Swati A. Bhatawadekar

Modeling stochastic and spatial heterogeneity in a human airway tree to determine variation in respiratory system resistance

Asthma is a variable disease with changes in symptoms and airway function over many time scales. Airway resistance (Raw) is variable and thought to reflect changes in airway smooth muscle activity, but just how variation throughout the airway tree and the influence of gas distribution abnormalities affect Raw is unclear. We used a multibranch airway lung model to evaluate variation in airway diameter size, the role of coherent regional variation, and the role of gas distribution abnormalities on mean Raw (Raw) and variation in Raw as described by the SD (SDRaw). We modified an anatomically correct airway tree, provided by Merryn Tawhai (The University of Auckland, New Zealand), consisting of nearly 4,000 airways, to produce temporal and spatial heterogeneity. As expected, we found that increasing the diameter variation by twofold, with no change in the mean diameter, increased SDRaw more than fourfold. Perhaps surprisingly, Raw was proportional to SDRaw under several conditions-when either mean diameter was fixed, and its SD varied or when mean diameter varied, and SD was fixed. Increasing the size of a regional absence in gas distribution (ventilation defect) also led to a proportionate increase in both Raw and SDRaw. However, introducing regional dependence of connected airways strongly increased SDRaw by as much as sixfold, with little change in Raw. The model was able to predict previously reported Raw distributions and correlation of SDRaw on Raw in healthy and asthmatic subjects. The ratio of SDRaw to Raw depended most strongly on interairway coherent variation and only had a slight dependence on ventilation defect size. These findings may explain the linear correlation between variation and mean values of Raw but also suggest that regional alterations in gas distribution and local coordination in ventilation amplify any underlying variation in airway diameters throughout the airway tree.

Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma.

Ventilation heterogeneity is an important marker of small airway dysfunction in asthma. The frequency dependence of respiratory system resistance (Rrs) from oscillometry is used as a measure of this heterogeneity. However, this has not been quantitatively assessed or compared with other outcomes from oscillometry, including respiratory system reactance (Xrs) and the associated elastance (Ers). Here, we used a multibranch model of the human lung, including an upper airway shunt, to match previously reported respiratory mechanics in mild to severe asthma. We imposed heterogeneity by narrowing a proportion of the peripheral airways to account for patient Ers at 5 Hz, and then narrowed central airways to account for the remaining Rrs at 18 Hz. The model required >75% of the small airways to be occluded to reproduce severe asthma. While the model produced frequency dependence in Rrs, it was upward-shifted below 5 Hz compared with in-vivo results, indicating that other factors, including more distributed airway narrowing or central airway wall compliance, are required. However, Ers quantitatively reflected the imposed heterogeneity better than the frequency dependence of Rrs, independent of the frequency range for the estimation, and thus was a more robust measure of small-airway function. Thus, Ers appears to have greater potential as a clinical measure of early small-airway disease in asthma.

Hyperpolarized 3He magnetic resonance imaging ventilation defects in asthma: relationship to airway mechanics

In patients with asthma, magnetic resonance imaging (MRI) provides direct measurements of regional ventilation heterogeneity, the etiology of which is not well‐understood, nor is the relationship of ventilation abnormalities with lung mechanics. In addition, respiratory resistance and reactance are often abnormal in asthmatics and the frequency dependence of respiratory resistance is thought to reflect ventilation heterogeneity. We acquired MRI ventilation defect maps, forced expiratory volume in one‐second (FEV1), and airways resistance (Raw) measurements, and used a computational airway model to explore the relationship of ventilation defect percent (VDP) with simulated measurements of respiratory system resistance (Rrs) and reactance (Xrs). MRI ventilation defect maps were experimentally acquired in 25 asthmatics before, during, and after methacholine challenge and these were nonrigidly coregistered to the airway tree model. Using the model coregistered to ventilation defect maps, we narrowed proximal (9th) and distal (14th) generation airways that were spatially related to the MRI ventilation defects. The relationships for VDP with Raw measured using plethysmography (r = 0.79), and model predictions of Rrs>14 (r = 0.91, P < 0.0001) and Rrs>9 (r = 0.88, P < 0.0001) were significantly stronger (P = 0.005; P = 0.03, respectively) than with FEV1 (r = −0.68, P = 0.0001). The slopes for the relationship of VDP with simulated lung mechanics measurements were different (P < 0.0001); among these, the slope for the VDP‐Xrs0.2 relationship was largest, suggesting that VDP was dominated by peripheral airway heterogeneity in these patients. In conclusion, as a first step toward understanding potential links between lung mechanics and ventilation defects, impedance predictions were made using a computational airway tree model with simulated constriction of airways related to ventilation defects measured in mild‐moderate asthmatics.

