Alveolar-capillary Membrane 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.

Mechanisms of gas transfer impairment utilizing nitric oxide following severe COVID-19 pneumonitis.

Reduced carbon monoxide diffusing capacity (DLCO ) is common after recovery from severe COVID-19 pneumonitis. The extent to which this relates to alveolar membrane dysfunction as opposed to vascular injury is uncertain. Simultaneous measurement of nitric oxide diffusing capacity (DLNO ) and DLCO can partition gas diffusion into its two components: alveolar-capillary membrane conductance (DmCO ) and capillary blood volume (VC ). We sought to evaluate DmCO and VC in the early and later recovery periods after severe COVID-19. Patients attended for post-COVID-19 clinical review and lung function testing including DLNO /DLCO . Repeat testing occurred when indicated and comparisons made using t-tests. Forty-nine (eight female) subjects (mean ± SD age: 58 ± 13, BMI: 34 ± 8) who had severe COVID-19 pneumonitis, WHO severity classification of 6 ± 1, and prolonged (21 ± 22 days) hospital stay, were assessed 2 months (61 ± 35 days) post discharge. DLCO adj (z-score -1.70 ± 1.49, 25/49 < lower limit of normal [LLN]) and total lung capacity (z-score -1.71 ± 1.30) were both reduced. DmCO and VC and were reduced to a similar extent (z-score -1.19 ± 1.05 and -1.41 ± 1.20, p = 0.4). Seventeen (one female) patients returned for repeat testing 4 months (122 ± 61 days) post discharge. In this subgroup with more impaired lung function, DLCO adj improved but remained below LLN (z-score -3.15 ± 0.83 vs. -2.39 ± 0.86, p = 0.01), 5/17 improved to >LNN. DmCO improved (z-score -2.05 ± 0.89 vs. -1.41 ± 0.78, p = 0.01) but VC was unchanged (z-score -2.51 ± 0.55 vs. -2.29 ± 0.59, p = 0.16). Alveolar membrane conductance is abnormal in the earlier recovery phase following severe COVID-19 but significantly improves. In contrast, reduced VC persists. These data raise the possibility that persisting effects of acute vascular injury may contribute to gas diffusion impairment long after severe COVID-19 pneumonitis.

Effects of exercise on thoracic blood volumes, lung fluid accumulation, and pulmonary diffusing capacity in heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) experience symptoms of exertional dyspnea that may be related to lung fluid accumulation during exercise. A computed tomography (CT)-based method was used to measure exercise-induced changes in extravascular lung fluid content and thoracic blood volumes and to determine the effect of lung fluid on lung diffusing capacity for carbon monoxide (DLCO) in stable subjects with HFpEF and healthy controls. Nine subjects with HFpEF (age = 68 ± 8 yr; body mass index = 32.1 ± 2.6 kg/m2) and eight healthy controls (62 ± 9 yr, 23.8 ± 2.4 kg/m2) performed triplicate rebreathe DLCO/DLNO (lung diffusing capacity for nitric oxide) tests in a supine position at rest and duplicate measurements during two 5-min submaximal exercise stages (15W and 35W) and recovery. Subjects subsequently performed a 5-min exercise bout (35W) inside a CT scanner, and extravascular lung fluid content and thoracic blood volumes were quantified at rest and immediately following exercise from thoracic and contrast perfusion scans, respectively. Subjects with HFpEF had a higher lung fluid content at rest compared with controls (means ± SD, HFpEF: 14.4 ± 1.7%, control: 12.8 ± 1.7%, P = 0.043) and a higher lung fluid content following exercise (15.2 ± 2.0% vs. 12.6 ± 1.5%, P = 0.009). Higher lung fluid content was associated with a lower DLCO and alveolar-capillary membrane conductance (Dm) in subjects with HFpEF (DLCO: R = -0.57, P = 0.022, Dm: R = -0.61, P = 0.012) but not in controls. Pulmonary blood volume was not altered by exercise and was similar between groups. Submaximal exercise elicited a greater accumulation of lung fluid in subjects with HFpEF compared with in controls, and lung fluid content was negatively correlated with lung diffusing capacity and alveolar-capillary membrane conductance in subjects with HFpEF.

