Helium and sulfur hexafluoride bolus washin in short-term microgravity.

We performed single-breath washout (SBW) tests in which He and sulfur hexafluoride (SF6) were inspired throughout the vital capacity inspirations or were inhaled as discrete boluses at different points in the inspiration. Tests were performed in normal gravity (1 G) and in up to 27 s of microgravity (microG) during parabolic flight. The phase III slope of the SBW could be accurately reconstructed from individual bolus tests when allowance for airways closure was made. Bolus tests showed that most of the SBW phase III slope results from events during inspiration at lung volumes below closing capacity and near total lung capacity, as does the SF6-He phase III slope difference. Similarly, the difference between 1 G and microG in phase III slopes for both gases was entirely accounted for by gravity-dependent events at high and low lung volumes. Phase IV height was always larger for SF6 than for He, suggesting at least some airway closure in close proximity to airways that remain open at residual volume. These results help explain previous studies in microG, which show large changes in gas mixing in vital capacity maneuvers but only small effects in tidal volume breaths.     

Tidal volume single-breath washin of SF6 and CH4 in transient microgravity.

We performed tidal volume single-breath washins (SBW) by using tracers of different diffusivity and varied the time spent in microgravity (microG) before the start of the tests to look for time-dependent effects. SF(6) and CH(4) phase III slopes decreased by 35 and 26%, respectively, in microG compared with 1 G (P < 0.05), and the slope difference between gases disappeared. There was no effect of time in microG, suggesting that neither the hypergravity period preceding microG nor the time spent in microG affected gas mixing at volumes near functional residual capacity. In previous studies using SF(6) and He (Lauzon A-M, Prisk GK, Elliott AR, Verbanck S, Paiva M, and West JB. J Appl Physiol 82: 859-865, 1997), the vital capacity SBW showed an increase in slope difference between gases in transient microG, the opposite of the decrease in sustained microG. In contrast, tidal volume SBW showed a decrease in slope difference in both microG conditions. Because it is only the behavior of the more diffusive gas that differed between maneuvers and microG conditions, we speculate that, in the previous vital capacity SBW, the hypergravity period preceding the test in transient microG provoked conformational changes at low lung volumes near the acinar entrance.     

Similar ventilation distribution in normal subjects prone and supine during tidal breathing.

Multiple-breath washout (MBW) tests, with end-expiratory lung volume at functional residual capacity (FRC) and 90% O(2), 5% He, and 5% SF(6) as an inspired gas mixture, were performed in healthy volunteers in supine and prone postures. The semilog plot of MBW N(2) concentrations was evaluated in terms of its curvilinearity. The MBW N(2) normalized slope analysis yielded indexes of acinar and conductive ventilation heterogeneity (Verbanck S, Schuermans D, Van Muylem A, Paiva M, Noppen M, and Vincken W. J App Physiol 83: 1907-1916, 1997). Also, the difference between SF(6) and He normalized phase III slopes was computed in the first MBW expiration. Only MBW tests with similar FRC in the prone and supine postures (P > 0.1; n = 8) were considered. Prone and supine postures did not reveal any significant differences in curvilinearity, N(2) normalized slope-derived indexes of conductive or acinar ventilation heterogeneity, nor SF(6)-He normalized phase III slope difference in the first MBW expiration (P > 0.1 for all). The absence of significant changes in any of the MBW indexes suggests that ventilation heterogeneity is similar in the supine and prone postures of normal subjects breathing near FRC.     

Lung function and ventilation inhomogeneity in rat lungs after allergen challenge.

We studied the early response to ovalbumin challenge in sensitized Brown-Norway rats through its effect on N(2), He, and SF(6) phase III slopes of the single-breath washout and on indexes of lung function. Sensitized rats showed varying degrees of response in terms of pulmonary pressure (PL), with increases ranging between 125 and 225% of baseline. The sensitized rats presented decreased quasistatic compliance, forced vital capacity, and end-expiratory flow, with all three lung function indexes showing a significant negative correlation with corresponding PL values. They also showed significant positive correlations of PL with the N(2), He, and SF(6) phase III slopes, reflecting diffusion-convection-dependent inhomogeneities generated by conformation changes throughout the entire rat lung. In addition, the rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the SF(6)-He slope difference because of a more marked SF(6) than He slope increase. This latter finding suggests that the degree of structural heterogeneity during early response is even more marked in the most peripheral rat lung generations.     

