Alveolar-capillary Conductance Research Articles

Pulmonary Capillary Recruitment Is Attenuated Post Left Ventricular Assist Device Implantation

There is limited knowledge of pulmonary physiology and pulmonary function after continuous flow-left ventricular assist device (CF-LVAD) implantation. Therefore, this study investigated whether CF-LVAD influenced pulmonary circulation by assessing pulmonary capillary blood volume and alveolar-capillary conductance in addition to pulmonary function in patients with heart failure. Seventeen patients with severe heart failure who were scheduled for CF-LVAD implantation (HeartMate II, III, Abbott, Abbott Park, IL or Heart Ware, Medtronic, Minneapolis, MN) participated in the study. They underwent pulmonary function testing (measures of lung volumes and flow rates) and unique measures of pulmonary physiology using a rebreathe technique that quantified the diffusing capacity of the lungs for carbon monoxide (DLCO) and diffusing capacity of the lungs for nitric oxide before and 3months after CF-LVAD implantation. After CF-LVAD, pulmonary function was not significantly changed (p >0.05). For lung diffusing capacity, alveolar volume (VA) was not changed (p=0.47), but DLCO was significantly reduced (p=0.04). After correcting for VA, DLCO/VA showed a trend toward reduction (p=0.08). For the alveolar-capillary component, capillary blood volume (Vc) was significantly reduced (p=0.04), and alveolar-capillary membrane conductance trended toward a reduction (p=0.06). However, alveolar-capillary membrane conductance/Vc was not altered (p=0.92). In conclusion, soon after CF-LVAD implantation, Vc is reduced likely because of pulmonary capillary derecruitment, which contributes to the decrease in lung diffusing capacity.

Influence of rapidly oscillating inspired O2 and N2 concentrations on pulmonary vascular function and lung fluid balance in healthy adults.

Introduction: Aircrew may experience rapidly oscillating inspired O2/N2 ratios owing to fluctuations in the on-board oxygen delivery systems (OBOG). Recent investigations suggest these oscillations may contribute to the constellation of physiologic events in aircrew of high-performance aircraft. Therefore, the purpose of this study was to determine whether these "operationally-relevant" environmental challenges may cause decrements in measures of pulmonary vascular physiology. Methods: Thirty healthy participants (Age: 29 ± 5years) were recruited and assigned to one of the three exposures. Participants were instrumented for physiologic monitoring and underwent baseline cardiopulmonary physiology testing (ground level) consisting of a rebreathe method for quantifying pulmonary blood flow (Qc), pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (Dm). Ultrasound was used to quantify "comet tails" (measure of lung fluid balance). After baseline testing, the participants had two 45min exposures to an altitude of 8,000ft where they breathed from gas mixtures alternating between 80/20 and 30/70 O2/N2 ratios at the required frequency (30s, 60s, or 120s), separated by repeat baseline measure. Immediately and 45min after the second exposure, baseline measures were repeated. Results: We observed no changes in Qc, Dm or Vc during the 60s exposures. In response to the 30s oscillation exposure, there was a significantly reduced Qc and Vc at the post-testing period (p = 0.03). Additionally, exposure to the 120s oscillations resulted in a significant decrease in Vc at the recovery testing period and an increase in the Dm/Vc ratio at both the post and recovery period (p < 0.01). Additionally, we observed no changes in the number of comet tails. Conclusion: These data suggest "operationally-relevant" changes in inspired gas concentrations may cause an acute, albeit mild pulmonary vascular derecruitment, reduced distention and/or mild pulmonary-capillary vasoconstriction, without significant changes in lung fluid balance or respiratory gas exchange. The operational relevance remains less clear, particularly in the setting of additional environmental stressors common during flight (e.g., g forces).