Relationship Between Lung Diffusion And Exercise Capacity In Heart Failure With Preserved Ejection Fraction

PURPOSE: Patients with heart failure with preserved ejection fraction (HFpEF) have impaired lung diffusion (DL) at rest and during exercise which may contribute to a reduced exercise capacity. However, it is unclear whether these impairments are solely due to alterations in pulmonary hemodynamics or related to other cardiopulmonary factors which may impair oxygen uptake such as the inability to recruit lung surface area. Therefore this study examined simultaneous measurements of DL for carbon monoxide (DLCO) and nitric oxide (DLNO), which allows for partitioning of DL into its alveolar-capillary membrane (Dm) and pulmonary capillary blood volume (Vc) components, to better understand the relationship between exertional changes in lung diffusion and exercise capacity. METHODS: HFpEF patients (N=17, age=62±9y, BMI=36±8kg/m2) undergoing exercise right heart catheterization performed simultaneous rebreathe DLCO/NO tests at rest and during each stage of incremental supine cycling exercise, and membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were calculated. Breath-by-breath pulmonary gas exchange was recorded throughout rest and exercise. RESULTS: All patients were hemodynamically diagnosed with HFpEF (pulmonary capillary wedge pressure >15 at rest and/or >25 mmHg during exercise). Overall lung and alveolar-capillary membrane diffusion increased from rest to peak exercise (DLCO: 11.8±4.0 to 16.2±7.4 ml/min/mmHg, DLNO: 33.1±11.5 to 48.4±21.9 ml/min/mmHg, Dm: 18.9±7.2 to 28.3±13.1 ml/min/mmHg; p’s<0.01). The change in DL was related to exercise capacity (change in DLCO vs. peak VO2: R=0.69, p<0.01, change in DLNO vs. peak VO2: R=0.65, p<0.01) and this was primarily driven by changes in Dm (change in Dm vs. peak VO2: R=0.63, p<0.01) but not Vc (change in Vc vs. peak VO2: R=0.15, p=0.582). CONCLUSIONS: These data highlight that a limited increase in lung diffusion and alveolar-capillary membrane conductance during exercise are associated with a lower VO2 peak in HFpEF patients. In addition to hemodynamic constraints previously reported in HFpEF, an inability to recruit lung surface area during exercise may also contribute to the reduced exercise capacity in these patients.

Effects of intrathoracic pressure, inhalation time, and breath hold time on lung diffusing capacity

The single breath hold maneuver for measuring lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) incorporates multiple sources of variability. This study examined how changes in intrathoracic pressure, inhalation time, and breath hold time affect DLCO, DLNO, alveolar-capillary membrane conductance (DmCO) and pulmonary capillary blood volume (Vc) at rest and during submaximal exercise. Thirteen healthy subjects (mean ± SD; age = 26 ± 3y) performed duplicate tests at rest and during submaximal exercise.DLCO and Vc were lower with a positive versus negative intrathoracic pressure during the breath hold at rest (DLCO: 22.2 ± 5.5 vs. 22.7 ± 5.5 ml/min/mmHg, p = 0.028; Vc: 46.5 ± 11.6 vs. 48.2 ± 11.7 ml, p = 0.018). However, during exercise, DLCO and Vc were higher with positive versus negative pressure (DLCO: 26.7 ± 5.5 vs. 25.7 ± 5.7 ml/min/mmHg, p = 0.014; Vc: 56.2 ± 12.6 vs. 53.9 ± 13.1 ml, p = 0.039). The inhalation time did not significantly affect DLCO, DLNO, DmCO or Vc.Short breath hold times (<4s) may yield high DLNO/DLCO ratios and non-physiologic DmCO values. The single breath hold maneuver is useful for evaluating gas transfer at rest and during exercise, however intrathoracic pressure, inhalation time, and breath hold time should be kept consistent between repeated tests.

Interstitial lung fluid balance in healthy lowlanders exposed to high-altitude

We aimed to assess lung fluid balance before and after gradual ascent to 5150m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11±10%) and Day 9 (10±9%) vs. sea-level (P≤0.047). DmCO increased from sea-level to Day 1 (9±6%), Day 5 (12±8%), and Day 9 (17±11%) (all P≤0.001) at EBC. There was no change in ULCs from sea-level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea-level following 8days of gradual exposure to high-altitude in healthy humans.