Single-breath washouts in a rotating stretcher.

Vital capacity single-breath washouts using 90% O2-5% He-5% SF6 as a test gas mixture were performed with subjects sitting on a stool (upright) or recumbent on a stretcher (prone, supine, lateral left, lateral right, with or without rotation at end of inhalation). On the basis of the combinations of supine and prone maneuvers, gravity-dependent contributions to N2 phase III slope and N2 phase IV height in the supine posture were estimated at 18% and 68%, respectively. Whereas both He and SF6 slope decreased from supine to prone, the SF6-He slope difference actually increased (P = 0.015). N2 phase III slopes, phase IV heights, and cardiogenic oscillations were smallest in the prone posture, and we observed similarities between the modifications of He and SF6 slopes from upright to prone and from upright to short-term microgravity. These results suggest that phase III slope is partially due to emptying patterns of small units with different ventilation-to-volume ratios, corresponding to acini or groups of acini. Of all body postures under study, the prone position most reduces the inhomogeneities of ventilation during a vital capacity maneuver at both inter- and intraregional levels.     

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.     

Adenosine 5'-monophosphate challenge elicits a more peripheral airway response than methacholine challenge

Adenosine 5'-monophosphate (AMP) and methacholine are commonly used to assess airway hyperreactivity. However, it is not fully known whether the site of airway constriction primarily involved during challenges with either agent is similar. Using a ventilation distribution test, we investigated whether the constriction induced by each agent involves the lung periphery in a similar fashion. Ventilation distribution was evaluated by the phase III slope (S) of the single-breath washout, using gases with different diffusivities like helium (He) and hexafluorosulfur (SF(6)). A greater postchallenge increase in S(He) reflects alterations at the level of terminal and respiratory bronchioles, while a greater increase in S(SF6) reflects alterations in alveolar ducts, increases to an equal extent reflecting alterations in more proximal airways where gas transport is still convective for both gases. S(SF6) and S(He) were measured in 15 asthma patients before and after airway challenges (20% forced expired volume in 1-s fall) with AMP and methacholine. S(He) increased to a greater extent than S(SF6) after AMP challenge (5.7 vs. 3.7%/l; P = 0.002), with both slopes increasing to an equal extent after methacholine challenge (3.1%/l; P = 0.959). The larger increase in S(He) following AMP challenge suggests distal ventilation impairment up to the level of terminal and respiratory bronchioles. With methacholine, the similar increases in S(He) and S(SF6) suggest a less distal impairment. AMP, therefore, seems to affect more extensively the very peripheral airways, whereas methacholine seems to have an effect on less distal airways.     

Ventilation-perfusion matching in long-term microgravity.

We studied the ventilation-perfusion matching pattern in normal gravity (1 G) and short- and long-duration microgravity (microG) using the cardiogenic oscillations in the sulfur hexaflouride (SF(6)) and CO(2) concentration signals during the phase III portion of vital capacity single-breath washout experiments. The signal power of the cardiogenic concentration variations was assessed by spectral analysis, and the phase angle between the oscillations of the two simultaneously expired gases was obtained through cross-correlation. For CO(2), a significant reduction of cardiogenic power was observed in microG, with respect to 1 G, but the reduction was smaller and more variable in the case of SF(6). A shift from an in-phase condition in 1 G to an out-of-phase condition was found for both short- and long-duration microG. We conclude that, although the distribution of ventilation and perfusion becomes more homogeneous in microG, significant inhomogeneities persist and that areas of high perfusion become associated with areas of relatively lower ventilation. In addition, these modifications seem to remain constant during long-term exposure to microG.     

Effects of hypergravity and anti-G suit pressure on intraregional ventilation distribution during VC breaths.