Hypoxia induced changes in lung fluid balance in humans is associated with beta-2 adrenergic receptor density on lymphocytes

BackgroundPrevious studies have demonstrated an important role for beta-2 adrenergic receptors (β2AR) in lung fluid clearance. The purpose of this investigation was to examine the relationship between β2AR density on lymphocytes and indices of lung water in healthy humans exposed to ∼17h of hypoxia (FIO2=12.5% in a hypoxia tent). MethodsThirteen adults (mean±SEM; age=31±3 years, BMI=24±1kg/m2, VO2 Peak=40±2 ml/kg/min) participated. Pulmonary function, CT derived lung tissue volume (Vtis-tissue, blood and water), lung diffusing capacity for carbon monoxide (DCO) and nitric oxide (DNO), alveolar-capillary conductance (DM), pulmonary capillary blood volume (Vc) and lung water (CT Vtis−Vc) were assessed before and after ∼17h normobaric hypoxia (FIO2=12.5%). β2AR density on lymphocytes was measured via radioligand binding. Arterial oxygen saturation (SaO2), cardiac output (Q), right ventricular systolic pressure (RVSP) and blood pressure (BP) were also assessed. ResultsAfter 17h hypoxia, SaO2 decreased from 97±1 (normoxia) to 82±4% and RVSP increased from 14±3 (normoxia) to 29±2mmHg (p<0.05) with little change in Q or BP. Vc and DM both increased with hypoxia with a small increase in DM/Vc ratio (p>0.05). CT Vtis decreased and lung water was estimated to decline 7±13%, respectively. β2AR density averaged 1497±187 receptors/lymphocyte and increased 21±34% with hypoxia (range −31 to +86%). The post-hypoxia increase in β2AR density was significantly related to the reduction in lung water (r=−0.64, p<0.05), with the subjects with the greatest increase in density demonstrating the largest decline in lung water. ConclusionsLung water decreases with 17h normobaric hypoxia are associated with changes in beta adrenergic receptor density on lymphocytes in healthy adults.

Lung fluid balance in patients with heart failure: effect of beta‐2 adrenergic‐receptor stimulation

Background β2-adrenergic receptor (β2AR) stimulation promotes lung fluid removal in animals and healthy humans. It is possible that lung fluid accumulation in heart failure (HF) patients is caused by impairment in lung fluid regulation via desensitization of the lung β2ARs. Purpose To determine the effect of an acute inhaled β2AR agonist on lung fluid in HF. Methods/Results 22 stable HF patients and 22 healthy age and gender matched subjects were studied. Lung fluid was estimated at baseline (BL) and up to 30 min after administration of nebulized albuterol by measuring lung diffusing capacity for CO (DLCO), alveolar-capillary conductance (Dm) and pulmonary capillary blood volume (Vc) using a rebreathe method. Pre-inhalation, DLCO was not different in HF vs. healthy subjects (16±5 vs. 19±4 ml/min/mmHg, P=0.06). By contrast, Dm/Vc was greater in HF vs. healthy subjects (0.42 ± 0.14 vs. 0.33 ± 0.15, P=0.04). In HF, group mean DLCO, Dm and Dm/Vc were not different pre- vs. post-albuterol. However, patients who had an increase in DLCO and Dm/Vc with albuterol administration had significantly lower BL values compared to patients who had no improvement (P<0.05). That is, β2AR stimulation improved DLCO and Dm/Vc only in subjects who had evidence for increased lung fluid at BL. Conclusion Stimulation of β2AR may stimulate fluid removal in stable HF patients who exhibit evidence for elevated lung water at rest. HL71478.

Calculating alveolar capillary conductance and pulmonary capillary blood volume: comparing the multiple- and single-inspired oxygen tension methods