The blood transfer conductance for nitric oxide: Infinite vs. finite θNO

Whether the specific blood transfer conductance for nitric oxide (NO) with hemoglobin (θNO) is finite or infinite is controversial but important in the calculation of alveolar capillary membrane conductance (DmCO) and pulmonary capillary blood volume (VC) from values of lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). In this review, we discuss the background associated with θNO, explore the resulting values of DmCO and VC when applying either assumption, and investigate the mathematical underpinnings of DmCO and VC calculations. In general, both assumptions yield reasonable rest and exercise DmCO and VC values. However, the finite θNO assumption demonstrates increasing VC, but not DmCO, with submaximal exercise. At relatively high, but physiologic, DLNO/DLCO ratios both assumptions can result in asymptotic behavior for VC values, and under the finite θNO assumption, DmCO values. In conclusion, we feel that the assumptions associated with a finite θNO require further in vivo validation against an established method before widespread research and clinical use.

Effect of β2-adrenergic receptor stimulation on lung fluid in stable heart failure patients

The purpose of this study was to determine: (1) whether stable heart failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) when compared with healthy control subjects; and (2) the effect of acute β2-adrenergic receptor (β2AR) agonist inhalation on lung fluid balance. Twenty-two stable HFrEF patients and 18 age- and gender-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), pulmonary capillary blood volume (Vc) (via re-breathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 minutes after administration of nebulized albuterol. EVLW was derived as Vtis - Vc. Before administration of albuterol, Vtis and EVLW were higher in HFrEF vs control (998 ± 200 vs 884 ± 123 ml, p = 0.041; and 943 ± 202 vs 802 ± 133 ml, p = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF patients (-4.6 ± 7.8%, p = 0.010; -4.6 ± 8.8%, p = 0.018) and control subjects (-2.8 ± 4.9%, p = 0.029; -3.0 ± 5.7%, p = 0.045). There was an inverse relationship between pre-albuterol values and pre- to post-albuterol change for EVLW (r2 = -0.264, p = 0.015) and DmCO (r2 = -0.343, p = 0.004) in HFrEF only. Lung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of β2ARs may cause fluid removal in HFrEF, especially in patients with greater evidence of increased lung water at baseline.

Impaired Pulmonary Diffusion in Heart Failure With Preserved Ejection Fraction

ObjectivesThe purpose of this study was to compare measures of gas exchange at rest and during exercise in patients with heart failure and preserved ejection fraction (HFpEF) with age- and sex-matched control subjects. BackgroundPatients with HFpEF display elevation in left heart pressures, but it is unclear how this affects pulmonary gas transfer or its determinants at rest and during exercise. MethodsPatients with HFpEF (n = 20) and control subjects (n = 26) completed a recumbent cycle ergometry exercise test with simultaneous measurement of ventilation and gas exchange. Diffusion of the lungs for carbon monoxide (DLCO) and its subcomponents, pulmonary capillary blood volume (VC) and alveolar-capillary membrane conductance (DM), were measured at rest, and matched for low-intensity (20 W) and peak exercise. Stroke volume was measured by transthoracic echocardiography to calculate cardiac output. ResultsCompared with control subjects, patients with HFpEF displayed impaired diastolic function and reduced exercise capacity. Patients with HFpEF demonstrated a 24% lower DLCO at rest (11.0 ± 2.3 ml/mm Hg/min vs. 14.4 ± 3.3 ml/mm Hg/min; p < 0.01) related to reductions in both DM (18.1 ± 4.9 ml/mm Hg/min vs. 23.1 ± 9.1 ml/mm Hg/min; p = 0.04), and VC (45.9 ± 15.2. ml vs. 58.9 ± 16.2 ml; p = 0.01). DLCO was lower in patients with HFpEF compared with control subjects in all stages of exercise, yet its determinants showed variable responses. With low-level exercise, patients with HFpEF demonstrated greater relative increases in VC, coupled with heightened ventilatory drive and more severe symptoms of dyspnea compared with control subjects. At 20-W exercise, DM was markedly reduced in patients with HFpEF compared with control subjects. From 20 W to peak exercise, there was no further increase in VC in patients with HFpEF, which in tandem with reduced DM, led to a 30% reduction in DLCO at peak exercise (17.3 ± 4.2 ml/mm Hg/min vs. 24.7 ± 7.1 ml/mm Hg/min; p < 0.01). ConclusionsSubjects with HFpEF display altered pulmonary function and gas exchange at rest and especially during exercise, which contributes to exercise intolerance. Novel therapies that improve gas diffusion may be effective to improve exercise tolerance in patients with HFpEF.

