur only after significant overall obstruction in the peripheral and more central airways. Combining Zrs and the MBNW may permit us to infer whether the disease is predominantly in the lung periphery or in the more central airways.