Biomedical subjects
Publications and source records attributed to P Haab.
The author describes some of the challenges which face present day teaching in respiratory physiology. These are 1. poor integration with basic science, 2. non-homogeneity of units and nomenclature, and 3. insufficient integration with what is taught in the third year. The author is optimistic about problem-oriented teaching integrating the first 3 years of medical school as a single whole.
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The effects of unequal distribution of blood flow on O2 uptake are studied on a model composed of 3 tissues compartments with blood flow/O2 requirement ratios in the relation 9:3:1 (unequal blood flow model), a model with 33% shunt blood flow (shunt model), and a single compartment model without shunt (reference model). Diffusion limitation is assumed to be absent. Total blood flow (Q), arterial O2 content (CaO2) and O2 requirement of tissue are varied singly, and the resulting (mixed) venous O2 content (CvO2) and O2 uptake are calculated. In the reference model, CvO2 become zero, and O2 uptake starts falling below the O2 requirement, as soon as the O2 delivery (Q.CaO2) becomes smaller than the O2 requirement. In contrast, in the unequal blood flow model, decrease in the ratio O2 uptake/O2 requirement and in CvO2 sets in earlier, and proceeds more gradually, with decreasing Q or CaO2 or increasing O2 requirement; this is, because O2 delivery limitation sets in sequentially in the compartments, starting with the least perfused compartment. The shunt model behaves similarly to the reference model if Q or O2 requirement is varied, and to the unequal blood flow model if CaO2 is varied. Some features such as the parallel fall of O2 uptake and of CVO2 with decreasing CaO2, common to the unequal blood flow and shunt models, are similar to expected effects of diffusion limitation. Therefore, when the influence of diffusion limitation on tissue O2 supply is to be investigated quantitatively, the effects of a possible unequal distribution of blood flow must be taken into account.
In this review the effects of carbon monoxide on tissular oxygenation, at doses which are compatible with life, are considered. In a first section the relative CO-O2 affinity (M*) of various O2 carrying proteins is compared; M* is about 220 for hemoglobin, 20-25 for myoglobin and close to unity for cytochrome oxidases. Thus most of the acute CO toxicity should not be considered as due to malfunction of the intracellular respiratory chain. In addition the differences in M* are caused more by the changes in O2 affinity than by those in CO affinity. The second section deals with the changes in the O2 equilibrium curve (OEC) induced by the presence of HbCO in blood, i.e. the hyperbolization of this curve due to the progressive loss of allostery due to the preferential binding of CO to Hb. The functional importance of this phenomenon lies in the fact that the lower part of the OEC is shifted to the left, whereas the upper part is shifted to the right to an extent which depends upon the amount of HbCO. Thus the effects of the so-called CO anemia are considered to be due both to the reduction of functional Hb and to the reduced partial pressure in the hypoxic range of the OEC. The third section presents recent data concerning the effect of HbCO on the VO2max of the isolated gastrocnemius preparation. The results were obtained in hypoxia under conditions where perfusion and arterial O2 content, i.e. O2 delivery, were the same with and without 30% HbCO. The salient finding is a 26% reduction of VO2max under conditions of CO anemia as compared to hypoxia alone. Interestingly, the PO2 of the venous effluent of the muscle is found to be the same in both cases which leads to the interpretation that it is not the reduction of the mean capillary PO2 but rather a decrease of the blood-to-mitochondria O2 conductance which causes the fall in VO2max.
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The four experiments summarized above demonstrate that there is a strong relationship between both measured muscle venous PO2 and calculated mean muscle capillary PO2 and VO2max. This is true for whole body or exercising muscle VO2max, and is seen both in isolated canine gastrocnemius and intact man. This behavior is exactly what would be expected if the diffusing properties for oxygen in skeletal muscle play a constraining role in setting maximum VO2. These data therefore support the hypothesis we advanced (Wagner, 1988a; Wagner, 1988b), that it is a quantitative integrative relationship between convective and diffusive phenomena that combine to set maximum VO2. A specific prediction of this integrative hypothesis (i.e., the non-uniqueness of VO2max as a function of convective oxygen delivery) was confirmed (Experiment 3). While at this point in time phenomena such as perfusion heterogeneity and muscle shunts cannot be quantitatively taken into account in such analyses, the remarkable concurrence between expectations of the hypothesis and experimental data continue to lend support to the basic idea that maximum VO2 is not limited by any single step of the oxygen transport pathway from atmosphere to mitochondria, but rather by the way in which each and every step combines with every other step to determine oxygen supply.