Relationship Between The Change In DLCO With Albuterol And The Change In DLCO With Exercise

Stimulation of the Beta2 Adrenergic Receptors (B2AR) induces lung fluid clearance through Epithelial Sodium channels (ENaC) on alveolar cells. We previously demonstrated that both albuterol and exercise increase the diffusing capacity of the lung (DLCO), alveolar-capillary membrane conductance (DM), and DM corrected for pulmonary capillary blood volume (Vc)(DM/Vc). The improvement in diffusing capacity with exercise could be a direct result of B2AR stimulation or simply an increase in lymphatic drainage due to augmentations in tidal volume (Vt) and minute ventilation (VE). PURPOSE: To investigate the relationship of the change in DLCO (and components, DM and Vc) with albuterol and the change in DLCO and components with exercise to determine B2AR involvement. METHODS: Healthy participants (N=30) completed a maximal VO2 test for baseline capacity, followed by 2 visits measuring lung diffusing capacity for carbon monoxide and nitric oxide, and functional ventilatory parameters. Measurements were taken at rest and 30-minutes post-albuterol administration or at peak exercise. RESULTS: At rest and at peak exercise there were significant relationships in DLCO, DM, and DM/Vc between the albuterol visit and the exercise visit (DLCO: r=0.90 and 0.78, DM: r=0.77 and 0.67, DM/Vc: r=0.58 and 0.48 for rest and peak exercise, respectively, p<0.05 for all). Exercise resulted in a significant increase in DLCO and DM, when compared to albuterol (DLCO=45±16% vs. 0.78±7.6%, DM=40±24% vs. 2.8±13% for exercise and albuterol, respectively, p<0.05). There was no relationship between changes in DLCO and DM with albuterol when compared to changes with exercise, but the change in DM/Vc under the two conditions was trending towards significance (r=0.35, DM/Vc=11.5±8.3% and DM/Vc=6.4±5.2% for exercise and albuterol, respectively, p=0.06). There was a significant relationship (p<0.05) between the change in Vt and DLCO with exercise, but not with albuterol. CONCLUSIONS: The relationship between lung diffusion parameters at peak exercise and following beta-agonist stimulation suggest that at least a portion of this increase is mediated by the B2AR. However, DLCO, considered to be a gross measure of the components of lung diffusion, is influenced by changes in ventilation with exercise. Supported by NIH Grant RO1 HL108962-05.

Type 1 Diabetes Duration Decreases Pulmonary Diffusing Capacity during Exercise

Background: Diabetes damages peripheral tissues; however, its effects on the lung are less known. Lung diffusing capacity (D_LCO) is influenced by alveolar-capillary membrane conductance (D_M) and pulmonary capillary blood volume (V_C), both of which are reduced in adults with type 1 diabetes (T1D). Objective: We sought to determine if diabetes duration affects D_LCO, D_M, V_C, and cardiac output (Q). Methods: 24 T1D patients (10.7-52.8 years) and 24 non-diabetic controls were recruited and had D_LCO, D_M, V_C, and Q measured at rest and during exercise (40, 70 and 90% VO₂max). Results: When stratified into two groups based on age (young, <20.6 years old), there were no significant differences in D_LCO, D_M, V_C, or Q (all of which were normalized to body surface area [BSA]) in the young group or in the old group. When stratified by diabetes duration (short duration, 0.33-8.9 years vs. long duration, 9.6-28 years), the T1D patients in the long duration group had lower D_LCO/BSA and D_M/BSA compared to the controls (p < 0.05). There were no differences in any of the variables in the short duration group. Conclusions: This study has shown that duration of diabetes is associated with decrements in diffusing capacity and its components.

Albuterol Improves Alveolar-Capillary Membrane Conductance in Healthy Humans.