Key elements for determining alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) from the lung diffusing capacity (Dl) for carbon monoxide (DlCO) or for nitric oxide (DlNO) are the reaction rate of carbon monoxide with hemoglobin (thetaCO) and the DmCO/DlNO relationship (alpha-ratio). Although a range of values have been reported, currently there is no consensus regarding these parameters. The study purpose was to define optimal parameters (thetaCO, alpha-ratio) that would experimentally substantiate calculations of Dm and Vc from the single-inspired O2 tension [inspired fraction of O2 (FiO2)] method relative to the multiple-FiO2 method. Eight healthy men were studied at rest and during moderate exercise (80-W cycle). Dm and Vc were determined by the multiple-FiO2 and single-FiO2 methods (rebreathe technique) and were tabulated by applying previously reported thetaCO equations (both methods) and by varying the alpha-ratio (single-FiO2 method) from 1.90 to 2.50. Values were then compared between methods throughout the examined alpha-ratios. Dm and Vc were critically dependent on the applied thetaCO equation. For the multiple-FiO2 method, Dm was highly variable between thetaCO equations (rest and exercise); the range of Vc was less widespread. For the single-FiO2 method, the thetaCO equation by Reeves and Park (1992) combined with an alpha-ratio between 2.08 and 2.26 gave values for Dm and Vc that most closely matched those from the multiple-FiO2 method and were also physiologically plausible compared with predicted values. We conclude that the parameters used to calculate Dm and Vc values from the single-FiO2 method (using DlCO and DlNO) can significantly influence results and should be evaluated within individual laboratories to obtain optimal values.

Optimizing the calculation of alveolar capillary conductance and pulmonary capillary blood volume with carbon monoxide and nitric oxide in humans

The classic method for determining alveolar‐capillary membrane conductance (DM) and pulmonary capillary blood volume (VC) involves measurement of lung diffusing capacity for carbon monoxide (DLCO) at multiple inspired O2 tensions (FIO2). Recently, the technique has been simplified by simultaneously measuring DLNO (nitric oxide) to determine values at a single FIO2. Controversy exists over equations for calculation of θCO (reaction rate of CO with Hgb) and the correct diffusion ratio for NO and CO (α) in the calculation of DMCO. The purpose of this study was to investigate how various published equations and ratios influence DM &amp; VC using both the multiple and single FIO2 methods. Eight healthy males were studied. DLCO &amp; DLNO were measured using the rebreathe method (inspired vol. ~75% of inspiratory capacity, FIO2 18, 35, &amp; 55%). DM &amp; VC were first calculated using five reported equations for θCO. Once DM &amp; VC were optimized based on reported predicted values, the DLNO method was compared using a range of α values. Using the multiple FIO2 method, depending on the equation for θCO, DM ranged from 47 to 103 ml/min/mmHg, and VC from 74 to 102 ml. For the calculation of DM &amp; VC using the DLNO method, α ranged from 1.5 to 4.0 in order to optimize DM &amp; VC values to the classic method. The determination of DM &amp; VC is critically dependent on the equations used for θCO which in turn affects the optimal ratio used to correct the DLNO method. NIH HL71478

Influence of acute graded hypoxia on the bronchial circulation in healthy humans

Reduced partial pressures of inspired O2 may influence the bronchial circulation through a number of mechanisms (e.g. altered pulmonary and systemic vascular pressures, lung fluid regulation, airway cooling &amp; drying from increased ventilation). The present study examined the impact of acute, graded hypoxia on bronchial blood flow (Qaw) in eight healthy adults (28 ± 9 years). Subjects were exposed to inspired O2 levels resulting in arterial O2 saturation (SaO2) values of 90% and 80% for 15 min each. To control for the mild hyperventilation that accompanies hypoxia, subjects then mimicked the 80% SaO2 ventilation (VE) rate with 21% FIO2 and again with CO2 added to the inspirate to maintain normocapnia. Qaw and cardiac output (CO) were measured using soluble gas techniques. Also measured were alveolar‐capillary conductance (Dm, index of lung fluid balance), pulmonary capillary blood volume (Vc), and systemic mean (MAP) and pulmonary arterial pressures (PAP). Hypoxia resulted in minimal change in MAP, a small rise in PAP, minimal change in CO and Vc, and a rise in Dm. There was also a non significant decrease in Qaw with hypoxia. Mild hyperventilation resulted in a significant fall in Qaw, but when normocapnia was maintained, Qaw returned to baseline values. These data suggest that acute, graded hypoxic exposure does not significantly impact Qaw, however, the hypocapnia associated with mild hyperventilation reduces Qaw.