The effects of increased gravity in the head-to-foot direction (+G(z)) and pressurization of an anti-G suit (AGS) on total and intraregional intra-acinar ventilation inhomogeneity were explored in 10 healthy male subjects. They performed vital capacity (VC) single-breath washin/washouts of SF(6) and He in +1, +2, or +3 G(z) in a human centrifuge, with an AGS pressurized to 0, 6, or 12 kPa. The phase III slopes for SF(6) and He over 25-75% of the expired VC were used as markers of total ventilation inhomogeneity, and the (SF(6) -- He) slopes were used as indicators of intraregional intra-acinar inhomogeneity. SF(6) and He phase III slopes increased proportionally with increasing gravity, but the (SF(6) -- He) slopes remained unchanged. AGS pressurization did not change SF(6) or He slopes significantly but resulted in increased (SF(6) -- He) slope differences at 12 kPa. In conclusion, hypergravity increases overall but not intraregional intra-acinar inhomogeneity during VC breaths. AGS pressurization provokes increased intraregional intra-acinar ventilation inhomogeneity, presumably reflecting the consequences of basilar pulmonary vessel engorgement in combination with compression of the basilar lung regions.     

Effects of body posture and tidal volume on inter- and intraregional ventilation distribution in healthy men.

The influences of body posture and tidal volume (VT) on inter- and intraregional ventilation inhomogeneity were assessed by normalized phase III slope (Sn(III)) analysis of multiple-breath washout recordings of SF(6) and He in 11 healthy men. Washouts with target VT of 750, 1,000, and 1,250 ml were performed standing and supine. A linear-fit method was used to establish the contributions of convection-dependent (interregional) (cdi) and diffusion-convection interaction-dependent (intraregional) inhomogeneity (dcdi). Overall inhomogeneity was defined as the sum of cdi and dcdi. The difference in first-breath Sn(III) for SF(6) vs. He, the (SF(6) - He)Sn(III), served as an index of intra-acinar inhomogeneity. Multiple-regression analysis revealed greater cdi supine vs. standing (P < 0.001) but no significant effects of posture on dcdi or overall inhomogeneity. Larger VT were associated with greater cdi (P < 0.001), particularly when supine, but reduced dcdi (P < 0.001), overall inhomogeneity (P < 0.001), and (SF(6) - He)Sn(III) (P = 0.031). In conclusion, during resting breathing overall and intraregional ventilation inhomogeneities remain unchanged when the supine posture is assumed and improve with larger VT, but supine posture and larger breaths result in greater interregional inhomogeneities.     

Effect of volume history on distribution of inspired gas in asthmatics

Twelve stable adult asthmatics slowly inhaled boluses of He at 20, 40, or 60% vital capacity (VC); these volumes were achieved either by expiring from total lung capacity (TLC) or by inspiring from residual volume (RV). Inspirations were continued to TLC and then were followed by slow expirations to RV while expired He was measured as a function of expired volume. At 20% VC slopes of alveolar plateaus (phase III) were positive, at 40% VC they were flat, and at 60% VC they were negative; at 20 and 60% VC the slopes were steeper than those in normals. When boluses were administered at 40 and 60% VC, He washout curves were independent of lung volume history. However at 20% VC the slope of phase III was significantly less positive when boluses were given after inspiration from RV than after expiration from TLC. In eight subjects, who were given inhaled beta-agonists, slopes of all He washouts decreased and became independent of volume history at 20% VC. We conclude that in asthmatics at low lung volumes the airways that determine ventilation distribution behave as though they have less hysteresis than the lung parenchyma probably due to increased airway tone.     

Tidal volume single breath washout of two tracer gases--a practical and promising lung function test

Background

Small airway disease frequently occurs in chronic lung diseases and may cause ventilation inhomogeneity (VI), which can be assessed by washout tests of inert tracer gas. Using two tracer gases with unequal molar mass (MM) and diffusivity increases specificity for VI in different lung zones. Currently washout tests are underutilised due to the time and effort required for measurements. The aim of this study was to develop and validate a simple technique for a new tidal single breath washout test (SBW) of sulfur hexafluoride (SF₆) and helium (He) using an ultrasonic flowmeter (USFM).

