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Background It would be valuable to have a noninvasive method of measuring impaired pulmonary gas exchange in patients with lung disease and thus reduce the need for repeated arterial punctures. This study reports the results of using a new test in a group of outpatients attending a pulmonary clinic. Methods Inspired and expired partial pressure of oxygen (PO 2 ) and Pco 2 are continually measured by small, rapidly responding analyzers. The arterial PO 2 is calculated from the oximeter blood oxygen saturation level and the oxygen dissociation curve. The PO 2 difference between the end-tidal gas and the calculated arterial value is called the oxygen deficit. Results Studies on 17 patients with a variety of pulmonary diseases are reported. The mean ± SE oxygen deficit was 48.7 ± 3.1 mm Hg. This finding can be contrasted with a mean oxygen deficit of 4.0 ± 0.88 mm Hg in a group of 31 normal subjects who were previously studied ( P 2 to calculate the alveolar-arterial oxygen gradient. Conclusions The results previously reported in normal subjects and the present studies suggest that this new noninvasive test will be valuable in assessing abnormal gas exchange in the clinical setting.

Capture of CO and NO by blood requires molecules to travel by diffusion from alveolar gas to haemoglobin molecules inside RBCs and then to react. One can attach to these processes two times, a time for diffusion and a time for reaction. This reaction time is known from chemical kinetics and, therefore, constitutes a unique physical clock. This paper presents a time-based bottom-up theory that yields a simple expression for DLCO and DLNO that produces quantitative predictions which compare successfully with experiments. Specifically, when this new approach is applied to DLCO experiments, it can be used to determine the value of the characteristic diffusion time, and the value of capillary volume (Vc). The new theory also provides a simple explanation for still unexplained correlations such as the observed proportionality between the so-called membrane conductance DM and Vc of Roughton and Forster’s interpretation. This new theory indicates that DLCO should be proportional to the haematocrit as found in several experiments.

In this paper, we model breathing at the level of a human alveolus by developing a novel mathematical framework that links pulmonary mechanics and gas exchange. Unlike previous models, the developed alveolar model comprises the alveolar gas mixture, capillaries perfused in the alveolar wall, pulmonary surfactant lining the alveolus and the pleural cavity. The inclusion of the multiple compartments affords interested researchers the chance to study the effect of several respiratory factors on breathing. Here, we investigate the effect of holding breath, breathing at different altitudes and frequencies, and varying cardiac output. The important role of pulmonary surfactant in breathing is also highlighted. In addition, we propose a new method to model the transport of oxygen and carbon dioxide between the alveolus and perfused capillaries, and provide a Lagrangian description of surfactant dynamics. Finally, the mechanical work of breathing at the level of the alveolus is derived and implemented to compare the required breathing effort in different scenarios. Numerical results are consistent with published experimental and computational work.

Increased end-tidal oxygen (ET-O(2)) and decreased end-tidal carbon dioxide (ET-CO(2)) gas tensions are noninvasively measurable correlates of ventilatory inefficiency, leading to increased ventilatory requirements relative to gas exchange among patients with chronic heart failure (CHF). We investigated the prognostic value of ET-O(2) and ET-CO(2) as predictors of CHF mortality.We measured resting ET-O(2) and ET-CO(2) electrochemically in 134 patients with symptomatic CHF in the supine position. We used Kaplan-Meier analysis, Cox proportional hazard models, and receiver operating characteristic curves to test our hypothesis.At a median follow-up of 16.5 months, 32 patients had died. ET-O(2) levels were increased (P = .001) and ET-CO(2) levels decreased (P = .002) with increased New York Heart Association class (I-IV). Survivors showed lower ET-O(2) (121 vs 118 mm Hg; P = .021) and higher ET-CO(2) (33.2 vs 32.1 mm Hg; P = .032) levels than nonsurvivors. Patients with ET-O(2) values ≥121 mm Hg and/or ET-CO(2) values31 mm Hg had an increased risk of death with hazard ratios of 2.93 (95% confidence interval [CI], 1.43-6.01) and 2.47 (95% CI, 1.23-4.97), respectively. Kaplan-Meier estimates for follow-up mortality with ET-O(2) ≥121 mm Hg and/or ET-CO(2)31 mm Hg were 83.8% (vs 60.1%; P = .0014) and 80.3% (vs 60.2%; P = .0061), respectively. Areas under the receiver operating characteristic curves for prediction of death with ET-O(2) and ET-CO(2) were both significant and similar to that of echocardiographic left ventricular function.In CHF, high levels of ET-O(2) and low levels of ET-CO(2) are associated with increased mortality. We suggest that the measurements may be useful prognostic markers for risk stratification.