Albuterol Improves Alveolar‐Capillary Membrane Conductance in Healthy Humans

The Beta-2 adrenergic receptors (β2ARs) are located on alveolar cells and the pulmonary lymphatics and regulate lung fluid clearance through activation of epithelial sodium channels on the alveolar cells and through the relaxation of the lymphatic vessels. We sought to determine the influence of an inhaled β2-selective agonist on alveolar-capillary conductance (DM) and pulmonary capillary blood volume (Vc) in healthy humans. To determine this, we assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide before and every 15 minutes for one-hour following the administration of nebulized albuterol (2.5mg, diluted to 3ml) in 28 healthy subjects (age=28±5yrs, ht=171±14cm, wt=75±17kg, BMI=26±8kg/m2, values are mean±SD). Cardiac output (Q, determined via acetylene wash-in), heart rate (HR), stroke volume (SV), systemic vascular resistance (SVR), blood pressure (BP), and oxygen saturation (SaO2) were also assessed at baseline and following the administration of albuterol. Albuterol resulted in elevations in HR, Q, and SV as well as a drop in SVR (% change from baseline, HR=4±11, 4±8, 4±8, and 4±8%; Q=15±17, 12±17, 9±19, and 4±17%; SV= 24±32, 16±27, 11±28, and 14±23%; and SVR= −15±12, −12±16, −7±20, and −4±17, at 15, 30, 45, and 60 minutes post-albuterol, respectively, P-ANOVA<0.05), but no change in BP. There was no change in DLCO, a decrease in Vc and an increase in DM when assessed alone or when corrected for Vc (%change from baseline, Vc=5±37, −5±30, −12±35, and −20±26%, DM= 0±18, 1±18, 6±22, and 5±19%; DM/Vc=10±44, 17±48, 47±70, and 48±70%, at 15, 30, 45, and 60 minutes post-nebulization, respectively, p<0.05). These data suggest that the administration of albuterol improves alveolar-capillary conductance in healthy humans, despite a small decrease in pulmonary capillary blood volume.

Flat beer vs. physiological improvement: effect of acetazolamide during hypoxic exercise

Flat beer <i>vs.</i> physiological improvement: effect of acetazolamide during hypoxic exercise

Genetic variation of the β2-adrenergic receptor is associated with differences in lung fluid accumulation in humans

The beta2-adrenergic receptors (beta2AR) play an important role in lung fluid regulation. Previous research has suggested that subjects homozygous for arginine at amino acid 16 of the beta2AR (Arg16) may have attenuated receptor function relative to subjects homozygous for glycine at the same amino acid (Gly16). We sought to determine if the Arg16Gly polymorphism of the beta2AR influenced lung fluid balance in response to rapid saline infusion. We hypothesized that subjects homozygous for Arg at amino acid 16 (n=14) would have greater lung fluid accumulation compared with those homozygous for Gly (n=15) following a rapid intravenous infusion of isotonic saline (30 ml/kg over 17 min). Changes in lung fluid were determined using measures of lung density and tissue volume (computerized tomography imaging) and measures of pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (DM, determined from the simultaneous assessment of the diffusing capacities of the lungs for carbon monoxide and nitric oxide). The saline infusion resulted in elevated catecholamines in both genotype groups (Arg16 283+/-117% vs. Gly16 252+/-118%, P>0.05). The Arg16 group had a larger decrease in DM and increase in lung tissue volume and lung water after saline infusion relative to the Gly16 group (DM -13+/-14 vs. 0+/-26%, P<0.05; lung tissue volume 13+/-11 vs. 3+/-11% and lung water +90+/-66 vs. +48+/-144 ml, P=0.10, P<0.05, for Arg vs. Gly16, respectively, means+/-SD). These data suggest that subjects homozygous for Arg at amino acid 16 of the beta2AR have a greater susceptibility for lung fluid accumulation relative to subjects homozygous for Gly at this position.