Contribution of rostral fluid shift to intrathoracic airway narrowing in asthma

In asthma, supine posture and sleep increase intrathoracic airway narrowing. When humans are supine, because of gravity fluid moves out of the legs and accumulates in the thorax. We hypothesized that fluid shifting out of the legs into the thorax contributes to the intrathoracic airway narrowing in asthma. Healthy and asthmatic subjects sat for 30 min and then lay supine for 30 min. To simulate overnight fluid shift, supine subjects were randomized to receive increased fluid shift out of the legs with lower body positive pressure (LBPP, 10-30 min) or none (control) and crossed over. With forced oscillation at 5 Hz, respiratory resistance (R5) and reactance (X5, reflecting respiratory stiffness) and with bioelectrical impedance, leg and thoracic fluid volumes (LFV, TFV) were measured while subjects were seated and supine (0 min, 30 min). In 17 healthy subjects (age: 51.8 ± 10.9 yr, FEV1/FVC z score: -0.4 ± 1.1), changes in R5 and X5 were similar in both study arms (P > 0.05). In 15 asthmatic subjects (58.5 ± 9.8 yr, -2.1 ± 1.3), R5 and X5 increased in both arms (ΔR5: 0.6 ± 0.9 vs. 1.4 ± 0.8 cmH2O·l-1·s-1, ΔX5: 0.3 ± 0.7 vs. 1.1 ± 0.9 cmH2O·l-1·s-1). The increases in R5 and X5 were 2.3 and 3.7 times larger with LBPP than control, however (P = 0.008, P = 0.006). The main predictor of increases in R5 with LBPP was increases in TFV (r = 0.73, P = 0.002). In asthmatic subjects, the magnitude of increases in X5 with LBPP was comparable to that with posture change from sitting to supine (1.1 ± 0.9 vs. 1.4 ± 0.9 cmH2O·l-1·s-1, P = 0.32). We conclude that in asthmatic subjects fluid shifting from the legs to the thorax while supine contributed to increases in the respiratory resistance and stiffness.NEW & NOTEWORTHY In supine asthmatic subjects, application of positive pressure to the lower body caused appreciable increases in respiratory system resistance and stiffness. Moreover, these changes in respiratory mechanics correlated positively with increase in thoracic fluid volume. These findings suggest that fluid shifts from the lower body to the thorax may contribute to overnight intrathoracic airway narrowing and worsening of asthma symptoms.

Oscillatory Mechanics in Asthma: Emphasis on Airway Variability and Heterogeneity.

Spirometry is one of the most widely used tests in the assessment and monitoring of asthma. However, spirometry cannot be performed in very young children and some adult patients, and is poorly sensitive to small airways, which are primarily involved in the pathophysiology of asthma. The forced oscillation technique (FOT) has emerged as a powerful alternative technique that instead characterizes respiratory mechanics during normal breathing with no forced maneuver. In this review we highlight the current state of the art of the FOT and its utility in the assessment of lung function in asthma. First we briefly discuss the clinical features and characteristics of asthma. This is followed by a discussion of the assessment of airway obstruction and airway hyperresponsiveness using spirometry. We then review the basics of FOT and its application in respiratory diseases. FOT data are particularly amenable to modeling as an aide to physiological interpretation, and we review several common approaches. This is followed by an in-depth discussion of the assessment of airway variability and heterogeneity using FOT in asthma. Finally, we speculate on the potential clinical utility of FOT in asthma.

