Revised one-step method for determination of cardiac output.

Cardiac output (Q) is a determinant of blood pressure and O(2) delivery and is critical in the maintenance of homeostasis, particularly during environmental stress and exercise. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine (Q). Historically, measurements during a breathhold, prolonged expiration and rebreathing to CO(2) equilibrium have been used; however, with limitations, especially during stress. Farhi and co-workers developed a single-step CO(2) rebreathing method, which was subsequently revised by his group, and has been shown to be reliable and compared closely to direct, invasive measures. V(CO2), P(ACO2), and P(VCO2) are determined during a 12-25s rebreathing, using the appropriate tidal volume, and (Q) is calculated. This method can provide accurate data in laboratory and field experiments during exercise, increased or decreased gravity, water immersion, lower body pressure, head-down tilt, altered ambient pressure or changes in inspired gas composition.

Cardiac output: a view from Buffalo.

Cardiac output (Q) is a primary determinant of blood pressure and O2 delivery and is critical in the maintenance of homeostasis, particularly during environmental stress. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine Q. Historically, measurements during a breathhold, prolonged expiration and rebreathing to CO2 equilibrium have been used; however, with limitations, especially during stress. Farhi and co-workers developed a single-step CO2 rebreathing method, which was subsequently revised by his group, and has been shown to be valid (compared to direct measures) and reliable. Carbon dioxide output (VCO2), partial pressure of arterial CO2 (PaCO2), and partial pressure of mixed venous CO2 (Pv(CO2)) are determined during 12-25 s of rebreathing, using the appropriate tidal volume, and Q is calculated. This method has the utility to provide accurate data in laboratory and field experiments during exercise, increased and micro-gravity, water immersion, lower body pressure, head-down tilt, and changes in gas composition and pressure. Utilizing the Buffalo CO2 rebreathing method it has been shown that the Q can adjust to a wide range of changes in environments maintaining blood pressure and O2 delivery at rest and during exercise.

Chemiluminescent measurements of nitric oxide pulmonary diffusing capacity and alveolar production in humans.

Measurements of nitric oxide (NO) pulmonary diffusing capacity (DL(NO)) multiplied by alveolar NO partial pressure (PA(NO)) provide values for alveolar NO production (VA(NO)). We evaluated applying a rapidly responding chemiluminescent NO analyzer to measure DL(NO) during a single, constant exhalation (Dex(NO)) or by rebreathing (Drb(NO)). With the use of an initial inspiration of 5-10 parts/million of NO with a correction for the measured NO back pressure, Dex(NO) in nine healthy subjects equaled 125 +/- 29 (SD) ml x min(-1) x mmHg(-1) and Drb(NO) equaled 122 +/- 26 ml x min(-1) x mmHg(-1). These values were 4.7 +/- 0.6 and 4.6 +/- 0.6 times greater, respectively, than the subject's single-breath carbon monoxide diffusing capacity (Dsb(CO)). Coefficients of variation were similar to previously reported breath-holding, single-breath measurements of Dsb(CO). PA(NO) measured in seven of the subjects equaled 1.8 +/- 0.7 mmHg x 10(-6) and resulted in VA(NO) of 0.21 +/- 0.06 microl/min using Dex(NO) and 0.20 +/- 0.6 microl/min with Drb(NO). Dex(NO) remained constant at end-expiratory oxygen tensions varied from 42 to 682 Torr. Decreases in lung volume resulted in falls of Dex(NO) and Drb(NO) similar to the reported effect of volume changes on Dsb(CO). These data show that rapidly responding chemiluminescent NO analyzers provide reproducible measurements of DL(NO) using single exhalations or rebreathing suitable for measuring VA(NO).

Determination of production of nitric oxide by lower airways of humans--theory.

Exercise and inflammatory lung disorders such as asthma and acute lung injury increase exhaled nitric oxide (NO). This finding is interpreted as a rise in production of NO by the lungs (VNO) but fails to take into account the diffusing capacity for NO (DNO) that carries NO into the pulmonary capillary blood. We have derived equations to measure VNO from the following rates, which determine NO tension in the lungs (PL) at any moment from 1) production (VNO); 2) diffusion, where DNO(PL) = rate of removal by lung capillary blood; and 3) ventilation, where V A(PL)/(PB - 47) = the rate of NO removal by alveolar ventilation (V A) and PB is barometric pressure. During open-circuit breathing when PL is not in equilibrium, d/dt PL[V(L)/ (PB - 47)] (where V(L) is volume of NO in the lower airways) = VNO - DNO(PL) - V A(PL)/(PB - 47). When PL reaches a steady state so that d/dt = 0 and V A is eliminated by rebreathing or breath holding, then PL = VNO/DNO. PL can be interpreted as NO production per unit of DNO. This equation predicts that diseases that diminish DNO but do not alter VNO will increase expired NO levels. These equations permit precise measurements of VNO that can be applied to determining factors controlling NO production by the lungs.

