Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.

RATIONALE: Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV). OBJECTIVES: To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma. METHODS: Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O2) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sVlow) and the remaining lung (sVhigh) were quantified and compared. MEASUREMENTS AND MAIN RESULTS: In the sVlow region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O2 conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sVlow region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O2 conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sVlow subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sVlow subregions that were hyperoxic under 80% O2 conditions. CONCLUSIONS: HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.

Peripheral lung function in patients with stable and unstable asthma.

BACKGROUND: Exacerbations of asthma are thought to be caused by airflow obstruction resulting from airway inflammation, bronchospasm, and mucus plugging. Histologic evidence suggests the small airways, including acinar air spaces, are involved; however, this has not been corroborated in vivo by measurements of peripheral small-airway function. OBJECTIVE: We sought to determine whether asthma severity is linked to small-airway function, particularly in patients with acute severe asthma. METHODS: Eighteen subjects admitted for an asthma exacerbation underwent lung function testing, including measures of acinar ventilation heterogeneity (S(acin)) and conductive ventilation heterogeneity (S(cond)) using the multiple-breath nitrogen washout. Treatment requirement was defined according to Global Initiative for Asthma scores. Data were compared with those obtained in 19 patients with stable asthma. RESULTS: For the asthma exacerbation group, the median FEV1 was 59% of predicted value (95% CI, 45% to 75% of predicted value), the median S(cond) value was 185% of predicted value (95% CI, 119% to 245% of predicted value), and the median S(acin) value was 225% of predicted value (95% CI, 143% to 392% of predicted value). FEV1 (percent predicted) was correlated with S(acin) (percent predicted) values (Spearman rho = -0.67, P = .006) but not with S(cond) (percent predicted) values (P > .1). The Global Initiative for Asthma score was significantly related to S(acin) (percent predicted) (Spearman rho = 0.59, P = .016) but not to S(cond) (percent predicted) values (P > .1). The unstable group was characterized by considerably lower forced vital capacity (P < .001) and higher S(cond) (P = .001) values than the unstable group. In a subgroup of 11 unstable patients who could be reviewed after 4 weeks, FEV1, forced vital capacity, S(acin), and S(cond) values showed marked improvements. CONCLUSION: Our findings suggest that unstable asthma is characterized by a combined abnormality in the acinar and conductive lung zones, both of which are partly reversible. Functional abnormality in the acinar lung zone in particular showed a direct correlation with airflow obstruction and treatment requirement in patients with acute severe asthma.

Mechanism underlying accelerated arterial oxygen desaturation during recurrent apnea.

RATIONALE: Brief recurrent apneas in preterm infants and adults can precipitate rapid and severe arterial O(2) desaturation for reasons that remain unclear. OBJECTIVES: We tested a mathematically derived hypothesis that when breathing terminates apnea, mixed-venous hypoxemia continues into the subsequent apnea; as a result, there is a surge in pulmonary O(2) uptake that rapidly depletes the finite alveolar O(2) store, thereby accelerating arterial O(2) desaturation. METHODS: Recurrent apneas were simulated in an experimental lamb model. Pulmonary O(2) uptake was calculated from continuously measured arterial and mixed-venous O(2) saturation and cardiac output. MEASUREMENTS AND MAIN RESULTS: Direct measurements revealed that asynchrony in the desaturation and resaturation of arterial and venous blood gave rise to dips and surges in O(2) uptake. After desaturation to 50%, a typical nadir in preterm infants, O(2) uptake surged to a peak of 176.9 ± 7.8% of metabolic rate. During subsequent apneas, desaturation rate was increased two- to threefold greater than during isolated apneas, in direct proportion to the magnitude of the surge in O(2) uptake (P < 0.001; R(2) = 0.897). Application of our mathematical model to a published recording of cyclic apneas in a preterm infant precisely reproduced the accelerated desaturation rates of up to 15% · s(-1) observed clinically. CONCLUSIONS: Rapid depletion of alveolar O(2) stores by surges in O(2) uptake almost completely explains the acceleration of desaturation that occurs during recurrent apnea. This powerful mechanism is likely to explain the severity of intermittent hypoxemia that is associated with neurocognitive and cardiovascular morbidities in preterm infants and adults.

PET Imaging Reveals Early Pulmonary Perfusion Abnormalities in HIV Infection Similar to Smoking.