We determined the oxygen isotope fractionation degree for oxygen utilized (delta(U)) in expired alveolar gas relative to inspired air in patients with chronic obstructive lung disease (COPD) and, for comparison, in two groups of healthy subjects, old and young. In addition, we determined Delta(rel)R(vent) and Delta(rel)R(tot). These determinants of delta(U) (=Delta(rel)R(tot)-Delta(rel)R(vent)) are related to the oxygen isotope fractionation which occurs in the first part of the O(2) pathway by ventilation of alveolar gas (Delta(rel)R(vent)) and by O(2) transport and utilization in the rest of the O(2) pathway from the alveolar space (Delta(rel)R(tot)). Mean delta(U) values for the three groups of subjects were close: 9.0, 9.0 and 9.9 per thousand, respectively, with no significant differences between groups. Mean Delta(rel)R(vent) for patients with COPD was substantially larger than for young, healthy subjects, 4.0 per thousand versus 0.94 per thousand, with P10(-3). This result indicates that the contribution of intrapulmonary gas transport by diffusion to Delta(rel)R(vent) is larger for patients with COPD than for young, healthy subjects. Mean Delta(rel)R(tot) for patients with COPD was also larger than for young, healthy subjects, 13.0 per thousand versus 10.84 per thousand, but this difference was not significant (P=0.06). Further, Delta(rel)R(tot) was much larger than Delta(rel)R(vent) for all groups of subjects (P10(-7)).

The aim of this study is to propose a new approach to estimate non-invasively arterial carbon dioxide partial pressure ( P a C O 2 ) . This approach was based on the reconstruction of alveolar gas composition over each breath from a tidally ventilated lung model ( P M C O 2 ) . Eight healthy young subjects were studied during a ramp exercise test on a cycle ergometer. Arterial samples were drawn at rest and every minute during the exercise test for determination of P a C O 2 . P a C O 2 was compared with indirect estimates of P C O 2 : P M C O 2 , end-tidal P C O 2 ( P E T C O 2 ) and an empirical equation involving P E T C O 2 and tidal volume ( P J C O 2 ) . The difference between estimated and measured P a C O 2 on the whole ramp exercise was −0.3 ± 1.9 mmHg for P M C O 2 , 1.0 ± 2.2 mmHg for P E T C O 2 and −1.7 ± 1.7 mmHg for P J C O 2 . P E T C O 2 and P J C O 2 were significantly different from actual P a C O 2 ( P P a C O 2 than the two other indirect methods during ramp exercise.

Equations governing oxygen transport from alveolar gas to red blood cells flowing through pulmonary capillaries are written down. Some analytical predictions are made on factors affecting the rate at which this process takes place. Numerical simulations are carried out to investigate the effect of red blood cell shape, capillary dimensions, haematocrit and choice of oxygen dissociation curve on pulmonary oxygen transport. These factors all have an effect on pulmonary transport, with the effect being much more marked for simulations with low oxygen levels, typical of those seen in some subjects with respiratory disease.

On October 24, 1981, Chris Pizzo and Yong Tenzing, members of the American Medical Research Expedition to Mt Everest (AMREE), stood on the highest point on earth and collected 6 alveolar gas samples. These, together with further data collected from the South Col (8050 m), provided the foundations for what is surely one of the most unique field experiments ever undertaken—the calculation of arterial blood gases from a mountaineer on the summit of Mt Everest (8848 m; Table). Without the accurate portable blood gas analyzers that many of us now take for granted, the AMREE team used the ‘‘Bohr Integration,’’ a complex computational method used primarily to calculate the diffusion capacity of oxygen inside the human lungs. By assuming this value, the AMREE team was able to calculate the mean alveolar-capillary PO2 difference and therefore deduce the PO2 of arterial blood. However, to complete this, a long list of measurements and assumptions would need to be made first, and it is this attention to detail that makes ‘‘Pulmonary Gas Exchange on the Summit of Mt Everest’’ such an exceptional piece of work.1 In what Edouard Wyss Dunant, the leader of the unsuccessful 1952 Swiss Expedition to Mt Everest, once described as the ‘‘todeszone’’ or ‘‘death zone,’’ the AMREE team conducted an unparalleled set of tests. Not only did they record the first accurate barometric pressure reading on the summit of Mt Everest, but they were also able to obtain 42 resting alveolar gas samples from various sites above 8000 m (Figure 1). These results showed, for the first time, the dramatic fall in alveolar