Short-term hypoxic exposure at rest and during exercise reduces lung water in healthy humans

Hypoxia and hypoxic exercise increase pulmonary arterial pressure, cause pulmonary capillary recruitment, and may influence the ability of the lungs to regulate fluid. To examine the influence of hypoxia, alone and combined with exercise, on lung fluid balance, we studied 25 healthy subjects after 17-h exposure to 12.5% inspired oxygen (barometric pressure = 732 mmHg) and sequentially after exercise to exhaustion on a cycle ergometer with 12.5% inspired oxygen. We also studied subjects after a rapid saline infusion (30 ml/kg over 15 min) to demonstrate the sensitivity of our techniques to detect changes in lung water. Pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (D(M)) were determined by measuring the diffusing capacity of the lungs for carbon monoxide and nitric oxide. Lung tissue volume and density were assessed using computed tomography. Lung water was estimated by subtracting measures of Vc from computed tomography lung tissue volume. Pulmonary function [forced vital capacity (FVC), forced expiratory volume after 1 s (FEV(1)), and forced expiratory flow at 50% of vital capacity (FEF(50))] was also assessed. Saline infusion caused an increase in Vc (42%), tissue volume (9%), and lung water (11%), and a decrease in D(M) (11%) and pulmonary function (FVC = -12 +/- 9%, FEV(1) = -17 +/- 10%, FEF(50) = -20 +/- 13%). Hypoxia and hypoxic exercise resulted in increases in Vc (43 +/- 19 and 51 +/- 16%), D(M) (7 +/- 4 and 19 +/- 6%), and pulmonary function (FVC = 9 +/- 6 and 4 +/- 3%, FEV(1) = 5 +/- 2 and 4 +/- 3%, FEF(50) = 4 +/- 2 and 12 +/- 5%) and decreases in lung density and lung water (-84 +/- 24 and -103 +/- 20 ml vs. baseline). These data suggest that 17 h of hypoxic exposure at rest or with exercise resulted in a decrease in lung water in healthy humans.

Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure.

Chronic heart failure (CHF) may impair lung gas diffusion, an effect that contributes to exercise limitation. We investigated whether diffusion improvement is a mechanism whereby physical training increases aerobic efficiency in CHF. Patients with CHF (n = 16) were trained (40 min of stationary cycling, 4 times/wk) for 8 wk; similar sedentary patients (n = 15) were used as controls. Training increased lung diffusion (DlCO, +25%), alveolar-capillary conductance (DM, +15%), pulmonary capillary blood volume (VC, +10%), peak exercise O2 uptake (peak VO2, +13%), and VO2 at anaerobic threshold (AT, +20%) and decreased the slope of exercise ventilation to CO2 output (VE/VCO2, -14%). It also improved the flow-mediated brachial artery dilation (BAD, from 4.8 +/- 0.4 to 8.2 +/- 0.4%). These changes were significant compared with baseline and controls. Hemodynamics were obtained in the last 10 patients in each group. Training did not affect hemodynamics at rest and enhanced the increase of cardiac output (+226 vs. +187%) and stroke volume (+59 vs. +49%) and the decrease of pulmonary arteriolar resistance (-28 vs. -13%) at peak exercise. Hemodynamics were unchanged in controls after 8 wk. Increases in DlCO and DM correlated with increases in peak VO2 (r = 0.58, P = 0.019 and r = 0.51, P = 0.04, respectively) and in BAD (r = 0.57, P < 0.021 and r = 0.50, P = 0.04, respectively). After detraining (8 wk), DlCO, DM, VC, peak VO2, VO2 at AT, VE/VCO2 slope, cardiac output, stroke volume, pulmonary arteriolar resistance at peak exercise, and BAD reverted to levels similar to baseline and to levels similar to controls. Results document, for the first time, that training improves DlCO in CHF, and this effect may contribute to enhancement of exercise performance.