Chronic obstructive pulmonary disease (COPD) is the most common noninfectious pulmonary disease among people living with HIV, independent of smoking. However, the cause for this enhanced susceptibility remains unclear, and the effects of HIV on pulmonary perfusion and ventilation are unknown. Methods: We used PET/CT in 46 smokers and nonsmokers, 23 of whom had documented HIV infection. Emphysema was assessed by CT and perfusion by 13N (13NN) PET scans. After removal of image noise, vertical and axial gradients in perfusion were calculated. We tested for differences in the total spatial heterogeneity of perfusion (CV2Qtotal) and its components (CV2Qtotal = CV2Qvgrad [vertical gradient] + CV2Qzgrad [axial gradient] + CV2Qr [residual heterogeneity]) among groups. Results: There were no significant differences in demographic parameters among groups, and all subjects had minimal radiographic evidence of emphysema. Compared with controls, nonsmokers living with HIV had a significantly greater CV2Qr/CV2Qtotal (0.48 vs. 0.36, P = 0.05) and reduced CV2Qvgrad/CV2Qtotal (0.46 vs. 0.65, P = 0.038). Smokers also had a reduced CV2Qvgrad/CV2Qtotal, however, there was no significant difference in CV2Qvgrad/CV2Qtotal between smokers living with and without HIV (0.39 vs. 0.34, P = 0.58), despite a decreased vertical perfusion gradient (Qvgrad) in smokers living with HIV. Conclusion: In nonsmokers living with well-controlled HIV and minimal radiographic emphysema, HIV infection contributes to pulmonary perfusion abnormalities similar to smokers. These data indicate the onset of subclinical pulmonary perfusion abnormalities that could herald the development of significant lung disease in these susceptible individuals.

A model investigation of the impact of ventilation-perfusion mismatch on oxygenation during apnea in preterm infants.

Ventilation-perfusion (V/Q) mismatch is a prominent feature of preterm infants and adults with lung disease. V/Q mismatch is known to cause arterial hypoxemia under steady-state conditions, and has been proposed as the cause of rapid arterial oxygen desaturation during apnea. However, there is little evidence to support a role for V/Q mismatch in the dynamic changes in arterial oxygenation that occur during apnea. Using a mathematical model, we quantified the effect of V/Q mismatch on the rate of desaturation during apnea to ascertain whether it could lead to rates of up to 10%s(-1) as observed in preterm infants. We used a lung-body model for the preterm infant that incorporated 50 parallel alveolar-capillary units that were ventilated and perfused with the severity of V/Q mismatch (sigma) defined conventionally according to sigma=S.D. of the distribution of V/Q ratios. Average desaturation rate 10s from apnea onset was strongly elevated with worsening V/Q mismatch as a result of an earlier desaturation of low V/Q units compared with high V/Q units. However, V/Q mismatch had little impact after apnea onset, with peak desaturation rate only substantially increased if mismatching caused a lowered resting arterial O(2) saturation. In conclusion, V/Q mismatch causes a more immediate onset of desaturation during apnea, and therefore places preterm infants and adults with lung disease at risk of hypoxemic dips. However, V/Q mismatch does not accelerate desaturation rate beyond apnea onset and cannot, therefore, explain the rapid desaturation observed during recurrent apnea in preterm infants.

A model analysis of arterial oxygen desaturation during apnea in preterm infants.

Rapid arterial O(2) desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O(2) desaturation during apnea (Sa(O)2) is complicated by the non-linear O(2) dissociation curve, falling pulmonary O(2) uptake, and by the fact that O(2) desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O(2) consumption accelerates Sa(O)2throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar P(O)2causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates Sa(O)2during stage 1, and finally, total blood O(2) capacity (blood volume and hemoglobin content) alone determines Sa(O)2during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.

Lung parenchymal and airway changes on CT imaging following allergen challenge and bronchoalveolar lavage in atopic and asthmatic subjects.

BACKGROUND: Computed tomography (CT) imaging findings in the lungs in the setting of an acute allergic response and following bronchoalveolar lavage (BAL) are not well established. Our goals are to characterize the pulmonary CT findings of acute allergic response in both asthmatic and non-asthmatic subjects and, secondarily, to characterize the pulmonary imaging findings following BAL. METHODS: In this prospective observational (cohort) study, we identified atopic, asthmatic (AA) and atopic, non-asthmatic (ANA) subjects. CT of the chest was performed following BAL and instillation of an allergen (AL) and of an inert diluent (DL). Two radiologists analyzed the CT examinations for airway and parenchymal changes. RESULTS: We had a cohort of 20 atopic subjects (AA=10, ANA=10; F=11, M=9; median age: 23.5 years, range: 18-48 years). Compared to diluent instillation and BAL, allergen instillation resulted in more significant bronchial wall thickening (AL=70%, DL=0%, BAL=0%, P<0.01), consolidations (AL=55%, DL=0%, BAL=15%, P<0.05), and septal thickening (AL=35%, DL=0%, BAL=0%, P<0.01). When present, consolidations tended to be more common in asthmatic subjects compared to non-asthmatics following instillation of the allergen, although this did not reach statistical significance (AA=80% vs. ANA=30%; P=0.07). BAL, on the other hand, resulted in more ground-glass opacities (BAL=15/20, 75% vs. AL=2/20, 10%, vs. DL=0/20, 0%; P<0.01). CONCLUSIONS: Acute allergic response in the lungs can result in significant bronchial wall thickening, septal thickening, and consolidations in those with atopy, particularly those with asthma. Localized ground-glass opacities may be expected following BAL, and care should be taken so as to not misinterpret these as significant pathology.