The main function of the lung is to exchange respiratory gases, oxygen and carbon dioxide. In order to achieve this it has a huge surface area (equivalent to the size of a tennis court in the fully mature adult) and a remarkably thin barrier between the capillary blood and alveolar gas. 1 However the entrance to this large exchanging surface is relatively small z and it is obstruction to the conducting airways that causes most respiratory morbidity in childhood. When a respiratory problem is clinically obvious or is suspected, the measurement of lung function has a role in (a) identifying or characterising the problem, (b) assessing the disease severity and (c) assessing disease progression and response to treatment. Measurements of lung function have also improved our understanding of the growth and development of the respiratory system. 3'4

A capnogram measures the concentration of carbon dioxide in the inspired and expired gas (in mmHg, kPa or vols %). For descriptive purposes it is often represented in an idealised form in text books. Figure 1 charts the theoretical changes in carbon dioxide (COz) concentration with time over a respiratory cycle. The almost vertical line PQ denotes the sudden increase in CO2 that occurs as alveolar gas enters the capnograph and the nearly horizontal plateau QR represents the CO2 concentration in the alveolar gas. The concentration at R is termed the end-tidal partial pressure of COz (&co~). At some time, just before or at R, inspiration begins and the flow in the breathing system changes direction. The exact time at which inspiration begins cannot be determined from the capnogram without a simultaneous flow signal or a knowledge of the circuit geometry because the first part of the inspired breath which passes the sampling site may well be alveolar gas from the end of expiration. Under these conditions the ‘plateau’ level of expired gas continues to be recorded even though inspiration is occurring. Once inspiration has started fresh gas soon replaces the alveolar gas at the sampling port and the concentration of COz falls rapidly to S. The horizontal line SP represents the concentration of CO:! in the inspired gas (P$oz). At some point between S and P inspiration ends, the flow reverses, and expiration begins. A flow signal is always required for the precise identification of the end of inspiration

Sildenafil Improves Exercise Peak Oxygen Consumption and Ventilation Efficiency by a Synergistic Effect on Endothelial Function and Alveolar Gas Diffusion in Heart Failure Patients Marco Guazzi, Paola Satariano, Fabio Di Marco, Cesare Fiorentini, Gabriele Tumminello1—Department of Cardiology, University of Milano, San Paolo Hospital, Milano, Italy; Respiratory Unit, San Paolo Hospital, Milano, Italy

In supplement to a previous study ( Respir. Physiol. 46: 193–201, 1981) further relationships are presented that are particularly suited for comaparing the extent of diffusion and perfusion limitation in alveolar gas transfer.

The effects of diffusion limitation in alveolar space (stratification) for inert gas retention and excretion by lungs with log-normal V A /Q distribution are calculated using the approach of Scheid et al. (Respir. Physiol. 44, 299–309, 1981). Since gases used in the multiple inert gas elimination technique have widely varying molecular weights (between 30 and 197), and therefore varying diffusivities, the effects of stratification are different for each gas. The result is a perturbation in the recovered V A /Q distributions that is calculated neglecting stratification effects. Application to inert gas elimination data obtained in the anesthetized rat by Truog et al. (J. Appl. Physiol. 47, 1112–1117, 1979) yields a value for the diffusion resistance in alveolar gas which would give rise to a P O 2 difference of 5 Torr, suggesting that stratification may exert a significant limitation to pulmonary O 2 transfer in rats.

NO and CO lung transfer values (T l ) were measured separately in 14 healthy subjects (7 men, 7 women), using the single breath technique. Five repetitive maneuvers were performed by each subject for T l NO and T l CO determinations. The inspired mixture contained either 8 ppm NO or 0.25% CO, with 2% He, 21% O2 in N2. In order to measure an appreciable fraction of NO in the alveolar gas it was necessary to shorten the breath holding time to 3 sec. T l NO was about five times greater than T l CO. This result suggests that the specific conductance of blood (ϑ) for NO is very high and that the second term of the second member of the equation 1/T l NO = 1/DmNO + 1/(ϑNO · Qc) is therefore negligible. DmCO and Qc values can thus be computed from T l NO and T l CO measurements. The results obtained with this method are very close to those reported in the literature; for men DmCO = 79.0 ± 14.3 ml · min−1 · Torr−1, Qc = 78.0 ± 13.2 ml and for women DmCO = 59.0 ± 10.1 ml · min−1 · Torr−1, Qc = 59.5 ± 11.6 ml.