Effects of physical exercise training on nocturnal symptoms in asthma: Systematic review

Introduction Nocturnal worsening of asthma symptoms is a common feature of asthma. Physical exercise training improves general asthma control; however, there is no evidence showing the effects of physical exercise on nocturnal asthma symptoms. Indeed, asthma patients with daytime and nighttime symptoms are physiologically different, and thus the effects of physical exercise on asthma may also be different in these two groups. The objective of this systematic review is to explore the effects of physical exercise on nocturnal asthma symptoms. Methods Searches were conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL and SPORTdiscus (last search on November 2017). Authors from studies that did not report nocturnal symptoms but used questionnaires and/or diaries were contacted for detailed information. Studies that provided results on nocturnal symptoms before and after physical activity intervention were included. Prevalence of nocturnal symptoms was calculated for each study from the percentage of study participants with nocturnal symptoms before and after intervention. Results Eleven studies were included (5 with children and 6 with adults). The prevalence of nocturnal symptoms at baseline ranged from 0% to 63% among children and from 50–73% among adults. In children and adults with nocturnal asthma, aerobic physical exercise reduced the prevalence and frequency of nocturnal symptoms. Conclusions Aerobic physical exercise improves nocturnal asthma in children and adults by reducing the prevalence and frequency of nocturnal symptoms. Physical exercise training could be used with conventional treatments to improve quality of life and asthma control in patients with nocturnal worsening of asthma.

Improvement in upright and supine lung mechanics with bariatric surgery affects bronchodilator responsiveness and sleep quality

Obesity and weight-loss have complex effects on respiratory physiology, but these have been insufficiently studied, particularly at early time points following weight-loss surgery and in the supine position. We evaluated 15 severely obese female participants before, and 5 weeks and 6 months after bariatric surgery using the Pittsburgh Sleep Quality Index (PSQI), spirometry, plethysmography, and oscillometry to measure respiratory system mechanics. Oscillometry and spirometry were conducted in the upright and supine position, and pre- and post-bronchodilation with 200µg of salbutamol. At 5 weeks post-surgery, weight-loss was 11.9±2.7kg with no effect on spirometric outcomes and a slight effect on oscillometric outcomes. However, at 6 months, weight-loss was 21.4±7.1kg with a 14.1±6.1% and 17.8±5.4% reduction in upright and supine Rrs,6, respectively. Ers also decreased by 25.7±9.4% and 20.2±7.2% in the upright and supine positions. No changes were observed in spirometry, but sleep quality improved from PSQI of 8.4±3.5 to 4.1±2.9. Bronchodilator responsiveness was low at baseline but increased significantly post-surgery, and this response was comparable to the improvement in Rrs produced by weight-loss. Modeling the impedance spectra with a two-compartment model demonstrated that improvements in lung mechanics with weight-loss begin in the upper or central compartment of the lungs and progress to include the peripheral compartment. Respiratory mechanics are impaired in the severely obese and is associated with poor sleep quality, but these improved substantially with weight-loss. Our data provide new evidence that severely obese individuals may have poor sleep quality due to abnormal respiratory mechanics that weight-loss improves.

Reduced Baseline Airway Caliber Relates to Larger Airway Sensitivity to Rostral Fluid Shift in Asthma

Background: We have previously shown that when asthmatics go supine, fluid shifts out of the legs, accumulates in the thorax, and exacerbates lower airway narrowing. In the retrospective analysis of our previous work presented here, we test the hypothesis that the sensitivity of this process relates inversely to baseline caliber of the lower airways. Methods: Eighteen healthy (six women) and sixteen asthmatic subjects (nine women) sat for 30 min, and then lay supine for 30 min. While supine, lower body positive pressure (LBPP, 40 mm Hg) was applied to displace fluid from the legs similar in amount to the overnight fluid shift. Respiratory resistance and reactance at 5 Hz (R5 and X5) and leg and thoracic fluid volumes (LFV and TFV) were measured at the beginning and end of the supine period. Results: With LBPP, healthy, and asthmatic subjects had similar changes in the LFV and TFV (p = 0.3 and 0.1, respectively). Sensitivity to fluid shift, defined by ΔR5/ΔTFV, was larger in the asthmatics than in the healthy subjects (p = 0.0001), and correlated with baseline R5 in the supine position in the asthmatics (p = 0.7, p = 0.003). No such association was observed in the healthy subjects (p = 0.6). In the asthmatics, women showed a greater reduction in X5 than men with LBPP (p = 0.009). Conclusions: Smaller baseline airway caliber, as assessed by larger R5, was associated with increased sensitivity to fluid shift in the supine position. We conclude that asthmatics with narrower small airways such as obese asthma patients, women with asthma and those with severe asthma may be more sensitive to the effects fluid shift while supine as during sleep.