Rate of formation of carboxyhemoglobin in exercising humans exposed to carbon monoxide.

The purpose of this study was to test the CFK equation for its prediction of the rate of formation of carboxyhemoglobin (HbCO) in exercising humans by use of measured values of the respiratory variables and to characterize the rate of appearance of HbCO with frequent blood sampling. Ten nonsmoking male subjects were exposed to carbon monoxide (CO) on two separate occasions distinguished by the level of activity. Steady-state exercise was conducted on a cycle ergometer at either a low (approximately 45 W) or moderate (approximately 90 W) power output. Each experiment began with an exposure of 3,000 ppm CO for 3 min during a rest period followed by three intermittent exposures ranging from 3,000 ppm CO for 1 min at low exercise to 667 ppm CO for 3 min at moderate exercise. Increases in HbCO were normalized against predicted values to account for individual differences in the variables that govern CO uptake. No difference in the normalized uptake of CO was found between the low- and moderate-exercise trials. However, the CFK equation underpredicted the increase in HbCO for the exposures at rest and the first exposure at exercise, whereas it overpredicted for the latter two exposures at exercise. The net increase in HbCO after all exposures (approximately 10% HbCO) deviated by less than 1% HbCO between the measured and predicted values. The rate of appearance of HbCO fits a sigmoidal shape with considerable overshoot at the end of exposure. This can be explained by delays in the delivery of CO to the blood sampling point (dorsal hand vein) and by a relatively small blood circulation time compared with other regions of the body. A simple circulation model is used to demonstrate the overshoot phenomenon.     

Response of newborn lambs to CO-induced hypoxia

This study was undertaken to measure the neonate's response to CO-induced hypoxia in the first 10 days of life. CO breathing was used to induce hypoxia because CO causes tissue hypoxia with no or minimal chemoreceptor stimulation. An inspired gas mixture of 0.25 to 0.5% CO in air was used to raise the blood carboxyhemoglobin (HbCO) progressively from 0 to 60% over approximately 20 min. The study, conducted in awake conscious lambs aged 2 and 10 days, consisted in measuring the response of ventilation and the change in arterial blood gases during the rise of HbCO. The results showed that the 2- and 10-day-old lambs tolerated very high HbCO levels without an increase in minute ventilation (VE) and without metabolic acidosis. At both ages, HbCO caused no VE change until HbCO levels rose to between 45 and 50% after which the VE change was exponential in some animals but minimal in others. The VE change was brought about by a rise in tidal volume and respiratory frequency. During the period of maturation from 2 to 10 days, there was a small shift to the right in the VE-HbCO response. In the 10-day-old lambs the VE response to high HbCO was greater than that of the 2-day-olds because of the lambs' higher respiratory frequency response. Six of the 10-day-old lambs but only two of the 2-day-old lambs showed a hypoxic tachypnea to HbCO of 55-65%. None of the lambs developed periodic breathing, dysrhythmic breathing, or recurrent apneas with an HbCO level as high as 60%.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo binding of carbon monoxide to cytochrome c oxidase in rat brain

The possibility of binding of CO to cytochrome c oxidase (cytochrome a,a3) in brain cortex has been examined in vivo by reflectance spectrophotometry. During ventilation with CO-containing gases, cytochrome a,a3 absorption at 605 nm increased in the parietal cortex of anesthetized rats during carboxyhemoglobin (HbCO) formation. HbCO levels, measured by changes in absorption at 569-586 nm in vivo, correlated positively with arterial HbCO by CO oximetry. Arterial blood pressure and calculated O2 content varied inversely with HbCO. During CO exposure, decreases in blood pressure, O2 content, and cytochrome a,a3 oxidation level could be reversed partly at constant HbCO by compression to 3 atmospheres absolute (ATA). After removing CO from inspired gas at 3 ATA, optical and physiological parameters recovered completely to control values except for minor persistent elevations of HbCO. Difference spectra from parallel experiments at constant HbCO revealed absorption minima at 588-592 nm and 600-605 nm as a result of hyperbaric exposure. Spectral analysis of these components was consistent with partial dissociation of a cytochrome a3-CO complex and cytochrome a reoxidation with increasing dissolved O2 in hyperbaric conditions.     