We recently found [at approximately 90% maximal O2 consumption (VO2max)] that as inspiratory PO2 (PIO2) was reduced, VO2 and mixed venous PO2 (PVO2) fell together along a straight line through the origin, suggesting tissue diffusion limitation of VO2max. To extend these observations to VO2max and directly examine effluent venous blood from muscle, six normal men cycled at VO2max while breathing air, 15% O2 and 12% O2 in random order on a single day. From femoral venous, mixed venous, and radial arterial samples, we measured PO2, PCO2, pH, and lactate and computed mean muscle capillary PO2 by Bohr integration between arterial (PaO2) and femoral venous PO2 (PfvO2). VO2 and CO2 production (VCO2) were measured by expired gas analysis, VO2max averaged 61.5 +/- 6.2 (air), 48.6 +/- 4.8 (15% O2), and 38.1 +/- 4.1 (12% O2) ml.kg-1.min-1. Corresponding values were 16.8 +/- 5.6, 14.4 +/- 5.0, and 12.0 +/- 5.0 Torr for PfVO2; 23.6 +/- 3.2, 19.1 +/- 4.2, and 16.2 +/- 3.5 Torr for PVO2; and 38.5 +/- 5.4, 30.3 +/- 4.1, and 24.5 +/- 3.6 Torr for muscle capillary PO2 (PmCO2). Each of the PO2 variables was linearly related to VO2max (r = 0.99 each), with an intercept not different from the origin. Similar results were obtained when the subjects were pushed to a work load 30 W higher to ensure that VO2max had been achieved. By extending our prior observations 1) to maximum VO2 and 2) by direct sampling of femoral venous blood, we conclude that tissue diffusion limitation of VO2max may be present in normal humans. In addition, since PVO2, PfVO2, and PmCO2 all linearly relate to VO2max, we suggest that whichever of these is most readily obtained is acceptable for further evaluation of the hypothesis.
Pulmonary gas exchange was studied in eight normal subjects both before and after 2 wk of altitude acclimatization at 3,800 m (12,470 ft, barometric pressure = 484 Torr). Respiratory and multiple inert gas tensions, ventilation, cardiac output (Q), and hemoglobin concentration were measured at rest and during three levels of constant-load cycle exercise during both normoxia [inspired PO2 (PIO2) = 148 Torr] and normobaric hypoxia (PIO2 = 91 Torr). After acclimatization, the measured alveolar-arterial PO2 difference (A-aPO2) for any given work rate decreased (P less than 0.02). The largest reductions were observed during the highest work rates and were 24.8 +/- 1.4 to 19.7 +/- 0.8 Torr (normoxia) and 22.0 +/- 1.1 to 19.4 +/- 0.7 Torr (hypoxia). This could not be explained by changes in ventilation-perfusion inequality or estimated O2 diffusing capacity, which were unaffected by acclimatization. However, Q for any given work rate was significantly decreased (P less than 0.001) after acclimatization. We suggest that the reduction in A-aPO2 after acclimatization is a result of more nearly complete alveolar/end-capillary diffusion equilibration on the basis of a longer pulmonary capillary transit time.
In order to compare the efficiency of sheep lung with that of dog, gaseous exchange in hypoxia (FIO2 0.12-0.13) with and without CO in the inspired air ( FICO 0.001) was measured in 12 sheep (mean body weight = 30.4 kg) under pentothal anesthesia and artificial ventilation. Alveolar-arterial pressure difference of O2, % venous admixture and amount of VA/Q inhomogeneity were found to be substantially larger than in dog. Steady-state pulmonary diffusing capacity estimates, computed by three different procedures were, both for O2 and for CO, about 40% smaller than in dog. The DLO2/DLCO ratios were not significantly different from those determined on dog data: thus, the presumed beneficial effect of sheep small erythrocytes on O2 transfer could not be demonstrated. Because its DLO2/MO2 ratio is lower than that of dog, sheep appears to be more adequate than dog as a model for human alveolar-arterial gas exchange.
O2 and CO pulmonary transfer data obtained in dogs under steady-state conditions in hypoxia by Savoy et al. (Respir. Physiol. 42: 43-59, 1980) have been submitted to reevaluation and have yielded new estimates of the lung diffusing capacity, DL. For the proposed DL computation it has been assumed that functional inhomogeneity can be considered as resulting from lognormal distributions of the VA/Q and VA/DL ratios. The standard deviation, sigma, of the VA/Q distribution is computed from the measured (PA -Pa)CO2, and the same sigma value is assumed to prevail for the VA/DL distributions. This is equivalent to assume constant DL/Q ratios in the entire lung. With the so defined distributions, DL values, called D sigma O2 and D sigma CO, were sought, for which the model calculations yielded O2 partial pressures and CO fluxes equal to those measured. Compared with DL estimates computed with conventional procedures, these results show that D sigma O2 is twice as large as DLO2 computed with ideal alveolar PO2 and that D sigma CO lies between DLCO computed with the mean alveolar PCO and that computed with the ideal alveolar PCO. The D sigma O2/D sigma CO ratio was on the average 1.2, a value which, unlike the ratios obtained with conventional DLO2 and DLCO estimates, is in good agreement with the characteristics of diffusion and of chemical association of O2 and CO with blood.
