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The dynamic changes in CO concentration [CO] during a single breath could be influenced by topographic inhomogeneity in the lung or by peripheral inhomogeneity due to a gas mixing resistance in the gas phase of the lung or to serial gradients in gas diffusion. Ten healthy subjects performed single-breath maneuvers by slowly inhaling test gas from functional residual capacity to one-half inspiratory capacity and slowly exhaling to residual volume with target breath-hold times of 0, 1.5, 3, 6, and 9 s. We calculated the three-equation single-breath diffusing capacity of the lung for CO (DLSBCO-3EQ) from the mean [CO] in both the entire alveolar gas sample and in four successive equal alveolar gas samples. DLSBCO-3EQ from the entire alveolar gas sample was independent of breath-hold time. However, with 0 s of breath holding, from early alveolar gas samples DLSBCO-3EQ was reduced and from late alveolar gas samples it was increased. With increasing breath-hold time, DLSBCO-3EQ from the earliest alveolar gas sample rapidly increased, whereas from the last alveolar gas sample it rapidly decreased such that all values from the small alveolar gas samples approached DLSBCO-3EQ from the entire alveolar sample. These changes correlated with ventilation inhomogeneity, as measured by the phase III He concentration slope and the mixing efficiency, and were larger for maneuvers with inspired volumes to one-half inspiratory capacity vs. total lung capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

In normal seated subjects we increased single-breath ventilation inhomogeneity by changing both the preinspiratory lung volume and breath-hold time and examined the ensuing effects on two different techniques of measuring the diffusing capacity of the lung for carbon monoxide (DLCO). We measured the mean single-breath DLCO using the three-equation method (DLCOSB-3EQ) and also measured DLCO over discrete intervals during exhalation by the "intrabreath" method (DLCOexhaled). We assessed the distribution of ventilation using the normalized phase III slope for helium (SN). DLCOSB-3EQ was unaffected by preinspiratory lung volume and breath-hold time. DLCOexhaled increased with increasing preinspiratory lung volume and decreased with increasing breath-hold time. These changes correlated with the simultaneously observed changes in ventilation inhomogeneity as measured by SN (P < 0.01). We conclude that measurements of DLCOexhaled do not accurately reflect the mean DLCO. Intrabreath methods of measuring DLCO are based on the slope of the exhaled CO concentration curve, which is affected by both ventilation and diffusion inhomogeneities. Although DLCOexhaled may theoretically provide information about the distribution of CO uptake, the concomitant effects of ventilation nonuniformity on DLCOexhaled may mimic or mask the effects of diffusion nonuniformity.

In patients with airflow obstruction, we found that ventilation inhomogeneity during vital capacity single-breath maneuvers was associated with decreases in the three-equation single-breath CO diffusing capacity of the lung (DLcoSB-3EQ) when breath-hold time (tBH) decreased. We postulated that this was due to a significant resistance to diffusive gas mixing within the gas phase of the lung. In this study, we hypothesized that this phenomenon might also occur in normal subjects if the breathing cycle were altered from traditional vital capacity maneuvers to those that increase ventilation inhomogeneity. In 10 normal subjects, we examined the tBH dependence of both DLcoSB-3EQ and the distribution of ventilation, measured by the mixing efficiency and the normalized phase III slope for helium. Preinspiratory lung volume (V0) was increased by keeping the maximum end-inspiratory lung volume (Vmax) constant or by increasing V0 and Vmax. When V0 increased while Vmax was kept constant, we found that the tBH-independent and the tBH-dependent components of ventilation inhomogeneity increased, but DLcoSB-3EQ was independent of V0 and tBH. Increasing V0 and Vmax did not change ventilation inhomogeneity at a tBH of 0 s, but the tBH-dependent component decreased. DLcoSB-3EQ, although independent of tBH, increased slightly with increases in Vmax. We conclude that in normal subjects increases in ventilation inhomogeneity with increases in V0 do not result in DLcoSB-3EQ becoming tBH dependent.

The purpose of this study was to determine the relationship between the three-equation diffusing capacity for carbon monoxide (DLcoSB-3EQ) and lung volume and to determine how this relationship was altered when maneuvers were immediately preceded by a deep breath. DLcoSB-3EQ maneuvers were performed in nine healthy subjects either immediately after a deep breath or after tidal breathing for 10 min. The maneuvers consisted of slow inhalation of test gas from functional residual capacity to 25, 50, 75, or 100% of the inspiratory capacity and, without breath holding, slow exhalation to residual volume. After either a deep breath or tidal breathing, we found that DLcoSB-3EQ decreased nonlinearly with decreasing lung volume. At all lung volumes, DLcoSB-3EQ was significantly greater when measured after a deep breath than after tidal breathing. This effect increased as lung volume decreased, so that the greatest difference between DLcoSB-3EQ after a deep breath and that after tidal breathing occurred at the lowest lung volume. We conclude that a deep breath or spontaneous sigh has a role in reestablishing the pathway for gas exchange during tidal breathing.