Cardiovascular response to submaximal exercise in sustained microgravity.

Cardiac output (Q), heart rate (HR), blood pressure, and oxygen consumption (VO2) were measured repeatedly both at rest and at two levels of exercise in six subjects during microgravity exposure. Exercise was at 30 and 60% of the workload producing the individual's maximal VO2 in 1 G. Three of the subjects were on a 9-day flight, Spacelab Life Sciences-1, and three were on a 15-day flight, Spacelab Life Sciences-2. We found no temporal differences during the flights. Thus we have combined all microgravity measurements to compare in-flight values with erect or supine control values. At rest, Q in flight was 126% of Q erect (P < 0.01) but was not different from Q supine, and HR in flight was 81% of HR erect (P < 0.01) and 91% of HR supine (P < 0.05). Thus resting stroke volume (SV) in flight was 155% of SV erect (P < 0.01) and 109% SV supine (P < 0.05). Resting mean arterial blood pressure and diastolic pressure were lower in flight than erect (P < 0.05). Exercise values were considered as functions of VO2. The increase in Q with VO2 in flight was less than that at 1 G (slope 3.5 vs. 6.1 x min-1.l-1.min-1). SV in flight fell with increasing VO2, whereas SV erect rose and SV supine remained constant. The blood pressure response to exercise was not different in flight from erect or supine. We conclude that true microgravity causes a cardiovascular response different from that seen during any of its putative simulations.

A blood-gas nomogram of the chick fetus: blood flow distribution between the chorioallantois and fetus.

This paper presents equations for quantifying the relationships between the O2 and CO2 concentrations and tensions in the blood of the 18-day chick fetus. A blood-gas nomogram showing these relationships is presented. Starting with the reported chorioallantoic artery and vein gas tensions and using the blood-gas equations, the range of embryonic arterial and venous gas tensions as well as the distribution of the cardiac output and the degree of mixing between the chorioallantoic and embryonic circulations are explored. It is concluded that at least 65% of the blood in the chorioallantoic artery consists of blood of embryonic mixed venous composition. A model of the blood flow distribution is proposed in which chorioallantoic and embryonic flows are equal, with 70% of the blood returning from the tissues of the embryo going to the chorioallantois and vice versa.

Biomedical support of man in space.

In its broadest sense, biomedical support of man in space must not be limited to assisting spacecraft crew during the mission; such support should also ensure that flight personnel be able to perform properly during landing and after leaving the craft. Man has developed mechanisms that allow him to cope with specific stresses in his normal habitat; there is indisputable evidence that, in some cases, the space environment, by relieving these stresses, has also allowed the adaptive mechanisms to lapse, causing serious problems after re-entry. Inflight biomedical support must therefore include means to simulate some of the normal stresses of the Earth environment. In the area of cardiovascular performance, we have come to rely heavily on complex feedback mechanisms to cope with two stresses, often combined: postural changes, which alter the body axis along which gravitational acceleration acts, and physical exercise, which increases the total load on the system. Unless the appropriate responses are reinforced continuously during flight, crew members may be incapacitated upon return. The first step in the support process must be a study of the way in which changes in g, even of short duration, affect these responses. In particular we should learn more about effects of g on the "on" and "off" dynamics, using a variety of approaches: increased acceleration on one hand at recumbency, immersion, lower body positive pressure, and other means of simulating some of the effects of low g, on the other. Once we understand this, we will have to determine the minimal exposure dose required to maintain the response mechanisms. Finally, we shall have to design stresses that simulate Earth environment and can be imposed in the space vehicle. Some of the information is already at hand; we know that several aspects of the response to exercise are affected by posture. Results from a current series of studies on the kinetics of tilt and on the dynamics of readjustment to exercise in different postures will be presented and discussed.