Quantification of pulmonary vascular occlusion in dogs by use of the diffusing capacity

The purpose of these experiments was to quantify stagnant intrapulmonary blood caused by a pulmonary arterial occlusion (PAO). The hypothesis was that the diffusing capacity of the lung for CO (DLCO) would be altered little by PAO when measured with the usual inspired concentrations (0.3%) of CO, since stagnant blood distal to the occlusion takes up CO for 20 s or more before significant CO backpressure would develop. However, higher levels of CO (i.e., greater than or equal to 3%) would equilibrate faster with capillary blood (within 5-10 s), and DLCO measured 10-20 s subsequent to the high CO exposure would reflect only the DLCO in the unoccluded regions. Thus the fractional reduction in DLCO measured with 3% CO, with respect to that measured with 0.3% CO, should be related to the fractional occlusion of the pulmonary artery in a predictable way. We occluded the right pulmonary artery (RPAO), the left pulmonary artery (LPAO), or the left lower lobar artery (LLPAO) and found that DLCO measured during rebreathing a 0.3% CO mixture was 80, 87, and 94%, respectively, of the preocclusion value, whereas the DLCO measured during rebreathing a 3.3% CO mixture was 59, 73, and 87% of the preocclusion value. A computer model was developed to predict the reduction in DLCO at different levels of CO exposure that would be caused by varying fractions of PAO. Our data indicated that RPAO corresponded to a 42% vascular occlusion, LPAO a 35% occlusion, and LLPAO a 20% occlusion. Measurement of DLCO using low and high concentrations of CO might be useful in assessing the fraction of vascular bed occluded and in following noninvasively the course of vascular occlusion in a variety of pulmonary diseases.     

Percent carboxyhemoglobin in resting humans exposed repeatedly to 1,500 and 7,500 ppm CO

Eleven nonsmoking male resting subjects were exposed to two transient CO profiles to examine whether the resultant carboxyhemoglobin (HbCO) differs with CO concentration for a fixed total CO dose and to determine the predictive capability of the theoretical model of Coburn et al. (J. Clin. Invest. 44: 1899-1910, 1965) using measured alveolar ventilation. One profile consisted of five sequential exposures to 1,500 ppm CO for 5 min each and spaced 3 min apart. The other consisted of five sequential exposures to 7,500 ppm CO for 1 min each and spaced 7 min apart. The subjects, therefore, were exposed to the same overall nominal dose of 37,500 ppm.min. During the experiment, the subject's ventilatory functions and respiratory gases were recorded continuously, and the resultant HbCO% was measured in venous blood samples by gas chromatography. Mean increase (+/- SD) in HbCO% per exposure was 2.08 +/- 0.27% for the 1,500 ppm CO exposures and 2.05 +/- 0.29% for the 7,500 ppm CO exposures with no significant difference between the two. When the measured values of the subject's alveolar ventilation were applied to the theoretical model of Coburn et al., the predicted rate of HbCO% formation was found to agree with the experimental results.     

Predicting the carboxyhemoglobin levels resulting from carbon monoxide exposures.

Data from a series of human exposures to carbon monoxide (CO) were analyzed to determine the fit to the theoretical Coburn-Forster-Kane (CFK) equation which describes CO absorption and excretion. The equation was found to predict carboxyhemoglobin (HbCO) saturations for both men and women at exercise rates ranging from sedentary to 300 kpm/min when they were exposed to steady CO concentrations of 50, 100, and 200 ppm for 0.33-5.25 h. Methods for determining values of each of the variables in the CFK equation were collected and a rational, efficient procedure for solving the equation by trial and error was outlined. The CFK equation was then used to prepare a graph, relating HbCO saturation to exposure duration and concentration, and also to describe the effect of several variables on the rate of CO uptake and equilibrium HbCO levels, important considerations in the determination of permissible public, occupational, and experimental exposure to CO.     

A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to inhalation of carbon monoxide.