SUMMARY Gas concentrations and ventilation levels have been measured within a conventional Magill circuit when conscious volunteers breathed a non-narcotic gas mixture at varying fresh gas flows. When evidence of rebreathing of alveolar gas was detected, the fresh gas flow was kept constant until a steady state developed. All subjects showed evidence of rebreathing when the fresh gas flow approached the predicted alveolar ventilation levels. A variety of subject-circuit interactions was seen and shown to be precipitated by naturally occurring breath-to-breath variations in ventilation. A single large breath could perturb the system. This could have a temporary effect, when the fresh gas flow was sufficient to wash the increased aliquot of expired carbon dioxide from the circuit. At other times a progressive response occurred as ventilatory stimulation as a result of the increased inspired carbon dioxide concentrations caused alveolar gas to reach the reservoir bag and converted the system behaviour from that of a simple added deadspace to that of a total mixing device. Whilst marked changes occurred commonly in both ventilation and inspired gas concentrations, only slight changes in end-tidal gas concentrations occurred.

Diffusional equilibrium of gas mixtures similar to inspired gas (21% O 2 and 79% N 2 , H 2 or SF 6 ) and alveolar gas (14% O 2 , 6% CO 2 and 80% N 2 , H 2 or SF 6 ) was investigated using a subdivided tube technique (Worth et al. , 1978). The following main results were obtained: 1. (1) No significant deviations from binary diffusion characteristics were observed for diffusion of CO 2 in any of the gas mixtures studied and for diffusion of O 2 in mixtures containing N 2 or SF 6 . Thus values for effective diffusion coefficients (D′, in cm 2 · sec −1 ) which were independent of time and site of gas sampling were obtained. Only for diffusion of O 2 in the H 2 containing mixture D′ decreased with time of sampling. 2. (2) For all conditions tested, the experimental values of D′ were in good agreement with theoretical predictions based on an approximate solution of the Stefan-Maxwell diffusion equations according to Toor (1964a,b) using the binary diffusion coefficient values determined previously (Worth et al. , 1978). It is concluded that the diffusive mixing of inspired gas with alveolar gas with respect to O 2 and CO 2 should follow binary diffusion characteristics with reasonable approximation.

We examined the influence of asymmetry on the interaction of convection and gas-phase diffusion within the acinus of the lung. Single breaths of O2 were simulated by solving a differential equation for gas transport in two trumpet shaped units which were joined at a branch point and whose relative lengths and volumes were made to vary. Despite synchronous bulk flow to the from the units, in proportion to their relative volumes, the shorter unit always reached a higher O2 concentration (FO2) at end inspiration. Interdependence of gas transport at the branch point resulted in a falling FO2 within the shorter unit during expiration. The FO2 at the exit of the model therefore decreased progressively throughout expiration, simulating a sloping alveolar plateau. The simulations suggest that despite the relatively short distances separating parallel intra-acinar pathways, convective-diffusive interactions in the presence of asymmetry may produce substantial inhomogeneity in alveolar gas concentrations. Furthermore, the slope of the N2 plateau in the normal mammalian lung is explicable on the basis of the asymmetrical airway anatomy and well defined physical processes.

A N 2 /CO 2 rebreathing method for determining the mixed venous oxygen tension has been evaluated both theoretically, using a mathematical model, and experimentally. Oxygen tension equilibrium between blood and rebreathed gas depends on the oxygen carrying capacity of the blood and the pulmonary blood flow. Under most circumstances, these will be inadequate for the success of the technique.

Measurements were made of PCO2 and PO2 in alveolar gas of dog lungs rebreathing in situ and in the pulmonary arterial blood. The PCO2 in alveolar gas was almost always found to be higher than that of the blood under a variety of experimental conditions. The Po2 was also usually higher in alveolar gas than in blood, but less consistently than in the case of CO2. The magnitude of the observed gradients showed no consistent relationship to duration of experiment or rate of blood flow through the lung. Respiratory acidosis increased the CO2 gradient, but reduced that for O2. Inhibition of blood carbonic anhydrase enhanced the CO2 gradient. When normalized with respect to plasma bicarbonate concentration, the CO2 gradient is inversely related to plasma pH. No definitive explanation is offered for these observations.

To investigate the mechanism of the immediate appearance of inhaled hydrogen at an electrode wedged into a small pulmonary artery, dog experiments were done whereby the appearance time was determind in various parts of the pulmonary arterial tree before and after the blood flow was stopped. With the electrode in a large artery the appearance time was longer after the circulation stopped. With the electrode in a wedged position the time was immediate with normal and interrupted blood flow. When the electrode was in a small artery, free not wedged, the time was often shorter with a normal circulation and became even less when the blood flow was stopped. The results indicate the alveolar gas diffuses to the pulmonary arteries retrograde to the blood flow. The diffusion may be in whole or in part intra- or extravascular.