On the basis of a very simple model for the association of diffusion and perfusion, an association common to many respiratory gas transfers, a simple equation is described that defines gas partial pressure equilibration in diffusion-perfusion-limited systems as a function of the ratio of D to beta bQ(D = diffusing capacity, beta b = blood capacitance coefficient, Q = perfusion). The equation applies to steady-state conditions and assumes D, beta b, and Q to be independent of gas partial pressures. In spite of the fact that this assumption may represent a gross simplification, the equation can be regarded as a powerful conceptual tool in the analysis of most gas exchange systems.
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Volume flow (Jv), potential difference (delta psi), short-circuit current (io) and electrical resistance (R) were measured simultaneously across bovine tracheal epithelium in vitro. Under basal conditions, with no applied hydrostatic or osmotic pressure gradients (delta P = 0, delta phi = 0), no spontaneous Jv was observed. delta psi was 31 +/- 2 mV (lumen negative ), io 161 +/- 8 microA cm-2 and R 202 +/- 9 omega cm2, n = 50. When a delta pi was applied, by adding 20 - 80 mM sucrose into the medium bathing either the luminal or the serosal side of the tissue, a linear relationship was found between delta pi and Jv toward the lumen or toward the serosa. The apparent hydraulic conductivity (apparent Lp) was 4.6 - 4.9 10(-6) cms-1 atm-1. Histamine 10(-4) M did not induce any spontaneous Jv under basal conditions and had no effect on io nor on R. However, histamine caused a 100% increase in Jv elicited by sucrose gradients. It was concluded that histamine exerts a selective action on the hydraulic conductivity of bovine tracheal epithelium. Experiments using H1-receptors antagonists (diphenhydramine, dimetindene, chloropyramine) and H2-antagonists (cimetidine, metiamide) or a H2-agonist (impromidine) showed that the increase of Lp induced by histamine was mediated via H2-receptors.
In view of the fact that the inhomogeneity effects on pulmonary diffusing capacity (DL) estimates are quite different for O2 and for CO, simultaneous determinations of steady-state DLCO and DLO2 were attempted and compared. To this end, pulmonary gas exchange was measured in 17 anesthetized and artificially ventilated dogs, in hypoxia with and without carbon monoxide in inspired gas (FIO2 = 0.12, FICO = 0.0009 to 0.0016). The diffusing capacity estimates were computed by two conventional procedures, the first (Dapp) taking into account the mean alveolar partial pressures and the second (DVDA) the ideal alveolar partial pressures. It was found that the presence of COHb in blood, inevitable in the steady-state DLCO procedure, leads to a marked underestimation of DLO2; therefore DLCO values could only be adequately compared to DLO2 values obtained in the absence of CO from inspired gas. These DLO2 were 18.5 and 33.4 mumol . min-1 . Torr-1 . kg-1 for the mean DappO2 and DVDAO2, respectively, whereas the DLCO values obtained after 15 to 25 min CO inspiration were 30.0 and 83.4 mumol . min-1 . Torr-1 . kg-1 for the mean DappCO and the mean DVDACO, respectively. The salient feature is that with both procedures the mean value of DLCO estimate is higher than the corresponding DLO2 estimate. This finding suggests that in anesthetized, artificially ventilated dogs DappO2 and DVDACO estimates obtained by steady-state procedures in hypoxia are largely influenced by inhomogeneity effects and of limited value for assessment of the diffusing properties of the lung. DappCO and DVDAO2 are also affected by inhomogeneities but to a lesser degree.
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Steady-state pulmonary gas exchange has been measured in hypoxia in 33 mongrel dogs with the aim of comparing DLO2 estimates obtained with three procedures differing by the models assumed for functional inhomogeneity. In the first procedure the lung was assumed to be homogeneous and the corresponding DLO2 estimate was 15 mumol . min-1. Torr-1 . kg-1. In the second procedure, which is the one commonly used in respiratory physiology, alveolar dead space was considered as the unique form of functional inhomogeneity and the corresponding DLO2 estimate was 31 mumol . min-1. Torr-1 . kg-1. In the third procedure, which has been specially worked out for this study, functional inhomogeneity was represented by a log-normal distribution of the VA/Q ratios and the corresponding DLO2 estimate was 50 mumol . min-1 . Torr-1 . kg-1. The relation between the DLO2 estimates by the second and by the third procedures was found to depend upon the blood pH. This could be explained on the basis of the effects of acidosis on the blood capacitances for O2 and for CO2. Analysis suggests that in hypoxia where normally the O2 capacitance is about half the CO2 one, the third procedure yields DLO2 estimates about twice as large as those obtained by the second one.
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