In 10 nonasthmatic subjects and 11 patients with asthma, we measured pulmonary resistance (RL), functional residual capacity (FRC), and specific conductance (sGaw) before, during, and after submaximal treadmill exercise. Nonasthmatic subjects did not change RL, FRC, or sGaw from base-line resting values during or after exercise. In patients with asthma, RL decreased significantly during exercise, both when exercise was begun from the control resting state and from conditions of elevated RL after a preceding period of exercise. When asthmatic patients inhaled a standardized dose of aerosolized histamine, the increase in RL during exercise was significantly less than the increase in RL when they breathed histamine at rest. When patients hyperventilated at rest with tidal volumes, breathing frequencies, and end-tidal CO2 tensions similar to those during exercise conditions, bronchodilatation also occurred, and the increase in RL following inhaled histamine during isocapnic hyperventilation was also less than at rest. Since bronchodilatation and inhibition of histamine-induced bronchoconstriction occur during both exercise and isocapnic hyperventilation, we suggest that the mechanism of bronchodilatation during exercise may not necessarily be related to metabolic factors associated with exercise.

It has been shown that measurements of the diffusing capacity of the lung for CO made during a slow exhalation [DLCO(exhaled)] yield information about the distribution of the diffusing capacity in the lung that is not available from the commonly measured single-breath diffusing capacity [DLCO(SB)]. Current techniques of measuring DLCO(exhaled) require the use of a rapid-responding (less than 240 ms, 10-90%) CO meter to measure the CO concentration in the exhaled gas continuously during exhalation. DLCO(exhaled) is then calculated using two sample points in the CO signal. Because DLCO(exhaled) calculations are highly affected by small amounts of noise in the CO signal, filtering techniques have been used to reduce noise. However, these techniques reduce the response time of the system and may introduce other errors into the signal. We have developed an alternate technique in which DLCO(exhaled) can be calculated using the concentration of CO in large discrete samples of the exhaled gas, thus eliminating the requirement of a rapid response time in the CO analyzer. We show theoretically that this method is as accurate as other DLCO(exhaled) methods but is less affected by noise. These findings are verified in comparisons of the discrete-sample method of calculating DLCO(exhaled) to point-sample methods in normal subjects, patients with emphysema, and patients with asthma.

Recent studies have shown that diffusing capacities measured at multiple intervals during a single exhalation [DLCO(exhaled)] remained constant with lung volume in normal subjects, but decreased with decreasing lung volume in patients who may have had diffusion nonuniformity. We have examined the theoretical basis of these results by determining what factors affected DLCO(exhaled) in a computerized lung model in which diffusion in each compartment remained constant with lung volume. DLCO(exhaled) decreased with decreasing lung volume when a small lung region lacked diffusion. However, the change in DLCO(exhaled) with lung volume was also affected by nonuniform ventilation and these effects could not be eliminated by correcting the carbon monoxide decay and the simultaneous decay of helium. DLCO(exhaled) values were also influenced by the exhaled flow rate in the presence of nonuniform ventilation and/or nonuniform diffusion. However, prolonging the period of breath holding prior to exhalation reduced DLCO(exhaled) values at all lung volumes when non-uniform diffusion was simulated, but did not affect DLCO(exhaled) when only nonuniform ventilation was simulated.

We studied 10 symptom-free lifetime non-smokers and 17 smokers all with normal pulmonary function studies. All subjects performed single-breath N2 washout tests by either exhaling slowly ("slow maneuver") from end inspiration (EI) to residual volume (RV) or exhaling maximally ("fast maneuver") from EI to RV. After either maneuver, subjects then slowly inhaled 100% O2 to total lung capacity (TLC) and without breath holding, exhaled slowly back to RV. In the nonsmokers seated upright phase III slope of single-breath N2 test (delta N2/l) was lower (P less than 0.01) for the fast vs. the slow maneuver, but this difference disappeared when the subjects repeated the maneuvers in the supine position. In contrast, delta N2/l was higher for the fast vs. the slow maneuver (P less than 0.01) in smokers seated upright. For the slow maneuver, delta N2/l was similar between smokers and nonsmokers but for the fast maneuvers delta N2/l was higher in smokers than nonsmokers (P less than 0.01). We suggest that the fast exhalation to RV decreases delta N2/l in normal subjects by decreasing apex-to-base differences in regional ratio of RV to TLC (RV/TLC) but increases delta N2/l in smokers, because regional RV/TLC increases distal to sites of small airways obstruction when the expiratory flow rate is increased.

In five treadmill-exercising, unsedated dogs, we studied the effect of inhaled Ascaris suum antigen aerosols on minute volume of ventilation (VE), respiratory frequency (f), tidal volume (VT), total pulmonary resistance (RL), and dynamic pulmonary compliance (CLdyn), before and during cooling of the vagus nerves. With the vagi warm, inhaled antigen increased VE (mean + 62%; P less than 0.01)by increasing f (mean + 180%; P less than 0.01), despite a decrease in VT (mean - 42%; P less than 0.01). RL increased (mean + 170%; P less than 0.001) and CLdyn decreased (mean - 43%; P less than 0.005). With the vagi cool, inhaled antigen no longer affected VE, f, or VT (P greater than 0.5), although RL still increased and CLdyn still decreased. Inhalation of a bronchodilator, terbutaline, prevented the broncho-constriction induced by antigen but did not prevent the ventilatory response. We conclude that vagal afferent pathways mediate the ventilatory response to inhaled antigen and suggest that the primary stimulus for this response is not airway narrowing.