Regional differences in diffusive conductance/perfusion ratio in the shell of the hen's egg.

Are both gas exchange and gas tensions uniform in different regions of the developing hen's egg? To answer this question we measured the O2 uptake and CO2 production of the whole egg, and at the same time the O2 and CO2 tensions of the air cell. The gas exchange ratio (R) of the whole egg differed from R calculated from air cell PO2 and PCO2 values, in agreement with the findings of Visschedijk [Br. Poultry Sci. 9:173-184 (1968)], who measured gas exchange separately over both the air cell region and the remainder of the egg. We constructed a diffusive shell conductance/perfusion (G/Q) line on the O2-CO2 diagram from a blood nomogram for the chick embryo in late development [Olszowka et al., Fed. Proc. 46:512 (1987)], and used this to analyze our results. The G/Q ratio for the area of shell over the air cell differs from that for the remainder of the egg. Our analysis permits us to calculate, for each area, the regional shell conductance, blood flow, and O2 and CO2 tensions in the gas spaces between the shell and the chorioallantoic capillaries.

Oxygen equilibrium curve shape and allohemoglobin interaction in sheep whole blood.

Adult sheep (Ovis aries) exhibit hemoglobin heterogeneity controlled by two autosomal alleles with codominant expression (Hb AA, AB, BB). Isoelectric points for Hb A and Hb B were 6.94 and 7.15, respectively; for Hb AB animals, the two allohemoglobins were present in equimolar concentrations (Hb A = 52%, Hb B = 48%). Dynamic O2 equilibrium curves (O2ECs) were generated for sheep whole blood at 39 degrees C using thin-film techniques. Half-saturation PO2 values (P50) at pH 7.50 were 31.3, 35.7, and 40.7 Torr for Hb AA, AB, and BB, respectively. CO2 Bohr coefficients at saturation (S) = 0.5 (delta log P50/delta pH) were similar for all phenotypes, ranging from -0.38 to -0.40. The Bohr slopes were also saturation independent between 0.2 and 0.8 S. Standard O2ECs for each phenotype were accurately fitted to three-constant third-order polynomial expressions. Sheep equilibrium curves were not isomorphic with other mammalian O2ECs (e.g., human and dog); sheep curves exhibited greater sigmoidicity. Furthermore, allohemoglobin interaction was not detected in heterozygous sheep. The blood O2 binding characteristics (P50, curve shape, and delta log PO2/delta pH) for Hb AB sheep and an experimental blood mixture containing equal proportions of Hb AA and Hb BB erythrocytes were equivalent.

Oxygen affinity and Bohr coefficients of dog blood.

Complete dynamic oxygen equilibrium curves (O2EC) on dog whole blood were measured at 25 and 39 degrees C using a spectrophotometric micro blood film technique. O2EC were run at three CO2 levels (2, 4, and 8%) for each of three base excess levels (-10, 0, +10 meq/l). The standard curve (ph 7.4) was determined for saturations 0-0.98. At 39 degrees C the standard curve O2 pressure at half-saturation (P50) was 31.5 Torr; fixed-acid Bohr factor, -0.488; CO2 Bohr factor, -0.498; delta log P50/delta log PCO2, -0.0045. CO2 Bohr slope was linear over the pH range of 7-8. Bohr factors were not significantly saturation dependent. At 25 degrees C P50 was 15.4 Torr and CO2 Bohr factor, -0.647. The temperature coefficient (delta log P50/delta T) equaled 0.022. Dog O2EC were shown with curve-fitting techniques to be isomorphic with human blood O2EC. The absence of significant oxylabile carbamate formation in dog red blood cells (RBC) was attributed to high 2,3-diphosphoglycerate (DPG) concentrations, 6.23 mM/l RBC, equal to a DPG/Hb4 ratio of 1.12. A simple two-constant equation S = [(37,900)/(P3 + 205P) + 1]-1, where S is saturation and P is oxygen tension, was found to fit the dog 39 degrees C standard curve.

Postinspiratory mixing in the lung and cardiogenic oscillations.