BACKGROUNDBeta-2 adrenergic receptors (β2ARs) are located throughout the body including airway and alveolar cells. The β2ARs regulate lung fluid clearance through a variety of mechanisms including ion transport on alveolar cells and relaxation of the pulmonary lymphatics. We examined the effect of an inhaled β2-agonist (albuterol) on alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (VC) in healthy humans.METHODSWe assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) at baseline, 30 minutes, and 60 minutes following nebulized albuterol (2.5 mg, diluted in 3 mL normal saline) in 45 healthy subjects. Seventeen subjects repeated these measures following nebulized normal saline (age = 27 ± 9 years, height = 165 ± 21 cm, weight = 68 ± 12 kg, BMI = 26 ± 9 kg/m2). Cardiac output (Q), heart rate, systemic vascular resistance (SVR), blood pressure, oxygen saturation, forced expiratory volume at one-second (FEV1), and forced expiratory flow at 50% of forced vital capacity (FEF50) were assessed at baseline, 30 minutes, and 60 minutes following the administration of albuterol or saline.RESULTSAlbuterol resulted in a decrease in SVR, and an increase in Q, FEV1, and FEF50 compared to saline controls. Albuterol also resulted in a decrease in VC at 60 minutes post albuterol. Both albuterol and normal saline resulted in no change in DLCO or DM when assessed alone, but a significant increase was observed in DM when accounting for changes in VC.CONCLUSIONThese data suggest that nebulized albuterol improves pulmonary function in healthy humans, while nebulization of both albuterol and saline results in an increase in DM/VC.

Pulmonary capillary reserve and exercise capacity at high altitude in healthy humans.

PurposeWe determined whether well-acclimatized humans have a reserve to recruit pulmonary capillaries in response to exercise at high altitude.MethodsAt sea level, lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary capillary blood volume (Vc) were measured at rest before maximal oxygen consumption (dot{V}{text{O}}_{2hbox{max} }) was determined in seven adults. Then, DLCO, DmCO and Vc were measured pre- and post-exhaustive incremental exercise at 5150 m after ~40 days of acclimatization.ResultsImmediately after exercise at high altitude, there was an increase in group mean DmCO (14 ± 10 %, P = 0.040) with no pre- to post-exercise change in group mean DLCO (46.9 ± 5.8 vs. 50.6 ± 9.6 ml/min/mmHg, P = 0.213) or Vc (151 ± 28 vs. 158 ± 37 ml, P = 0.693). There was, however, a ~20 % increase in DLCO from pre- to post-exercise at high altitude (51.2 ± 0.2 vs. 61.1 ± 0.2 ml/min/mmHg) with a concomitant increase in DmCO (123 ± 2 vs. 156 ± 4 ml/min/mmHg) and Vc (157 ± 3 vs. 180 ± 8 ml) in 2 of the 7 participants. There was a significant positive relationship between the decrease in dot{V}{text{O}}_{2hbox{max} } from sea level to high altitude and the change in DLCO and lung diffusing capacity for nitric oxide (DLNO) from rest to end-exercise at high altitude.ConclusionThese data suggest that recruitment of the pulmonary capillaries in response to exercise at high altitude is limited in most well-acclimatized humans but that any such a reserve may be associated with better exercise capacity.

Optimizing the calculation of DM,CO and VC via the single breath single oxygen tension DLCO/NO method

Alveolar-capillary membrane conductance (DM,CO) and pulmonary-capillary blood volume (VC) are calculated via lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) using the single breath, single oxygen tension (single-FiO2) method. However, two calculation parameters, the reaction rate of carbon monoxide with blood (θCO) and the DM,NO/DM,CO ratio (α-ratio), are controversial. This study systematically determined optimal θCO and α-ratio values to be used in the single-FiO2 method that yielded the most similar DM,CO and VC values compared to the ‘gold-standard’ multiple-FiO2 method. Eleven healthy subjects performed single breath DLCO/DLNO maneuvers at rest and during exercise. DM,CO and VC were calculated via the single-FiO2 and multiple-FiO2 methods by implementing seven θCO equations and a range of previously reported α-ratios. The RP θCO equation (Reeves, R.B., Park, H.K., 1992. Respiration Physiology 88 1–21) and an α-ratio of 4.0–4.4 yielded DM,CO and VC values that were most similar between methods. The RP θCO equation and an experimental α-ratio should be used in future studies.