We have developed a model that predicts the distribution of carbon monoxide (CO) in the body resulting from acute inhalation exposures to CO. The model includes a lung compartment, arterial and venous blood compartments, and muscle and nonmuscle soft tissues with both vascular and nonvascular subcompartments. In the model, CO is allowed to diffuse between the vascular and nonvascular subcompartments of the tissues and to combine with myoglobin in the nonvascular subcompartment of muscle tissue. The oxyhemoglobin dissociation curve is represented by a modified Hill equation whose parameters are functions of the carboxyhemoglobin (HbCO) level. Values for skeletal muscle mass and cardiac output are calculated from prediction formulas based on age, weight, and height of individual subjects. We demonstrate that the model fits data from CO rebreathing studies when diffusion of CO into the muscle compartment is considered. The model also fits responses of HbCO to single or multiple exposures to CO lasting for a few minutes each. In addition, the model reproduces reported differences between arterial and venous HbCO levels and replicates predictions from the Coburn-Forster-Kane equation for CO exposures of a 1- to 83-h duration. In contrast to approaches based on the Coburn-Forster-Kane equation, the present model predicts uptake and distribution of CO in both vascular and tissue compartments during inhalation of either constant or variable levels of CO.     

Fetal breathing and sleep state responses to graded carboxyhemoglobinemia in sheep

To investigate CO effects on brain oxygenation, graded carboxyhemoglobinemia (HbCO) was produced in nine unanesthetized fetal sheep by infusing CO-laden erythrocytes in exchange for fetal blood. For the 1st h after this procedure, the mean fetal carboxyhemoglobin levels were 16.5 +/- 0.4% [control (C) = 1.4 +/- 0.4%] for mild HbCO, 22.7 +/- 0.6% (C = 1.8 +/- 0.4%) for moderate HbCO, and 27.8 +/- 0.5% (C = 2.1 +/- 0.7%) for severe HbCO. This induction of HbCO significantly reduced mean preductal arterial PO2 values to 4.3 Torr below control for mild HbCO, 4.6 Torr below control for moderate HbCO, and 5.5 Torr below control for severe HbCO. The respective arterial O2 contents were decreased by 17, 21, and 29%. Mean arterial pH was lowered only during severe HbCO, and arterial PCO2 values were unchanged. HbCO produced a fetal tachycardia. Mean arterial blood pressure was only increased during severe HbCO. The incidences of rapid eye movements and breathing activity were decreased by HbCO in a dose-dependent manner. When related to calculated brain tissue PO2, these decreases were similar to those measured during hypoxic hypoxia and anemia, suggesting that carboxyhemoglobin effects result solely from diminished oxygenation. It is concluded that 1) the peripheral arterial chemoreceptors in the fetus apparently have little effect on hypoxic inhibition of breathing and 2) the carboxyhemoglobin concentrations required to inhibit fetal breathing are greater than those likely to be encountered clinically.     

Influence of carbon monoxide on hemoglobin-oxygen binding.

The oxygen dissociation curve and Bohr effect were measured in normal whole blood as a function of carboxyhemoglobin concentration [HbCO]. pH was changed by varying CO2 concentration (CO2 Bohr effect) or by addition of isotonic NaOH or HCl at constant PCO2 (fixed acid Bohr effect). As [HbCO] varied through the range of 2, 25, 50, and 75%, P50 was 26.3, 18.0, 11.6, and 6.5 mmHg, respectively. CO2 Bohr effect was highest at low oxygen saturations. This effect did not change as [HbCO] was increased. However, as [HbCO] was increased from 2 to 75%, the fixed acid Bohr factor increased in magnitude from -0.20 to -0.80 at very low oxygen saturations. The effect of molecular CO2 binding (carbamino) on oxygen affinity was eliminated at high [HbCO]. These results are consistent with the initial binding of O2 or CO to the alpha-chain of hemoglobin. The results also suggest that heme-heme interaction is different for oxygen than for carbon monoxide.     

Prenatal exposure to low levels of carbon monoxide alters sciatic nerve myelination in rat offspring

Prenatal exposure to low concentrations of carbon monoxide (CO, 75 and 150 ppm from day 0 to day 20 of gestation), resulting in maternal blood HbCO concentrations equivalent to those maintained by human cigarette smokers, leads to subtle myelin alterations in the sciatic nerve of male rat offspring. The rapid growth spurt in pup body weight was related to the period of maximal increase in myelin sheath thickness in both control and CO-exposed animals. A significant reduction in myelin sheath thickness of sciatic nerve fibers, paralleled by changes in the frequency distribution, occurred in both 40- and 90-day-old rats exposed in utero to CO (75 and 150 ppm). Myelin deficit observed in 75 and 150 ppm CO-exposed animals showed up only after the major spurt in myelination but not early during development. The subtle myelin alterations observed in CO-exposed offspring were not accompanied by changes in developmental pattern of axon diameters and did not result in a gross impairment of motor activity. These results suggest that the myelination process is selectively targeted by a prenatal exposure model simulating the CO exposure observed in human cigarette smokers.     

