Effects of Kinematic Hardening of Mucus Polymers in an Airway Closure Model.

The formation of a liquid plug inside a human airway, known as airway closure, is computationally studied by considering the elastoviscoplastic (EVP) properties of the pulmonary mucus covering the airway walls for a range of liquid film thicknesses and Laplace numbers. The airway is modeled as a rigid tube lined with a single layer of an EVP liquid. The Saramito-Herschel-Bulkley (Saramito-HB) model is coupled with an Isotropic Kinematic Hardening model (Saramito-HB-IKH) to allow energy dissipation at low strain rates. The rheological model is fitted to the experimental data under healthy and cystic fibrosis (CF) conditions. Yielded/unyielded regions and stresses on the airway wall are examined throughout the closure process. Yielding is found to begin near the closure in the Saramito-HB model, whereas it occurs noticeably earlier in the Saramito-HB-IKH model. The kinematic hardening is seen to have a notable effect on the closure time, especially for the CF case, with the effect being more pronounced at low Laplace numbers and initial film thicknesses. Finally, standalone effects of rheological properties on wall stresses are examined considering their physiological values as baseline.

Prone-position decreases airway closure in a patient with ARDS undergoing venovenous extracorporeal membrane oxygenation.

PURPOSE: Airway closure is a interruption of communication between larger and smaller airways. The presence of airway closure during mechanical ventilation may lead to the overestimation of driving pressure (DP), introducing errors in the assessment of respiratory mechanics and in positive end-expiratory pressure (PEEP) setting on the ventilator. Patients with severe acute respiratory distress syndrome (ARDS) may exhibit the airway closure phenomenon, which can be easily diagnosed with a low-flow inflation. Prone positioning is a therapeutic manoeuver proven to reduce mortality in ARDS patients, and has been widely implemented also in patients requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO). To date, the impact of prone positioning on changes in airway closure has not been described. METHODS: We present an image analysis of the pressure waveform during volume-controlled ventilation and low-flow inflations before and after prone positioning in an ARDS patient on VV ECMO. RESULTS: A high airway opening pressure level (23 cmH2O) was detected in the supine position during tidal ventilation. Airway closure was confirmed by using a low-flow inflation. Prone positioning significantly attenuated airway closure, with the airway opening pressure decreasing to 13 cmH2O. After re-supination, airway closure was lower as compared with supine position at baseline (17 cmH2O). CONCLUSION: Prone positioning reduced airway closure in an ARDS patient on VV ECMO support.

Advanced respiratory mechanics assessment in mechanically ventilated obese and non-obese patients with or without acute respiratory distress syndrome.

BACKGROUND: Respiratory mechanics is a key element to monitor mechanically ventilated patients and guide ventilator settings. Besides the usual basic assessments, some more complex explorations may allow to better characterize patients' respiratory mechanics and individualize ventilation strategies. These advanced respiratory mechanics assessments including esophageal pressure measurements and complete airway closure detection may be particularly relevant in critically ill obese patients. This study aimed to comprehensively assess respiratory mechanics in obese and non-obese ICU patients with or without ARDS and evaluate the contribution of advanced respiratory mechanics assessments compared to basic assessments in these patients. METHODS: All intubated patients admitted in two ICUs for any cause were prospectively included. Gas exchange and respiratory mechanics including esophageal pressure and end-expiratory lung volume (EELV) measurements and low-flow insufflation to detect complete airway closure were assessed in standardized conditions (tidal volume of 6 mL kg-1 predicted body weight (PBW), positive end-expiratory pressure (PEEP) of 5 cmH2O) within 24 h after intubation. RESULTS: Among the 149 analyzed patients, 52 (34.9%) were obese and 90 (60.4%) had ARDS (65.4% and 57.8% of obese and non-obese patients, respectively, p = 0.385). A complete airway closure was found in 23.5% of the patients. It was more frequent in obese than in non-obese patients (40.4% vs 14.4%, p < 0.001) and in ARDS than in non-ARDS patients (30% vs. 13.6%, p = 0.029). Respiratory system and lung compliances and EELV/PBW were similarly decreased in obese patients without ARDS and obese or non-obese patients with ARDS. Chest wall compliance was not impacted by obesity or ARDS, but end-expiratory esophageal pressure was higher in obese than in non-obese patients. Chest wall contribution to respiratory system compliance differed widely between patients but was not predictable by their general characteristics. CONCLUSIONS: Most respiratory mechanics features are similar in obese non-ARDS and non-obese ARDS patients, but end-expiratory esophageal pressure is higher in obese patients. A complete airway closure can be found in around 25% of critically ill patients ventilated with a PEEP of 5 cmH2O. Advanced explorations may allow to better characterize individual respiratory mechanics and adjust ventilation strategies in some patients. Trial registration NCT03420417 ClinicalTrials.gov (February 5, 2018).