Preclinical evaluation of an 111In/225Ac theranostic targeting transformed MUC1 for triple negative breast cancer.

Rationale: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer. TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells. Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC. Methods: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy. hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry). Lastly, in vivo biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model. Results: hTAB004 was shown to bind and internalize into tMUC1-expressing cells. A production method of 225Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and 111In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed. The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum. In NSG female mice bearing orthotopic HCC70 xenografts, the in vivo tumor concentration of 111In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection). A single 225Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001, day 22) and increased survival compared to controls (P<0.007). The human dosimetry results were comparable to other clinically used agents. Conclusion: The results obtained with hTAB004 suggest that the 111In/225Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.

Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

BACKGROUND: Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure. METHODS: Using CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways. FINDINGS: The changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV. CONCLUSIONS: Our data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge.

BACKGROUND: Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways. METHODS: In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. RESULTS: In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85-0.97] vs. 0.90 [0.86-0.98] vs. 0.59 [0.55-0.67]; p<0.05. Mean-normalized ventilation 0.89 [0.88-0.98] vs. 0.95 [0.89-1.02] vs. 0.63 [0.52-0.67], p<0.05). In contrast, no significant differences were found in Fgas between baseline, diluent and allergen lobes or in Ki. Total cell counts, eosinophil and neutrophil cell counts (cells/ml BAL) were significantly greater in the allergen lobe compared to the baseline lobe (all P<0.05). CONCLUSIONS: Despite having no clinical symptoms of a lower airway allergic response (cough and wheeze) allergic non-asthmatic subjects have a pulmonary response to allergen exposure which manifests as reduced ventilation and perfusion.

The effect of omalizumab on ventilation and perfusion in adults with allergic asthma.

Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.

Respiratory system reactance is an independent determinant of asthma control.

The mechanisms underlying not well-controlled (NWC) asthma remain poorly understood, but accumulating evidence points to peripheral airway dysfunction as a key contributor. The present study tests whether our recently described respiratory system reactance (Xrs) assessment of peripheral airway dysfunction reveals insight into poor asthma control. The aim of this study was to investigate the contribution of Xrs to asthma control. In 22 subjects with asthma, we measured Xrs (forced oscillation technique), spirometry, lung volumes, and ventilation heterogeneity (inert-gas washout), before and after bronchodilator administration. The relationship between Xrs and lung volume during a deflation maneuver yielded two parameters: the volume at which Xrs abruptly decreased (closing volume) and Xrs at this volume (Xrscrit). Lowered (more negative) Xrscrit reflects reduced apparent lung compliance at high lung volumes due, for example, to heterogeneous airway narrowing and unresolved airway closure or near closure above the critical lung volume. Asthma control was assessed via the 6-point Asthma Control Questionnaire (ACQ6). NWC asthma was defined as ACQ6 > 1.0. In 10 NWC and 12 well-controlled subjects, ACQ6 was strongly associated with postbronchodilator (post-BD) Xrscrit (R(2) = 0.43, P < 0.001), independent of all measured variables, and was a strong predictor of NWC asthma (receiver operator characteristic area = 0.94, P < 0.001). By contrast, Xrs measures at lower lung volumes were not associated with ACQ6. Xrscrit itself was significantly associated with measures of gas trapping and ventilation heterogeneity, thus confirming the link between Xrs and airway closure and heterogeneity. Residual airway dysfunction at high lung volumes assessed via Xrscrit is an independent contributor to asthma control.

Automated detection of the phase III slope during inert gas washout testing.

We describe a method to determine the phase III slope for the purpose of calculating indexes of ventilation heterogeneity, S(acin) and S(cond), from the multiple breath nitrogen washout test (MBNW). Our automated method applies a recursive, segmented linear regression technique to each breath of the MBNW test and determines the best point of transition, or breakpoint, between each phase of the washout. A sample set of 50 MBNW tests (controls, asthma, and COPD) was used to establish the conditions in which the phase III slope obtained from the automated technique best matched that obtained by two manual interpreters. We then applied our technique to a test set of 30 subjects (with an even number of subjects in each of the above groups) and compared these results against the manual analysis of a third independent manual interpreter. Indexes of ventilation heterogeneity were determined using both methods and compared. The phase III slopes determined by the automatic technique best matched the manual interpreter when the phase III slope was calculated from the phase II-III transition point plus the addition of 50% of the phase II volume to the end of the expiration. Calculation of the indexes S(acin) and S(cond) showed no overall difference between analysis methods in either S(acin) (P = 0.14) or S(cond) (P = 0.59) when the set threshold was applied to our automated analysis. Our analysis method provides an alternate means for rapid quantification of the MBNW test, removing operator dependence without alteration in either S(acin) or S(cond).