Carboxy- and oxyhemoglobin in pregnant ewe and fetus after inhalation of marijuana, marijuana placebo and tobacco cigarette smoke

We measured carboxyhemoglobin (HbCO) and oxyhemoglobin (HbO2) percent saturations and blood gases in four near-term pregnant ewes and their fetuses, during and for 6 hours after 9-12 minutes of smoke inhalation from one high-potency marijuana cigarette (M), a marijuana placebo cigarette (P), and a reference tobacco cigarette (T). Maternal HbCO reached maximum levels at or soon after the exposure (M, 2.8%; P, 3.5%; T, 6.3% above baseline) and fell to baseline values by 6 hours. Fetal HbCO rose slowly reaching a plateau at 3 hours (M, 0.7%; P, 1.1%; T, 2.0% above baseline) which was maintained for at least three additional hours. Reductions in maternal and fetal HbO2 after exposure to marijuana placebo and reference tobacco cigarettes reflected these rises in HbCO. After exposure to marijuana cigarettes, however, fetal HbO2 dropped precipitously by 17% of baseline and showed a prolonged rate of return to presmoking HbO2 levels. Although P exposure caused a greater change in HbCO in the fetus than did M, it had a less-profound effect on fetal oxygenation.     

腹腔注射法制备一氧化碳中毒迟发性脑病大鼠模型

目的:建立可靠的急性一氧化碳(CO)中毒迟发性脑病的动物模型。方法:雄性SD大鼠,分次腹腔注射CO染毒制备模型,动态监测尾血碳氧血红蛋白(HbCO)浓度;Morris水迷宫检测大鼠1-5w逃避潜伏期;尼氏染色及TUNEL原位末端凋亡染色检测大脑皮质及海马细胞损伤及凋亡。结果:染毒后,大鼠出现典型的CO重度中毒症状,体内血液HbCO浓度迅速升高,使用分次腹腔注射法,大鼠可维持长时间(>12h)高HbCO状态(HbCO>48%);中毒组大鼠水迷宫检测认知功能较对照组下降,病理学检查显示大鼠出现脑细胞损伤、凋亡明显。结论:本研究建立了一种较为符合迟发性脑病临床特征的动物模型,具有简单、可靠、重复性好的特点,为深入研究急性CO中毒致迟发性脑损伤的机制提供可靠基础。     

Maximal aerobic capacity at several ambient concentrations of CO at several altitudes

To assess the nature of the combined effect of the hypoxias of altitude (ALT) and CO exposure, 11 men and 12 women nonsmokers served as subjects in a double-blind experiment. The exposure conditions were four ambient CO levels (0, 50, 100, and 150 ppm) at each of four ALT (55, 1,524, 2,134, and 3,048 m). Each subject, after attaining the required ALT and ambient CO level, performed a maximal aerobic capacity test (VO2max). Blood samples were obtained before, at 50-W, 100-W, 150-W, and maximum work loads and at the 5th min of recovery. Blood were analyzed for hemoglobin, hematocrit, plasma proteins, lactates, and carboxyhemoglobin (HbCO). VO2max was similar at 55 and 1,524 m and decreased by 4 and 8% from the 55-m value at 2,134 and 3,048 m, respectively. On the basis of all statistical analyses, we concluded that VO2max values measured in men were only slightly diminished due to increased ambient CO. HbCO attained at maximum was highest at 55 m and lowest at 3,048 m. Women's HbCO concentrations were lower than men's. At maximal work loads CO shifted into extravascular spaces and returned to the vascular space within 5 min after exercise stopped. The independence of altitude and CO hypoxias on parameters of the maximum aerobic capacity test and a decrease in the CO to HbCO uptake with increasing altitude were demonstrated and attributed in part to the decrease in driving pressure of CO at altitude.     