A novel capnogram analysis to guide ventilation during cardiopulmonary resuscitation: clinical and experimental observations.

BACKGROUND: Cardiopulmonary resuscitation (CPR) decreases lung volume below the functional residual capacity and can generate intrathoracic airway closure. Conversely, large insufflations can induce thoracic distension and jeopardize circulation. The capnogram (CO2 signal) obtained during continuous chest compressions can reflect intrathoracic airway closure, and we hypothesized here that it can also indicate thoracic distension. OBJECTIVES: To test whether a specific capnogram may identify thoracic distension during CPR and to assess the impact of thoracic distension on gas exchange and hemodynamics. METHODS: (1) In out-of-hospital cardiac arrest patients, we identified on capnograms three patterns: intrathoracic airway closure, thoracic distension or regular pattern. An algorithm was designed to identify them automatically. (2) To link CO2 patterns with ventilation, we conducted three experiments: (i) reproducing the CO2 patterns in human cadavers, (ii) assessing the influence of tidal volume and respiratory mechanics on thoracic distension using a mechanical lung model and (iii) exploring the impact of thoracic distension patterns on different circulation parameters during CPR on a pig model. MEASUREMENTS AND MAIN RESULTS: (1) Clinical data: 202 capnograms were collected. Intrathoracic airway closure was present in 35%, thoracic distension in 22% and regular pattern in 43%. (2) Experiments: (i) Higher insufflated volumes reproduced thoracic distension CO2 patterns in 5 cadavers. (ii) In the mechanical lung model, thoracic distension patterns were associated with higher volumes and longer time constants. (iii) In six pigs during CPR with various tidal volumes, a CO2 pattern of thoracic distension, but not tidal volume per se, was associated with a significant decrease in blood pressure and cerebral perfusion. CONCLUSIONS: During CPR, capnograms reflecting intrathoracic airway closure, thoracic distension or regular pattern can be identified. In the animal experiment, a thoracic distension pattern on the capnogram is associated with a negative impact of ventilation on blood pressure and cerebral perfusion during CPR, not predicted by tidal volume per se.

Airway closing index in school-age children during exercise bronchoprovocation.

OBJECTIVE: Airway Closing Index (ACI), the ratio of % change in FVC to % change in FEV1 with bronchoprovocation, may represent changes in airflow due to airway closure, as opposed to airway narrowing. The objective of this study was to evaluate ACI during exercise bronchoprovocation (EB) in children. METHODS: Children, 6 to 18 years of age, who underwent EB using a stationary bicycle ergometer over a 6-year period were reviewed. Pulmonary function, including ACI, in patients with a positive exercise challenge, defined as ≥10% decrease in FEV1 following exercise, were compared to patients with a negative challenge. RESULTS: A total of 1030 children with a median age of 13 (IQR 11-15) underwent EB, of which 376 (37%) had a positive exercise challenge. There was wide variability in ACI, with a median of 0.75 (0.28-1.21). Median ACI in those with a positive test was 0.68 (IQR 0.41-0.93) compared to 0.84 (IQR 0.09-1.06) for those with a negative test, p = 0.017. Median ACI was higher in older children (p < 0.001) and females (p < 0.0001). Median percent change in FEV1 following bronchodilator for children in the highest quintile for ACI was 4.5 (IQR 1.3-8.1) compared to 5.5 (IQR 2-9.2) for children in the lowest quintile, p = 0.04. CONCLUSIONS: There is wide variability in the ACI in children undergoing EB. ACI was lower in children with a positive challenge, the significance is unknown. Children with higher ACI may have increased airway closure with bronchoprovocation, and less response to bronchodilators.

Reversibility of total airway closure and alveolar consolidation in a COVID-19 patient: A case study.