Diffusion between the bronchiole and the exchange surfaces of a typical respiratory unit is simulated by that in a simple model having the shape of a figure of revolution. The model is constructed so as to have the same distributions of surface and volume with distance from the port as does the respiratory unit sketched by Miller. Calculated diffusions in the Miller sketch of a unit and in the model are compared.

There is dispute about the validity of the nitrogen rebreathing technique for determination of Pv O 2 . This theoretical analysis examines the circumstances under which the technique is likely to be applicable. When the plateau method is used the probable error in Pv O 2 is ±2.5 mm Hg at rest, and of the order of ±1 mm Hg during exercise. Provided the rebreathing bag size is reasonably chosen, Denison's extrapolation technique gives results at least as accurate as those obtained by the plateau method. At rest, however, extrapolation should be to 30 rather than to 20 sec.

Alveolar gas pressures were measured in the acclimatized higlanders and lowlanders at sea level and at various altitudes in the Himalayas as well as at 4540 m in the Peruvian Andes. These and compiled data show that P A CO 2 , decreased with the increase of altitude generally but there are two important differences in the pattern of alveolar gas pressure fall between the two groups. P A CO 2 in the highlanders, who were born and had lived at high altitude, was higher than that in the lowlanders acclimatized to the same altitude. This P A CO 2 changed less in the highlanders than in the lowlanders with the changes of altitude or the barometric pressure (P B ), ΔP CO 2 /ΔP B being .019 and .050 respectively. Thus with the increase of altitude the difference in P A CO 2 , between the two groups increased and with the decrease of altitude there was a decrease. At around 1250 m (P B 650mm Hg) the two groups obtained a similar P A CO 2 , (ca. 36 mm Hg). Further decrease of altitude did not appear to increase this value in the highlanders unlike in the lowlanders. This and similar evidence from the alveolar P CO 2 -P O 2 curves demonstrate that both respiratory threshold and sensitivity to hypoxia are lower in the high-landers than in the lowlanders. It is concluded that these parameters of respiration in adult individuals from sea level do not change at altitude regardless of the time of their acclimatization and that the characteristic low respiratory response to hypoxia in highlanders with lifetime hypoxia is irreversible.

The Bohr model of the lung is examined, and all assumptions involved are specified. The weakest assumptions are those required to produce constant alveolar gas concentrations, e.g., simultaneous inhalation and exhalation; these lead to a “static” model. With more realistic assumptions we arrive at a dynamic version of the Bohr two-compartment model. Computed solution of the equations of this model demonstrates two phenomena, i.e., cardiogenic oscillations and increasing carbon dioxide/decreasing oxygen tension in the exhaled gas, not shown by the static model. Experimental results for the changes in exhaled gas concentration are in fair agreement with the model results. It is interesting to observe that the alveolar gas concentrations computed with this lumped parameter model are very similar to the corresponding curves from the distributed parameter model presented by Flumerfelt and Crandall [3].

Physiologic dead space has been measured in five cases of the Hamman-Rich syndrome using arterial carbon dioxide tension for alveolar carbon dioxide tension. At rest physiologic dead space was increased in three cases, sometimes grossly. The dead space/tidal volume ratio was elevated in all cases. On exercise physiologic dead space increased greatly; its ratio to tidal volume showed no appreciable change from the resting ratio and was excessive in all cases. The increase was too great to be accounted for by errors in the method or an artefact caused by venous admixture. It is attributed to the development of focal emphysema. Increase in dead space correlates well with, and is believed to account partially for, clinical severity. In this condition the dead space is too high at rest and on exercise for one to obtain "alveolar air" by end tidal sampling. Similarly the assumption of a dead space is unjustified. The meaning of "physiologic dead space" is discussed. Attention is drawn to the fact that it must be defined in terms of blood gas and not alveolar gas tensions, since the term itself implies our inability to choose any sample of air as representative of alveolar air.

The first part of this paper reviews two recent methods for obtaining mixed venous blood gas tensions. In the first ( Kim et al., 1966), Pvco2 is obtained from analysis of the change in alveolar gas composition during a single expiration. In the second ( Cerretelli et al., 1966a), both PvO2 and PvcO2 are obtained by rebreathing. Both techniques are well suited to study during exercise. When the Pv values thus obtained are used to calculate pulmonary blood flow (cardiac output in the normal man during steady state), it is necessary to know the alveolar gas tensions, the alveolararterial tension differences and the blood dissociation curves for the subject under study. The sources of error in this procedure are reviewed.