A mathematical model for the computation of carboxyhaemoglobin in human blood as a function of exposure time.

A mathematical model is developed for the carbon monoxide (CO) uptake by the blood by taking into account the molecular diffusion, convection, facilitated diffusion and the non-equilibrium kinetics of CO with haemoglobin. The overall rate for the combination of CO with haemoglobin is derived by including the dissociation of CO from carboxyhaemoglobin (COHb). The resulting coupled system of nonlinear partial differential equation with physiologically relevant initial, entrance and boundary conditions is solved numerically. A fixed point iterative technique is used to deal with nonlinearities. The concentration of COHb in the blood is computed as a function of exposure time and ambient CO concentration. The COHb levels computed from our model are in good agreement with those measured experimentally. Also, results computed from our model give better approximation to the experimental values compared with the results from other models. The time taken by the blood COHb to attain 95% of its equilibrium value is computed. The COHb concentration in the blood increases with the increase in ventilation rate, association rate coefficient of CO with haemoglobin and total haemoglobin content in the blood, and with the decrease in dissociation rate coefficient of CO with haemoglobin and mean capillary blood PO2. It is found that the COHb level in the blood is not affected significantly because of endogenous production of CO in the body under normal condition. However, the effect may be significant in the patients with haemolytic anaemia.     

腹腔注射法制备一氧化碳中毒迟发性脑病大鼠模型

目的：建立可靠的急性一氧化碳（CO）中毒迟发性脑病的动物模型。方法：雄性SD大鼠,分次腹腔注射CO染毒制备模型,动态监测尾血碳氧血红蛋白（HbCO）浓度;Morris水迷宫检测大鼠1-5w逃避潜伏期;尼氏染色及TUNEL原位末端凋亡染色检测大脑皮质及海马细胞损伤及凋亡。结果：染毒后,大鼠出现典型的CO重度中毒症状,体内血液HbCO浓度迅速升高,使用分次腹腔注射法,大鼠可维持长时间（〉12h）高HbCO状态（HbCO〉48%）;中毒组大鼠水迷宫检测认知功能较对照组下降,病理学检查显示大鼠出现脑细胞损伤、凋亡明显。结论：本研究建立了一种较为符合迟发性脑病临床特征的动物模型,具有简单、可靠、重复性好的特点,为深入研究急性CO中毒致迟发性脑损伤的机制提供可靠基础。     

Dynamic measurements of CO diffusing capacity using discrete samples of alveolar gas

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.     

Evaluation of lung diffusing capacity by physiological and morphometric techniques

Determinations of pulmonary diffusing capacity for CO (DLCO) by physiological and morphometric techniques have resulted in substantially different values for both DLCO and its major components. To evaluate the differences in these methods of measurement of DLCO, measurements were made under controlled conditions on isolated perfused dog lungs. Multiple gas-rebreathing techniques were used to measure DLCO, the membrane component of the diffusing capacity for CO (DmCO), and pulmonary capillary blood volume (Vc) in both anesthetized dogs and after isolation and perfusion of their lungs. The isolated perfused lungs were than perfusion fixed for morphometric analysis of the components of DLCO. The values obtained morphometrically for Vc were similar to those measured by physiological techniques. Perfusion fixation did not substantially alter the morphometric estimate of DmCO when compared with previous values obtained on inflation fixed lungs. However, the morphometric estimate of DmCO was over 10 times higher than that estimated physiologically. Analysis of the potential errors in the techniques suggests that the correct value for DmCO is substantially higher than that commonly estimated by use of physiological techniques and that the explanation for the difference is due to a number of factors that can influence the binding of CO to hemoglobin under in vivo conditions. The net effect of these factors can be represented by an unknown in each component of the Roughton-Forster relationship so that 1/DL = 1/(U1.Dm) + 1/(U2.theta Vc), where theta is the binding rate for CO to hemoglobin. Because the magnitudes of the unknown terms (U1 and U2) in the Roughton-Forster relationship are likely to be large, this relationship cannot be reliably used to determine Dm and Vc.     

Kinetics of CO uptake and diffusing capacity in transition from rest to steady-state exercise.