Coronavirus disease 2019 (COVID-19) may be complicated by life-threatening pneumonia requiring tracheal intubation, mechanical ventilation and veno-venous extracorporeal membrane oxygenation (vvECMO). It is not yet clear to what extent and after which delay the most severe cases of COVID-19 pneumonia are reversible. Here, we present a 39-year-old patient who developed a severe COVID-19-attributed acute respiratory distress syndrome (ARDS) resulting in complete alveolar consolidation and airway closure for several weeks. His remarkable ventilatory pattern was established using ventilator airway pressure curve analysis and computed tomography imaging. The patient was managed with supportive care, mechanical ventilation and vvECMO. He received dexamethasone and tocilizumab as immunomodulatory drugs. Despite multiple complications, he recovered and was weaned from vvECMO, ventilator and oxygen on days 75, 95 and 99 post-intubation, respectively. He was discharged from hospital on day 113. This case study strongly supports the remarkable potential for reversibility of ARDS in COVID-19 patients and discusses the implications for critical care nursing regarding mechanical ventilation and ECMO device management in patients who may become entirely dependent on vvECMO for oxygenation and carbon dioxide elimination.

Exhaled particles and small airways.

BACKGROUND: Originally, studies on exhaled droplets explored properties of airborne transmission of infectious diseases. More recently, the interest focuses on properties of exhaled droplets as biomarkers, enabled by the development of technical equipment and methods for chemical analysis. Because exhaled droplets contain nonvolatile substances, particles is the physical designation. This review aims to outline the development in the area of exhaled particles, particularly regarding biomarkers and the connection with small airways, i e airways with an internal diameter < 2 mm. MAIN BODY: Generation mechanisms, sites of origin, number concentrations of exhaled particles and the content of nonvolatile substances are studied. Exhaled particles range in diameter from 0.01 and 1000 µm depending on generation mechanism and site of origin. Airway reopening is one scientifically substantiated particle generation mechanism. During deep expirations, small airways close and the reopening process produces minute particles. When exhaled, these particles have a diameter of < 4 µm. A size discriminating sampling of particles < 4 µm and determination of the size distribution, allows exhaled particle mass to be estimated. The median mass is represented by particles in the size range of 0.7 to 1.0 µm. Half an hour of repeated deep expirations result in samples in the order of nanogram to microgram. The source of these samples is the respiratory tract ling fluid of small airways and consists of lipids and proteins, similarly to surfactant. Early clinical studies of e g chronic obstructive pulmonary disease and asthma, reported altered particle formation and particle composition. CONCLUSION: The physical properties and content of exhaled particles generated by the airway reopening mechanism offers an exciting noninvasive way to obtain samples from the respiratory tract lining fluid of small airways. The biomarker potential is only at the beginning to be explored.

Older age and obesity are associated with increased airway closure in response to methacholine in patients with asthma.

BACKGROUND AND OBJECTIVE: The reduction of forced expiratory volume in 1 s (FEV1 ) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1 /forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC). METHODS: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1 , and calculated as %ΔFVC/%ΔFEV1 . RESULTS: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. CONCLUSION: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index.

BMI but not central obesity predisposes to airway closure during bronchoconstriction.

BACKGROUND AND OBJECTIVE: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.

Obstruction phenotype as a predictor of asthma severity and instability in children.

BACKGROUND: Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability. OBJECTIVE: We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability. METHODS: Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than -1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV1/FVC z score of less than -1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability. RESULTS: Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit (P < .03) and None (P < .001) phenotypes. Patients with the A Trpg phenotype also had the highest Composite Asthma Severity Index score, the highest asthma treatment step, the greatest variability in FEV1 over time, and the greatest sensitivity to methacholine challenge. CONCLUSIONS: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.

Comparison of two methods of determining lung de-recruitment, using the forced oscillation technique.

Airway closure has proved to be important in a number of respiratory diseases and may be the primary functional defect in asthma. A surrogate measure of closing volume can be identified using the forced oscillation technique (FOT), by performing a deflation maneuver and examining the resultant reactance (Xrs) lung volume relationship. This study aims to determine if a slow vital capacity maneuver can be used instead of this deflation maneuver and compare it to existing more complex techniques. Three subject groups were included in the study; healthy (n = 29), asthmatic (n = 18), and COPD (n = 10) for a total of 57 subjects. Reactance lung volume curves were generated via FOT recordings during two different breathing manoeuvres (both pre and post bronchodilator). The correlation and agreement between surrogate closing volume (Volcrit) and reactance (Xrscrit) at this volume was analysed. The changes in Volcrit and Xrscrit pre and post bronchodilator were also analysed. Across all three subject groups, the two different measures of Volcrit were shown to be statistically equivalent (p > 0.05) and demonstrated a strong fit to the data (R2 = 0.49, 0.78, 0.59, for asthmatic, COPD and healthy subject groups, respectively). A bias was evident between the two measurements of Xrscrit with statistically different means (p < 0.05). However, the two measurements of Xrscrit displayed the same trends. In conclusion, we have developed an alternative technique for measuring airway closure from FOT recordings. The technique delivers equivalent and possibly more sensitive results to previous methods while being simple and easily performed by the patient.