To examine the effect of preinspiratory lung volume (PILV) on ventilation distribution, we performed multiple-breath N2 washouts (MBNW) in seven normal subjects breathing 1-liter tidal volumes over a wide range of PILV above closing capacity. We measured the following two independent indexes of ventilation distribution from the MBNW: 1) the normalized phase III slope of the final breaths of the washout (Snf) and 2) the alveolar mixing efficiency during that portion of the washout where 80-90% of the lung N2 had been cleared. Three of the subjects also performed single-breath N2 washouts (SBNW) by inspiring 1-liter breaths and expiring to residual volume at PILV = functional residual capacity (FRC), FRC + 1.0, and FRC - 0.5, respectively. From the SBNW we measured the phase III slope over the expired volume ranges of 0.75-1.0, 1.0-1.6, and 1.6-2.2 liters (S0.75, S1.0, and S1.6, respectively). Between a PILV of 0.92 +/- 0.09 (SE) liter above FRC and a PILV of 1.17 +/- 0.43 liter below FRC, Snf decreased by 61% (P less than 0.001) and alveolar mixing efficiency increased from 80 to 85% (P = 0.05). In addition, Snf and alveolar mixing efficiency were negatively correlated (r = 0.74). In contrast, over a similar volume range, S1.0 and S1.6 were greater at lower PILV. We conclude that, during tidal breathing in normal subjects, ventilation distribution becomes progressively more inhomogeneous at higher lung volumes over a range of volumes above closing capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Using three conventional methods and a new method we measured the single-breath diffusing capacity for carbon monoxide [DLCO(SB)] in a group of normal subjects. Whereas the conventional methods calculated DLCO(SB) from a single equation valid only for breath holding, the new method used three equations, one for each phase of the single-breath maneuver, i.e., inhalation, breath holding, and exhalation. We found that while the conventional methods of calculating DLCO(SB) were greatly affected by variations in the way in which the single-breath maneuver was performed and/or the way in which the alveolar gas sample was collected, these variations had little effect on the calculations of DLCO(SB) using the new method. These results were in close agreement with results from a computerized mathematical lung model in which the diffusing capacity did not change with lung volume. We concluded that the new method significantly improves the accuracy and precision of DLCO(SB) measurements while reducing the effects of maneuver variability. For these reasons comparisons of DLCO(SB) values between patients and normal subjects or between two groups with different pulmonary function may be more valid using the new method than using conventional methods.

We examined the effect of airway closure on ventilation distribution during tidal breathing in six normal subjects. Each subject performed multiple-breath N2 washouts (MBNW) at tidal volumes of 1 liter over a range of preinspiratory lung volumes (PILV) from functional residual capacity (FRC) to just above residual volume. All subjects performed washouts at PILV below their measured closing capacity. In addition five of the subjects performed MBNW at PILV below closing capacity with end-inspiratory breath holds of 2 or 5 s. We measured the following two independent indexes of ventilation maldistribution: 1) the normalized phase III slope of the final breaths of the washout (Snf) and 2) the alveolar mixing efficiency of those breaths of the washout where 80-90% of the initial N2 had been cleared. Between a mean PILV of 0.28 liter above closing capacity and that 0.31 liter below closing capacity, mean Snf increased by 132% (P less than 0.005). Over the same volume range, mean alveolar mixing efficiency decreased by 3.3% (P less than 0.05). Breath holding at PILV below closing capacity resulted in marked and consistent decreases in Snf and increases in alveolar mixing efficiency. Whereas inhomogeneity of ventilation decreases with lung volume when all airways are patent (J. Appl. Physiol. 66: 2502-2510, 1989), airway closure increases ventilation inequality, and this is substantially reduced by short end-inspiratory breath holds. These findings suggest that the predominant determinant of ventilation distribution below closing capacity is the inhomogeneous closure of airways subtending regions in the lung periphery that are close together.

The single-breath diffusing capacity of the lung for CO [DLCO(SB)] is considered a measure of the conductance of CO across the alveolar-capillary membrane and its binding with hemoglobin. Although incomplete mixing of inspired gas with alveolar gas could theoretically influence overall diffusion, conventional calculations of DLCO(SB) spuriously overestimate DLCO(SB) during short breath-holding periods when incomplete mixing of gas within the lung might have the greatest effect. Using the three-equation method to calculate DLCO(SB) which analytically accounts for changes in breath-hold time, we found that DLCO(SB) did not change with breath-hold time in control subjects but increased with increasing breath-hold time in both patients with asthma and patients with emphysema. The increase in DLCO(SB) with increasing breath-hold time correlated with the phase III slope of the single-breath N2 washout curve. We suggest that in patients with ventilation maldistribution, DLCO(SB) may be decreased for the shorter breath-hold maneuvers because overall diffusion is limited by the reduced transport of CO from the inspired gas through the alveolar gas prior to alveolar-capillary gas exchange.