Effect of airway smooth muscle tone on airway distensibility measured by the forced oscillation technique in adults with asthma.

Airway distensibility appears to be unaffected by airway smooth muscle (ASM) tone, despite the influence of ASM tone on the airway diameter-pressure relationship. This discrepancy may be because the greatest effect of ASM tone on airway diameter-pressure behavior occurs at low transpulmonary pressures, i.e., low lung volumes, which has not been investigated. Our study aimed to determine the contribution of ASM tone to airway distensibility, as assessed via the forced oscillation technique (FOT), across all lung volumes with a specific focus on low lung volumes. We also investigated the accompanying influence of ASM tone on peripheral airway closure and heterogeneity inferred from the reactance versus lung volume relationship. Respiratory system conductance and reactance were measured using FOT across the entire lung volume range in 22 asthma subjects and 19 healthy controls before and after bronchodilator. Airway distensibility (slope of conductance vs. lung volume) was calculated at residual volume (RV), functional residual capacity (FRC), and total lung capacity. At baseline, airway distensibility was significantly lower in subjects with asthma at all lung volumes. After bronchodilator, distensibility significantly increased at RV (64.8%, P < 0.001) and at FRC (61.8%, P < 0.01) in subjects with asthma but not in control subjects. The increased distensibility at RV and FRC in asthma were not associated with the accompanying changes in the reactance versus lung volume relationship. Our findings demonstrate that, at low lung volumes, ASM tone reduces airway distensibility in adults with asthma, independent of changes in airway closure and heterogeneity.

The bronchodilator response of in vivo specific airway compliance in adults with asthma.

A new technique has been developed to determine in vivo airway compliance in humans that is specific to airway size and transpulmonary pressure, and can be represented as a three-dimensional surface. As yet, the ability of this technique to detect changes in specific airway compliance with disease status has not been demonstrated. The aim of this study was to assess whether this technique could determine changes in airway compliance which are thought to occur with altered smooth muscle tone in adults with asthma. Airway compliance was measured and displayed as a surface in adults with asthma before and after a reduction in smooth muscle tone by bronchodilator administration. Compliance, with respect to airway size, was calculated at three specific lung volumes; functional residual capacity (FRC), total lung capacity (TLC), and midway between FRC and TLC (MID). After bronchodilator, airway compliance increased at FRC and MID in the smaller airways (<3 mm). Furthermore, airway compliance under both conditions was greater in the smaller airways compared to the larger airways. In conclusion, our method may have future utility in assessing changes in airway compliance in respiratory diseases such as asthma.

A method to determine in vivo, specific airway compliance, in humans.

In order to understand the pathophysiology of diseases such as asthma and chronic obstructive pulmonary disease, it is essential to measure the mechanical properties of the airways. Currently, there are no methods to measure and quantify in vivo airway compliance in humans. In order to develop a method, we generated a curve-fitting algorithm that combines airway diameter measurements by high resolution computed tomography with pressure-volume curves obtained by the esophageal balloon technique. Our method allows the description of diameter-pressure curves for airways of varying size, presented as a 3D surface, from which specific airway compliance can be determined at any transpulmonary pressure. Applying this method to data from two healthy subjects, we found that small airways are more compliant than large airways and specific airway compliance was greatest at low transpulmonary pressures. In conclusion, our 3D surface is a useful tool to measure and quantify in vivo specific airway compliance in humans.

A dynamic model for assessing the impact of diffusing capacity on arterial oxygenation during apnea.

Preterm infants have a reduced pulmonary diffusing capacity that has been invoked to explain rapid arterial O(2)-desaturation during apnea, despite little evidence to support this view. We explored the role of diffusion limitation on O(2)-desaturation during apnea by developing a mathematical model of gas exchange in which O(2) dynamically loads the blood traversing the pulmonary capillary. While normal diffusing capacity DL((O(2)) had negligible impact on apneic desaturation, reduced DL((O(2)) advanced the onset of desaturation during apnea. Unexpectedly, despite considerable diffusion limitation, its influence on O(2)-desaturation disappeared within 15s, because its impact in slowing alveolar O(2) depletion maintained a higher driving pressure for diffusion. In contrast, reduced DL((O(2)) substantially slowed reoxygenation following apnea. Our findings do not support the hypothesis that reduced DL((O(2)) explains the rapid apneic desaturation observed in preterm infants. Instead, the signature of reduced DL((O(2)) is a prolonged hypoxemia following apnea, potentially causing a persistence of hypoxic conditions when heart rate and cardiac workload reach a peak.