Influence of distinct asthma phenotypes on lung function following weight loss in the obese.

BACKGROUND AND OBJECTIVE: There appears to be two distinct clinical phenotypes of obese patients with asthma-those with early-onset asthma and high serum IgE (TH2-high), and those with late-onset asthma and low serum IgE (TH2-low). The aim of the present study was to determine in the two phenotypes of obese asthma the effect of weight loss on small airway function. METHODS: TH2-low (n = 8) and TH2-high (n = 5) obese asthmatics underwent methacholine challenge before and 12 months following bariatric surgery. Dose-response slopes as measures of sensitivity to airway closure and narrowing were measured as maximum % fall forced vital capacity (FVC) and forced expiratory volume in 1 s/FVC, respectively, divided by dose. Resting airway mechanics were measured by forced oscillation technique. RESULTS: Weight loss reduced sensitivity to airway closure in TH 2-low but not TH2-high obese asthmatics (pre-post mean change ± 95% confidence interval: 1.8 ± 0.8 doubling doses vs -0.3 ± 1.7 doubling doses, P = 0.04). However, there was no effect of weight loss on the sensitivity to airway narrowing in either group (P = 0.8, TH2-low: 0.8 ± 1.0 doubling doses, TH2-high: -1.1 ± 2.5 doubling doses). In contrast, respiratory resistance (20 Hz) improved in TH2-high but not in TH2-low obese asthmatics (pre-post change median interquartile range: 1.5 (1.3-2.8) cmH2O/L/s vs 0.6 (-1.8-0.8) cmH2O/L/s, P = 0.03). CONCLUSIONS: TH2-low obese asthmatics appear to be characterized by increased small airway responsiveness and abnormalities in resting airway function that may persist following weight loss. However, this was not the case for TH2-high obese asthmatics, highlighting the complex interplay between IgE status and asthma pathophysiology in obesity.

A new physiological manikin to test and compare ventilation devices during cardiopulmonary resuscitation.

Background: There is a lack of bench systems permitting to evaluate ventilation devices in the specific context of cardiac arrest. Objectives: The objective of the study is to assess if a new physiological manikin may permit to evaluate the performances of medical devices dedicated to ventilation during cardiopulmonary resuscitation (CPR). Methods: Specific CPR-related features required to reproduce realistic ventilation were implemented into the SAM (Sarthe Anjou Mayenne) manikin. In the first place, the manikin ability to mimic ventilation during CPR was assessed and compared to real-life tracings of airway pressure, flow and capnogram from three out of hospital cardiac arrest (OHCA) patients. In addition, to illustrate the interest of this manikin, ventilation was evaluated during mechanical continuous chest compressions with two devices dedicated to CPR: the Boussignac cardiac arrest device (B-card - Vygon; Ecouen France) and the Impedance Threshold Device (ITD - Zoll; Chelmsford, MA). Results: The SAM manikin enabled precise replication of ventilation tracings as observed in three OHCA patients during CPR, and it allowed for comparison between two distinct ventilation devices. B-card generated a mean, maximum and minimum intrathoracic pressure of 6.3 (±0.1) cmH2O, 18.9 (±1.1) cmH2O and -0.3 (±0.2) cmH2O respectively; while ITD generated a mean, maximum and minimum intrathoracic pressure of -1.6 (±0.0) cmH2O, 5.7 (±0.1) cmH2O and -4.8 (±0.1) cmH2O respectively during CPR. B-card allowed to increase passive ventilation compared to the ITD which resulted in a dramatic limitation of passive ventilation. Conclusion: The SAM manikin is an innovative model integrating specific physiological features that permit to accurately evaluate and compare ventilation devices during CPR.

Airway opening pressure maneuver to detect airway closure in mechanically ventilated pediatric patients.