Influence of lung volume, fluid and capillary recruitment during positional changes and exercise on thoracic impedance in heart failure

It is unclear how dynamic changes in pulmonary–capillary blood volume (Vc), alveolar lung volume (derived from end-inspiratory lung volume, EILV) and interstitial fluid (ratio of alveolar capillary membrane conductance and pulmonary capillary blood volume, Dm/Vc) influence lung impedance (ZT). The purpose of this study was to investigate if positional change and exercise result in increased EILV, Vc and/or lung interstitial fluid, and if ZT tracks these variables. Methods12 heart failure (HF) patients underwent measurements (ZT, EILV, Vc/Dm) at rest in the upright and supine positions, during exercise and into recovery. Inspiratory capacity was obtained to provide consistent measures of EILV while assessing ZT. ResultsZT increased with lung volume during slow vital capacity maneuvers (p<0.05). Positional change (upright→supine) resulted in an increased ZT (p<0.01), while Vc increased and EILV and Dm/Vc decreased (p<0.05). Moreover, during exercise Vc and EILV increased and Dm/Vc decreased (p<0.05), whereas, ZT did not change significantly (p>0.05). ConclusionImpedance appears sensitive to changes in lung volume and body position which appear to generally overwhelm small acute changes in lung fluid when assed dynamically at rest or during exercise.

Confusion in reporting pulmonary diffusing capacity for nitric oxide and the alveolar-capillary membrane conductance for nitric oxide

We read with interest the paper by Magini and col- leagues on the measurement of pulmonary diffusing capacity for nitric oxide in patients with heart failure (ejection fraction<40%). 1 In their study they report pulmonary diffusing capacity and the individual com- ponents of pulmonary diffusing capacity in 50 patients with heart failure (65 years of age), and 50 control sub- jects (61 years of age). We feel that there are two prob- lems with this paper that warrant discussion. First, the mean values for pulmonary diffusing capacity for nitric oxide (DLNO) for the healthy subjects are too low, and second, both their alveolar-membrane conductances (DmNO and DmCO) and pulmonary capillary blood volume (Vc) calculations, and hence conclusions, are incorrect. First, the values for DLNO for the healthy volunteers appear too low. If we assume that the women's and men's mean height in the healthy volunteers was 163 and 173 cm, respectively, then the mean DLNO values should be 96-113 and 140-154 ml/min/mm Hg, for women and men, respectively. 2,3 The combined average for DLNO should be then 118-133 ml/min/mm Hg. The author's mean values of 89 ml/min/mm Hg for the healthy volunteers are 25-33% lower than predicted. However, their values for pulmonary diffusing capacity for carbon monoxide (DLCO) were correct and the healthy volunteers was close to 100% of that pre- dicted. 2,3 Thus, if the mean DLNO in the control group is under-predicted by at least 25%, then the DLNO values in the heart failure patients could be under predicted by � 25% too. Since DLNO and DLCO are measured simultaneously, and DLCO values were appropriate (close to 100% of those predicted), there must be some mathematical error in the calcula- tion of DLNO and/or their breath-hold time was

Reply to commentary on: Confusion in reporting pulmonary diffusion capacity for nitric oxide and the alveolar-capillary membrane conductance for nitric oxide

We read with interest the commentary by Gerald Zavorsky and Colin Borland on our paper on lung diffusion for nitric oxide (DLNO) vs lung diffusion for carbon monoxide (DLCO) in normal subjects and in patients with heart failure. Both authors are worldwide recognised experts. We are therefore indebted with them for the time and thought they gave to our work. The criticisms that they raise are both methodological and physiological. Indeed, DLNO measurement for clinical purposes has been introduced only a few years ago since the commercial apparatus has been available. Studies about simultaneous DLNO/DLCO evaluation have been conducted with different analysers and different NO concentrations so the method is still far from being standardised. However, we recognise that our DLNO values in normal subjects, obtained in a sizeable number of subjects, are lower than those previously reported by Zavorsky et al. In any case the apparatus we used (Jaeger/Vyasis PFT Masterscreen) was calibrated for gas analysis using automated procedures and the linearity of analysers was factory checked. The formula used is:

