Exploring the sites and kinetics of bronchodilator response to β-2 agonists in asthma

Background We previously documented, in asthma patients, three different profiles of bronchodilation induced by short acting β-2 mimetics (SABA), characterized by dilation up to central, pre-acinar and intra-acinar airways assessed by ventilation distribution tests and associated with no change, increase and decrease of fractional exhaled nitric oxide (FENO) respectively. Aim To investigate the dynamics of these profiles over the entire SABA action period, assuming that airways bronchodilation could exhibit varying kinetics due to differences in the distribution of β-2 receptors in both the central and peripheral human airways. Methods FENO, FEV1, and the slope (S) of He and SF6 phase III (single-breath test) were measured in asthma patients before, and up to six hours after SABA inhalation (salbutamol 400µg). SHe and SSF6 decrease reflects pre- and intra-acinar obstruction relief respectively. Results 30 asthma patients (12F/18M, age: 45±18 years) were divided into groups with positive (NO+, n=9), negative (NO-, n=11) and no (NO=, n=10) FENO acute change. In the NO- group, FEV1 increased for up to four hours, whereas FENO, SHe and SF6 decreased in the early phase only. In stark contrast, in the NO+ group, FEV1 increased in the early phase only while the FENO increase and the SHe decrease lasted for up to four hours. Conclusion This study documents various profiles of SABA-induced bronchodilation in asthma patients, differing both by sites and dynamics of the bronchodilator process. So, detailed understanding of the bronchodilator effect of β2-agonists in asthma should not solely be limited to studying their impact on FEV1.

Effects of inspiratory pause on CO2 elimination and arterial Pco2 in acute lung injury

A high respiratory rate associated with the use of small tidal volumes, recommended for acute lung injury (ALI), shortens time for gas diffusion in the alveoli. This may decrease CO2 elimination. We hypothesized that a postinspiratory pause could enhance CO2 elimination and reduce PaCO2 by reducing dead space in ALI. In 15 mechanically ventilated patients with ALI and hypercapnia, a 20% postinspiratory pause (Tp20) was applied during a period of 30 min between two ventilation periods without postinspiratory pause (Tp0). Other parameters were kept unchanged. The single breath test for CO2 was recorded every 5 min to measure tidal CO2 elimination (VtCO2), airway dead space (VDaw), and slope of the alveolar plateau. PaO2, PaCO2, and physiological and alveolar dead space (VDphys, VDalv) were determined at the end of each 30-min period. The postinspiratory pause, 0.7 ± 0.2 s, induced on average <0.5 cmH2O of intrinsic positive end-expiratory pressure (PEEP). During Tp20, VtCO2 increased immediately by 28 ± 10% (14 ± 5 ml per breath compared with 11 ± 4 for Tp0) and then decreased without reaching the initial value within 30 min. The addition of a postinspiratory pause significantly decreased VDaw by 14% and VDphys by 11% with no change in VDalv. During Tp20, the slope of the alveolar plateau initially fell to 65 ± 10% of baseline value and continued to decrease. Tp20 induced a 10 ± 3% decrease in PaCO2 at 30 min (from 55 ± 10 to 49 ± 9 mmHg, P < 0.001) with no significant variation in PaO2. Postinspiratory pause has a significant influence on CO2 elimination when small tidal volumes are used during mechanical ventilation for ALI.

Single-breath test in lateral decubitus reflects function of single lungs grafted for interstitial lung disease

After single-lung transplantation (SLT) for emphysema, heterogeneity of ventilation distribution in the graft can be assessed by measuring the slope of the alveolar plateau, computed from a single-breath test, performed in lateral decubitus with this lung in the nondependent position. We tested the validity of this technique in patients with SLT for interstitial lung diseases (ILD). Twelve patients with SLT for ILD, 12 nontransplanted patients with ILD, and 10 healthy control subjects performed single-breath washouts in right and left lateral decubitus; nitrogen slope ( SN2) and the difference between SF6 and He slopes ( SSF6- SHe) were measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in both postures by computerized tomography. Slopes were unaffected by posture in normal control subjects and patients with ILD. On the other hand, SN2 and SSF6- SHe in transplant recipients were smaller with the graft in the nondependent than in the dependent position (0.366 ± 0.445 vs. 1.035 ± 0.498 for SN2; 0.094 ± 0.201 vs. 0.218 ± 0.277 for SSF6- SHe). Values of SN2 and SSF6- SHe obtained in the former position were similar to those obtained in normal controls, while values obtained in the latter position were similar to those obtained in nontransplanted patients with ILD. Computerized tomography studies with the graft in the nondependent position indicated that this lung contributed 82% of the volume expired below functional residual capacity. We conclude that, in patients with SLT for ILD, the slope of the alveolar plateau obtained with the graft in the nondependent position reflects heterogeneity of ventilation distribution in this lung.