Methods

The tracer gas mixture contained 5% SF₆ and 26.3% He, had similar total MM as air, and was applied for a single tidal breath in 13 healthy adults. The USFM measured MM, which was then plotted against expired volume. USFM and mass spectrometer signals were compared in six subjects performing three SBW. Repeatability and reproducibility of SBW, i.e., area under the MM curve (AUC), were determined in seven subjects performing three SBW 24 hours apart.

Results

USFM reliably measured MM during all SBW tests (n = 60). MM from USFM reflected SF₆ and He washout patterns measured by mass spectrometer. USFM signals were highly associated with mass spectrometer signals, e.g., for MM, linear regression r-squared was 0.98. Intra-subject coefficient of variation of AUC was 6.8%, and coefficient of repeatability was 11.8%.

Conclusion

The USFM accurately measured relative changes in SF₆ and He washout. SBW tests were repeatable and reproducible in healthy adults. We have developed a fast, reliable, and straightforward USFM based SBW method, which provides valid information on SF₆ and He washout patterns during tidal breathing.     

Exercise throughout 6 degrees head-down tilt bed rest preserves thermoregulatory responses.

Spaceflight and its bed rest analog [6 degrees head-down tilt (HDT)] decrease plasma and blood volume and aerobic capacity. These responses may be associated with impaired thermoregulatory responses observed during exercise and passive heating after HDT exposure. This project tested the hypothesis that dynamic exercise during 13 days of HDT bed rest preserves thermoregulatory responses. Throughout HDT bed rest, 10 subjects exercised for 90 min/day (75% of pre-HDT maximum heart rate; supine). Before and after HDT bed rest, each subject exercised in the supine position at the same workload in a 28 degrees C room. The internal temperature (Tcore) threshold for the onset of sweating and cutaneous vasodilation, as well as the slope of the relationship between the elevation in Tcore relative to the elevation in sweat rate (SR) and cutaneous vascular conductance (CVC; normalized to local heating maximum), were quantified pre- and post-HDT. Tcore thresholds for the onset of cutaneous vasodilation on the chest and forearm (chest: 36.79 +/- 0.12 to 36.94 +/- 0.13 degrees C, P = 0.28; forearm: 36.76 +/- 0.12 to 36.91 +/- 0.11 degrees C, P = 0.16) and slope of the elevation in CVC relative to Tcore (chest: 77.9 +/- 14.2 to 80.6 +/- 17.2%max/ degrees C; P = 0.75; forearm: 76.3 +/- 11.8 to 67.5 +/- 14.3%max/ degrees C, P = 0.39) were preserved post-HDT. Moreover, the Tcore threshold for the onset of SR (36.66 +/- 0.12 to 36.74 +/- 0.10 degrees C; P = 0.36) and the slope of the relationship between the elevation in SR and the elevation in Tcore (1.23 +/- 0.19 to 1.01 +/- 0.14 mg x cm(-2) x min(-1) x degrees C(-1); P = 0.16) were also maintained. Finally, after HDT bed rest, peak oxygen uptake and plasma and blood volumes were not different relative to pre-HDT bed rest values. These data suggest that dynamic exercise during this short period of HDT bed rest preserves thermoregulatory responses.     

Effects of microgravity elicited by parabolic flight on abdominal aortic pressure and heart rate in rats.

Abdominal aortic pressure (AAP), heart rate (HR), and aortic nerve activity (ANA) during parabolic flight were measured by using a telemetry system to clarify the acute effect of microgravity (microG) on hemodynamics in rats. While the animals were conscious, AAP increased up to 119 +/- 3 mmHg on exposure to microG compared with the value at 1 G (95 +/- 3 mmHg; P < 0.001), whereas AAP decreased immediately on exposure to microG under urethane anesthesia (microG: 72 +/- 9 mmHg vs. 1 G: 78 +/- 8 mmHg; P < 0.05). HR also increased during microG in conscious animals (microG: 349 +/- 12 beats/min vs. 1 G: 324+9 beats/min; P < 0.01), although no change was observed under anesthesia. ANA, which was measured under anesthesia, decreased in response to acute microG exposure (microG: 33 +/- 7 counts/s vs. 1 G: 49 +/- 5 counts/s; P < 0.01). These results suggest that microG essentially induces a decrease of arterial pressure; however, emotional stress and body movements affect the responses of arterial pressure and HR during exposure to acute microG.     