Subjects inspired a 300-ml bolus of indicator gas cocktail (5% each of SF6, Ar, Ne, and He) form residual volume (RV), then inspired air to functional residual capacity (FRC). There was no evidence that a 10-s breath hold changed the relative concentrations or amounts of indicator gases in phases III and IV of expiration or allowed additional gas to mix into the RV, but the breath hold caused cardiogenic oscillations (CO) in expired gas to decrease in height. The units responsible for cardiogenic troughs and peaks are different from the units responsible for phases III and IV, respectively, in that the oscillation troughs had a lower He/SF6 ratio than the peaks whereas phase III had a higher He/SF6 than phase IV. We explain the CO as due to variation in mechanical properties, leading to variation in response to the pressure wave caused by the heart, in units that are relatively near to each other. We conclude that there is little or no postinspiratory mixing between distant lung units, but the dampening of CO suggests that units that are close to each other can mix if time is allowed.

Transpleural diffusion of carbon dioxide.

Carbonic anhydrase in lung tissue might play a role in speeding the movement of CO2 between blood and alveolus. To test this hypothesis, we measured the transpleural diffusion rate of CO2 and compared it to that of oxygen, argon, and nitrogen, before and after inhibition of carbonic anhydrase activity with acetazolamide. Experiments were performed in exsanguinated dog lungs, which allowed study of CO2 dynamics in the absence of carbonic anhydrase activity from erythrocytes. The relative rate of movement of CO2 and the other gases into and out of the lung, agreed with that predicted solely on the basis of molecular weight and solubility. We conclude that there is no evidence for facilitated diffusion of CO2 across the pleural tissue.

Amount and rates of CO2 storage in lung tissue.

The slope of the lung tissue CO2 dissociation curve and the rate of storage of CO2 in the lung tissue were studied at 22 degrees C and at 37 degrees C in 21 isolated, bloodless dog lungs with a total of 465 separate observations. Results at the two temperatures were similar. The slope of the tissue dissociation curve of lung tissue at a PCO2 of 40 torr was approximately 0.3 ml CO2 X 100 g wet tissue-1 X torr-1. Normally, this storage was 90% complete in about 5 seconds. After carbonic anhydrase inhibition by acetazolamide, the total storage capacity was unchanged, but the rate at which storage occurred decreased significantly, so that it took about 25 seconds for 90% of the storage to be completed.

Cardiac output determination by simple one-step rebreathing technique.

We have developed a rebreathing technique for measuring cardiac output in resting or exercising subjects. The data needed are the subject's CO2 dissociation curve, the initial volume and CO2 fraction of the rebreathing bag, and a record of CO2 at the mouth during the maneuver. From these one can obtain all the values required to solve the Fick equation. The combined error due to inaccuracy in reading the tracings and to the simplifying assumptions was found to be small (mean = 0.5%, SD ;.5%). Cardiac output values determined with this technique in normal subjects were on the average 2% higher than those obtained simultaneously with an acetylene rebreathing method (n = 49, SD = 11%). Among the advantages of the technique are that it requires analysis of a single gas, takes less than thirty seconds per determination, allows one to obtain repeated measurements at rapid intervals, is not affected by the ability of lung tissue to store CO2, and eliminates many of the assumptions usually made in non-invasive measurements of cardiac output.

Lung carbonate dehydratase (carbonic anhydrase), CO2 stores and CO2 transport.

A study of CO2 storage in excised, exsanguinated lungs revealed that CO2 stores include a compartment which reaches equilibration very rapidly (less than 3s) and a slower compartment which equilibrates with a half-time of approximately 15 s. Inhibition of carbonate dehydratase (carbonic anhydrase, EC 4.2.1.1) does not change the slope of the total CO2 dissociation curve of the lung but does increase the slow compartment at the expense of the fast. CO2 diffusion across the pleura is approximately 20 times faster than that of O2, a relationship that is not affected by inhibition of carbonate dehydratase. The role of tissue CO2 stores in limiting respiratory fluctuations of PCO2 or pH in arterial blood is only minor and may be of significance only in rapid, deep inspiration. CO2 uptake or release by the stores is out of phase with blood CO2 exchange. As a consequence, the time course of CO2 exchange at the mouth during expiration cannot be used to predict alveolar or capillary CO2 exchange.

Can VA/Q distributions in the lung be recovered from inert gas retention data?

It has been suggested that the true distribution of ventilation-perfusion ratios can be determined from measurements made during the excretion of six different inert gases. This report shows that a number of considerably different distribution patterns will yield the same retention data, even in the absence of analytical error. Therefore, although analysis of inert gas retention data will allow one to arrive at a VA/Q distribution, it will not necessarily be the correct distribution.