The effect of increased physical activity on pulmonary diffusing capacity in unfit women

The purpose of the study was to determine whether short-term high-intensity aerobic interval training improves resting pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO). Twenty-eight sedentary women [mean (SD) age 32(11)years, body mass index 24.3(5.7)kgm(-2)] were randomly assigned to either a self-directed moderate-intensity physical activity (n=14) group or a supervised high-intensity aerobic interval training group (n=14). The moderate physical activity group and the aerobic interval training group increased weekly physical activity energy expenditure by 800 and 1600kcalweek(-1), respectively. After 6weeks, aerobic capacity increased to a similar exent in both groups (mean improvement8%, effect size0.39). The DLNO, but not DLCO, increased to a similar extent in both groups, by 4% or 3.0(5.7) [95% confidence interval 0.8, 5.2]mlmin(-1)mmHg(-1)m(-2) from pre- to post-training (effect size0.27). There was no correlation between the change in aerobic capacity and the change in DLNO (P>0.05) or between the change in aerobic capacity and the change in total weekly physical activity energy expenditure (P>0.05). Interval training does not provide additional improvements in DLNO or aerobic capacity compared with self-directed moderate-intensity physical activity (4-6metabolic equivalent tasks, 800kcalweek(-1), for 6weeks) in unfit women. Despite the slight improvement in both DLNO and aerobic capacity, true meaningful physiological changes in these parameters remain questionable.

Mechanisms for reduced pulmonary diffusing capacity in haematopoietic stem-cell transplantation recipients

Lung diffusing capacity for CO (DLCO) is compromised in haematopoietic stem-cell transplantation (HSCT) recipients. We derived alveolar–capillary membrane conductance (DM,CO) and pulmonary capillary volume (VC) from DLCO and diffusing capacity for NO (DLNO). Forty patients were studied before and 6 weeks after HSCT. Before HSCT, DLNO and DLCO were significantly lower than in 30 healthy controls. DM,CO was ∼40% lower in patients than in controls (p<0.001), whereas VC did not differ significantly. After HSCT, DLNO and DM,CO further decreased, the latter by ∼22% from before HSCT (p<0.01) while VC did not change significantly. Lung density, serum CRP and reactive oxygen metabolites were significantly increased, with the latter being correlated (R2=0.71, p<0.001) with the decrement in DLNO. We conclude that DLNO and, to a lesser extent, DLCO are compromised before HSCT mainly due to a DM,CO reduction. A further reduction of DM,CO without VC loss occurs after HSCT, possibly related to development of oedema, or interstitial fibrosis, or both.

Abstract 18573: Genetic Variation of the Alpha-Subunit of the Epithelial Sodium Channel Influences the Lung Fluid Response to Hypoxia in Healthy Humans

Cardiogenic pulmonary edema is a life-threatening complication in patients with heart failure (HF) resulting from increased alveolar Cl- secretion and inhibition of alveolar epithelial Na+ channels (ENaC). Not all HF patients develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic component to edema formation in response to cardiac failure. The ENaC are crucial for alveolar fluid clearance, with the alpha subunit demonstrating particular importance. We have previously found that genetic variation of the alpha subunit (SCNN1A) of ENaC, an alanine (A) to threonine (T) substitution, influences ion regulation during exercise and in response to albuterol. In the present study, we sought to determine the influence of the threonine variant (T663; AT/TT group) on lung fluid regulation in response to normobaric hypoxia, an environmental condition known to increase pulmonary capillary hydrostatic stress in healthy humans. Lung ion and fluid changes were assessed using exhaled Na+ (ENa+) and the lung diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar-capillary membrane conductance (DM). 19 healthy subjects (n=8 vs. 11, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m2 , for AA and AT/TT, respectively) completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo (P) or inhaled amiloride (Aml, 1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa+, DLCO, and DM assessed at baseline and following 12 hours of hypoxic exposure. There was an effect of genotype on the ENa+ response to hypoxia with placebo that was abolished with amiloride, but no effect of genotype on the diffusing capacity of the lung (Table). These results suggest that genetic variation of SCNN1A may influence ion regulation in the lung under conditions of elevated hydrostatic stress.