In the transition from rest to steady-state exercise, O2 uptake from the lungs (VO2) depends on the product of pulmonary blood flow and pulmonary arteriovenous O2 content difference. The kinetics of pulmonary blood flow are believed to be somewhat faster than changes in pulmonary arteriovenous O2 content difference. We hypothesized that during CO breathing, the kinetics of CO uptake (VCO) and diffusing capacity for CO (DLCO) should be faster than VO2 because changes in pulmonary arteriovenous CO content difference should be relatively small. Six subjects went abruptly from rest to constant exercise (inspired CO fraction = 0.0005) at 40, 60, and 80% of their peak VO2, measured with an incremental test (VO2peak). At all exercise levels, DLCO and VCO rose faster than VO2 (P less than 0.001), and DLCO rose faster than VCO (P less than 0.001). For example, at 40% VO2peak, the time constant (tau) for DLCO in phase 2 was 19 +/- 5 (SD), 24 +/- 5 s for VCO, and 33 +/- 5 s for VO2. Both VCO and DLCO increased with exercise intensity but to a lesser degree than VO2 at all exercise intensities (P less than 0.001). In addition, no significant rise in DLCO was observed between 60 and 80% VO2peak. We conclude that the kinetics of VCO and DLCO are faster than VO2, suggesting that VCO and DLCO kinetics reflect, to a greater extent, changes in pulmonary blood flow and thus recruitment of alveolar-capillary surface area. However, other factors, such as the time course of ventilation, may also be involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of factors that influence rates of carbon monoxide uptake, distribution, and washout from blood and extravascular tissues using a multicompartment model.

To better understand factors that influence carbon monoxide (CO) washout rates, we utilized a multicompartment mathematical model to predict rates of CO uptake, distribution in vascular and extravascular (muscle vs. other soft tissue) compartments, and washout over a range of exposure and washout conditions with varied subject-specific parameters. We fitted this model to experimental data from 15 human subjects, for whom subject-specific parameters were known, multiple washout carboxyhemoglobin (COHb) levels were available, and CO exposure conditions were identical, to investigate the contributions of exposure conditions and individual variability to CO washout from blood. We found that CO washout from venous blood was biphasic and that postexposure times at which COHb samples were obtained significantly influenced the calculated CO half times (P < 0.0001). The first, more rapid, phase of CO washout from the blood reflected the loss of CO to the expired air and to a slow uptake by the muscle compartment, whereas the second, slower washout phase was attributable to CO flow from the muscle compartment back to the blood and removal from blood via the expired air. When the model was used to predict the effects of varying exposure conditions for these subjects, the CO exposure duration, concentration, peak COHb levels, and subject-specific parameters each influenced washout half times. Blood volume divided by ventilation correlated better with half-time predictions than did cardiac output, muscle mass, or ventilation, but it explained only approximately 50% of half-time variability. Thus exposure conditions, COHb sampling times, and individual parameters should be considered when estimating CO washout rates for poisoning victims.     

Red cell distribution and the recruitment of pulmonary diffusing capacity.

The distribution of red blood cells in alveolar capillaries is typically nonuniform, as shown by intravital microscopy and in alveolar tissue fixed in situ. To determine the effects of red cell distribution on pulmonary diffusive gas transport, we computed the uptake of CO across a two-dimensional geometric capillary model containing a variable number of red blood cells. Red blood cells are spaced uniformly, randomly, or clustered without overlap within the capillary. Total CO diffusing capacity (DLCO) and membrane diffusing capacity (DmCO) are calculated by a finite-element method. Results show that distribution of red blood cells at a fixed hematocrit greatly affects capillary CO uptake. At any given average capillary red cell density, the uniform distribution of red blood cells yields the highest DmCO and DLCO, whereas the clustered distribution yields the lowest values. Random nonuniform distribution of red blood cells within a single capillary segment reduces diffusive CO uptake by up to 30%. Nonuniform distribution of red blood cells among separate capillary segments can reduce diffusive CO uptake by >50%. This analysis demonstrates that pulmonary microvascular recruitment for gas exchange does not depend solely on the number of patent capillaries or the hematocrit; simple redistribution of red blood cells within capillaries can potentially account for 50% of the observed physiological recruitment of DLCO from rest to exercise.