Single-breath test in lateral decubitus reflects function of single lungs grafted for interstitial lung disease.

After single-lung transplantation (SLT) for emphysema, heterogeneity of ventilation distribution in the graft can be assessed by measuring the slope of the alveolar plateau, computed from a single-breath test, performed in lateral decubitus with this lung in the nondependent position. We tested the validity of this technique in patients with SLT for interstitial lung diseases (ILD). Twelve patients with SLT for ILD, 12 nontransplanted patients with ILD, and 10 healthy control subjects performed single-breath washouts in right and left lateral decubitus; nitrogen slope (S(N(2))) and the difference between SF(6) and He slopes (S(SF(6))-S(He)) were measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in both postures by computerized tomography. Slopes were unaffected by posture in normal control subjects and patients with ILD. On the other hand, S(N(2)) and S(SF(6))-S(He) in transplant recipients were smaller with the graft in the nondependent than in the dependent position (0.366 +/- 0.445 vs. 1.035 +/- 0.498 for S(N(2)); 0.094 +/- 0.201 vs. 0.218 +/- 0.277 for S(SF(6))-S(He)). Values of S(N(2)) and S(SF(6))-S(He) obtained in the former position were similar to those obtained in normal controls, while values obtained in the latter position were similar to those obtained in nontransplanted patients with ILD. Computerized tomography studies with the graft in the nondependent position indicated that this lung contributed 82% of the volume expired below functional residual capacity. We conclude that, in patients with SLT for ILD, the slope of the alveolar plateau obtained with the graft in the nondependent position reflects heterogeneity of ventilation distribution in this lung.     

Vital capacity, respiratory muscle strength, and pulmonary gas exchange during long-duration exposure to microgravity.

Extended exposure to microgravity (microG) is known to reduce strength in weight-bearing muscles and was also reported to reduce respiratory muscle strength. Short- duration exposure to microG reduces vital capacity (VC), a surrogate measure for respiratory muscle strength, for the first few days, with little change in O2 uptake, ventilation, or end-tidal partial pressures. Accordingly we measured VC, maximum inspiratory and expiratory pressures, and indexes of pulmonary gas exchange in 10 normal subjects (9 men, 1 woman, 39-52 yr) who lived on the International Space Station for 130-196 days in a normoxic, normobaric atmosphere. Subjects were studied four times in the standing and supine postures preflight at sea level at 1 G, approximately monthly in microG, and multiple times postflight. VC in microG was essentially unchanged compared with preflight standing [5.28 +/- 0.08 liters (mean +/- SE), n = 187; 5.24 +/- 0.09, n = 117, respectively; P = 0.03] and considerably greater than that measured supine in 1G (4.96 +/- 0.10, n = 114, P < 0.001). There was a trend for VC to decrease after the first 2 mo of microG, but there were no changes postflight. Maximum respiratory pressures in microG were generally intermediate to those standing and supine in 1G, and importantly they showed no decrease with time spent in microG. O2 uptake and CO2 production were reduced (approximately 12%) in extended microG, but inhomogeneity in the lung was not different compared with short-duration exposure to microG. The results show that VC is essentially unchanged and respiratory muscle strength is maintained during extended exposure to microG, and metabolic rate is reduced.     

Sustained microgravity reduces the human ventilatory response to hypoxia but not to hypercapnia.