Reduced pulmonary function in children with the Fontan circulation affects their exercise capacity

Most children with functionally univentricular hearts nowadays are treated surgically by creating a total cavopulmonary connection. In the resulting Fontan circulation, the venous return and the pulmonary arterial bed are coupled in series, bypassing the heart. This gives the potential for interaction between the abnormal circulation and function of the lungs. In this study, we investigated the pattern of impairment of pulmonary function, and its relation to decreased exercise capacity.We performed spirometry in 33 (85 percent) of 39 eligible Norwegian children, aged from 8 to 16, with a total cavopulmonary connection, along with whole body plethysmography, the carbon monoxide single breath test, and a peak treadmill exercise test. The single breath test showed a mean corrected diffusing capacity of 66.5 percent of predicted, giving a z score of minus 2.88. The mean residual volume measured by whole body plethysmography was 146.8 percent, equivalent to a z score of 2.46, whereas the mean residual volume measured by the single breath test was 102.4 percent of predicted, this being the same as a z score of 0.43. The mean peak treadmill exercise test was 70.0 percent of predicted, equivalent with a z score of minus 3.07. Mean forced vital capacity was 85.7 percent of predicted, the equivalent z score being minus 0.92. Lung function correlated with the peak treadmill exercise test.We have shown, therefore, that children with the Fontan circulation have reduced diffusing capacity, possibly caused by the abnormal circulation through the lungs. The difference between residual volume measured by plethysmography and the single breath test implies trapping of air. The correlation of parameters for lung function with peak consumption of oxygen during exercise indicates that the abnormalities of pulmonary function may affect physical capacity.

Single-breath test in lateral decubitus reflects function of single lungs grafted for emphysema

The slope of alveolar plateau for nitrogen derived from the single-breath test is useful to assess the function of bilateral lung grafts, but this technique is not applicable to patients with single-lung grafts due to the confounding influence of the native lung. We tested the hypothesis that the nitrogen slope measured in lateral decubitus with the graft in nondependent position may primarily reflect the distribution of ventilation in this lung. Fifteen patients with single-lung transplantation for emphysema, 10 healthy controls, and 7 patients with advanced emphysema performed single-breath washouts in right and left lateral decubitus; nitrogen slope was measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in the two postures by computerized tomography. Nitrogen slope was unaffected by posture in normal controls and emphysema patients. On the other hand, nitrogen slope in transplant recipients was invariably smaller, with the graft in nondependent vs. in dependent position. Values of nitrogen slope with the graft in nondependent position were similar to those obtained in normal controls but significantly smaller than those obtained in emphysema patients. Computerized tomography studies in this position indicated that the volume expired below functional residual capacity was exclusively contributed by the graft. We conclude that, in patients with single-lung transplantation for emphysema, 1) measuring nitrogen slope in lateral decubitus allows to distinguish between the graft and the native lung, and 2) nitrogen slope obtained with the graft in nondependent position reflects ventilation distribution in this lung.

Effect of pulmonary perfusion on the slopes of single-breath test of CO2

The objective of this study was to evaluate the effects of lung perfusion on the slopes of phases II ( SII) and III ( SIII) of a single-breath test of CO2 (SBT-CO2). Fourteen patients submitted to cardiac surgery were studied during weaning from cardiopulmonary bypass (CPB). Pump flow was decreased in 20% steps, from 100% (total CPB = 2.5 l·min−1·m−2) to 0%. This maneuver resulted in a progressive and opposite increase in pulmonary blood flow (PBF) while maintaining ventilator settings constant. SBT-CO2, respiratory, and hemodynamic variables remained unchanged before and after CPB, reflecting a constant condition at those stages. SIII was similar before and after CPB (19.6 ± 2.8 and 18.7 ± 2.1 mmHg/l, respectively). SIII was lowest during 20% PBF (8.6 ± 1.9 mmHg/l) and increased in proportion to PBF until exit from CPB (15.6 ± 2.2 mmHg/l; P < 0.05). Similarly, SII and the CO2 area under the curve increased from 163 ± 41 mmHg/l and 4.7 ± 0.6 ml, respectively, at 20% PBF to 313 ± 32 mmHg/l and 7.9 ± 0.6 ml ( P < 0.05) at CPB end. When SII and SIII were normalized by the mean percent expired CO2, they remained unchanged during the protocol. In summary, the changes in PBF affect the slopes of the SBT-CO2. Normalizing SII and SIII eliminated the effect of changes in the magnitude of PBF on the shape of the SBT-CO2 curve.

Respiratory and circulatory activities in carotid body-resected humans

The respiratory and circulatory activities of patients who underwent carotid body resection (CBR) more than two decades ago were reviewed. No significant ventilatory response to continuous hypoxia was observed. However, in response to stimulation of peripheral chemoreceptors, transient hyperventilation occurred before hypoxemic blood arrived at the central nervous system (single-breath test), which indicated the presence of weak peripheral chemosensitivity. Because of this slight residual peripheral chemosensitivity, which was found shortly after the operation and apparently remained more or less unchanged for greater than 20 years, peripheral chemoreceptor activity, which has been reported in other animal species, does not seem to have returned. Delayed hypoxic hyperventilation reported in dogs and cats with CBR was not observed. Hypoxia significantly depressed the ventilatory response to CO2, but the delayed ventilatory depression with time that has been demonstrated in normal subjects did not occur. In our circulatory studies, hypoxia augmented the heart rate and slightly depressed the stroke volume and total peripheral resistance in the systemic circulation but induced no appreciable changes in arterial blood pressure or cardiac output. We used these results to partition the relative contributions to the overall circulatory response of carotid body stimulation, pulmonary inflation, and other modifying influences. From these calculations, it was inferred that the carotid body reflex plays a dominant role in vascular activities whereas the pulmonary inflation reflex dominates in cardiac activities in humans.