We measured the isocapnic hypoxic ventilatory response and the hypercapnic ventilatory response by using rebreathing techniques in five normal subjects (ages 37-47 yr) before, during, and after 16 days of exposure to microgravity (microG). Control measurements were performed with the subjects in the standing and supine postures. In both microG and in the supine position, the hypoxic ventilatory response, as measured from the slope of ventilation against arterial O(2) saturation, was greatly reduced, being only 46 +/- 10% (microG) and 52 +/- 11% (supine) of that measured standing (P < 0.01). During the hypercapnic ventilatory response test, the ventilation at a PCO(2) of 60 Torr was not significantly different in microG (101 +/- 5%) and the supine position (89 +/- 3%) from that measured standing. Inspiratory occlusion pressures agreed with these results. The findings can be explained by inhibition of the hypoxic but not hypercapnic drive, possibly as a result of an increase in blood pressure in carotid baroreceptors in microG and the supine position.     

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).     

Paradoxical helium and sulfur hexafluoride single-breath washouts in short-term vs. sustained microgravity

Lauzon, Anne-Marie, G. Kim Prisk, Ann R. Elliott, SylviaVerbanck, Manuel Paiva, and John B. West. Paradoxical helium andsulfur hexafluoride single-breath washouts in short-term vs. sustainedmicrogravity. J. Appl. Physiol. 82(3):859-865, 1997.During single-breath washouts in normal gravity (1 G), the phase III slope of sulfur hexafluoride(SF₆) is steeper than that ofhelium (He). Two mechanisms can account for this:1) the higher diffusivity of Heenhances its homogeneous distribution; and2) the lower diffusivity ofSF₆ results in a more peripherallocation of the diffusion front, where airway asymmetry is larger.These mechanisms were thought to be gravity independent. However, weshowed during the Spacelab Life Sciences-2 spaceflight that insustained microgravity (µG) theSF₆-to-He slope difference isabolished. We repeated the protocol during short periods (27 s) of µG(parabolic flights). The subjects performed a vital-capacityinspiration and expiration of a gas containing 5% He-1.25%SF₆-balanceO₂. As in sustained µG, thephase III slopes of He and SF₆decreased. However, during short-term µG, theSF₆-to-He slope differenceincreased from 0.17 ± 0.03%/l in 1 G to 0.29 ± 0.06%/l inµG, respectively. This is contrary to sustained µG, in which theSF₆-to-He slope difference decreased from 0.25 ± 0.03%/l in 1 G to 0.01 ± 0.06%/lin µG. The increase in phase III slope difference in short-term µGwas caused by a larger decrease of He phase III slope compared with that in sustained µG. This suggests that changes in peripheral gasmixing seen in sustained µG are mainly due to alterations in thediffusive-convective inhomogeneity of He that require >27 s of µGto occur. Changes in pulmonary blood volume distribution or cardiogenicmixing may explain the differences between the results found inshort-term and sustained µG.

     

Gas mixing in dog lungs studied by single-breath washout of He and SF6

Simultaneously measured helium (He) and sulfur hexafluoride (SF6) single-breath washout was studied in 16 anesthetized paralyzed dogs ventilated with a special hydraulically operated ventilatory servo system. After equilibration of lung gas with 1% He and 1% SF6, the maneuver consisting of inspiration of a test gas-free mixture at constant rate (VI), a variable time of breath holding, and an expiration at constant rate (VE), was performed. Fractional concentrations of He and SF6, recorded against expired volume, were analyzed in terms of slope of the alveolar plateau (S) and series (Fowler) dead space (VD). In control conditions (VI = 0.5 l/s, VE = 0.1 l/s) S was about 10% of alveolar-to-inspired concentration difference per liter expirate both for He and SF6. Both SHe and SSF6 were inversely related to VI and VE, the relative changes being more pronounced with varying VE. SHe/SSF6 was higher or lower than unity depending on VI and VE. Both SHe and SSF6 decreased with increasing preinspiratory lung volume. Breath holding up to 10 s slightly decreased SHe and SSF6 while SHe/SSF6 was unchanged. The contribution of continuing gas exchange to S assessed from comparative measurements using the reversed (single breath washin) technique ranged from 6 to 23% in the various conditions. The VDHe/VDSF6 ratio was 0.84 and was little affected in the various settings. Results indicate that the substantial alveolar gas inhomogeneity in the dog lung and the mechanism accounting for S are little diffusion dependent. By exclusion sequential filling and emptying of lung units is believed to constitute the most important mechanism responsible for the sloping alveolar plateau.