Background: Airway closure, which refers to the complete collapse of the airway, has been described under mechanical ventilation during anesthesia and more recently in adult patients with acute respiratory distress syndrome (ARDS). A ventilator maneuver can be used to identify airway closure and measure the pressure required for the airway to reopen, known as the airway opening pressure (AOP). Without that maneuver, AOP is unknown to clinicians. Objective: This study aims to demonstrate the technical adaptation of the adult maneuver for children and illustrate its application in two cases of pediatric ARDS (p-ARDS). Methods: A bench study was performed to adapt the maneuver for 3-50 kg patients. Four maneuvers were performed for each simulated patient, with 1, 2, 3, and 4 s of insufflation time to deliver a tidal volume (Vt) of 6 ml/kg by a continuous flow. Results: Airway closure was simulated, and AOP was visible at 15 cmH2O with a clear inflection point, except for the 3 kg simulated patient. Regarding insufflation time, a 4 s maneuver exhibited a better performance in 30 and 50 kg simulated patients since shorter insufflation times had excessive flowrates (>10 L/min). Below 20 kg, the difference in resistive pressure between a 3 s and a 4 sec maneuver was negligible; therefore, prolonging the maneuver beyond 3 s was not useful. Airway closure was identified in two p-ARDS patients, with the pediatric maneuver being employed in the 28 kg patient. Conclusions: We propose a pediatric AOP maneuver delivering 6 ml/kg of Vt at a continuous low-flow inflation for 3 s for patients weighing up to 20 kg and for 4 s for patients weighing beyond 20 kg.

Explorative study on lower inflection point dynamics during cardiopulmonary resuscitation: Potential implications for airway management.

INTRODUCTION: In patients undergoing cardiopulmonary resuscitation (CPR) after an Out-of-Hospital Cardiac Arrest (OHCA), intrathoracic airway closure can impede ventilation, adversely affecting patient outcomes. This explorative study investigates the evolution of intrathoracic airway closure by analyzing the lower inflection point (LIP) during the inspiration phase of CPR, aiming to identify the potential thresholds for alveolar recruitment. METHODS AND MATERIALS: Eleven OHCA patients undergoing CPR with endotracheal intubation and manual bag ventilation were included. Flow and pressure measurements were obtained using Sensirion SFM3200AW and Wika CPT2500 sensors attached to the endotracheal tube, connected to a Surface Go Tablet for data collection. Flow data was analyzed in Microsoft Excel, while pressure data was processed using the Wika USBsoft2500 application. Analysis focused on the inspiration phase of the first 6-8 breaths, with an additional 2 breaths recorded and analyzed at the end of CPR. RESULTS: Across the cohort, the median tidal volume was 870.00 milliliter (mL), average flow was 31.90 standard liters per minute (slm), and average pressure was 17.21 cmH2O. The calculated average LIP was 31.47 cmH2O. Most cases (72.7%) exhibited a negative trajectory in LIP evolution during CPR, with 2 cases (18.2%) showing a positive trajectory and 1 case remaining inconclusive. The average LIP in the first 8 breaths was significantly higher than in the last 2 breaths (p = 0.018). No significant correlation was found between average LIP and return of spontaneous circulation (ROSC), compression depth, frequency, or end-tidal CO2 (EtCO2). However, a significant negative correlation was observed between the average LIP of the last 2 breaths and CPR duration (p = 0.023). VALIDATION: LIP calculation in low-flow ventilations using the novel mathematical method yielded values consistent with those reported in the literature. DISCUSSION/CONCLUSION: These explorative data demonstrate a predominantly negative trajectory in LIP evolution during CPR, suggesting potential challenges in maintaining airway patency. Limitations include a small sample size and sensor recording issues. Further research is warranted to explore the evolution of LIP and its implications for personalized ventilation strategies in CPR.

Impact of airway closure and lung collapse on inhaled nitric oxide effect in acute lung injury: an experimental study.

BACKGROUND: Efficacy of inhaled therapy such as Nitric Oxide (iNO) during mechanical ventilation may depend on airway patency. We hypothesized that airway closure and lung collapse, countered by positive end-expiratory pressure (PEEP), influence iNO efficacy. This could support the role of an adequate PEEP titration for inhalation therapy. The main aim of this study was to assess the effect of iNO with PEEP set above or below the airway opening pressure (AOP) generated by airway closure, on hemodynamics and gas exchange in swine models of acute respiratory distress syndrome. Fourteen pigs randomly underwent either bilateral or asymmetrical two-hit model of lung injury. Airway closure and lung collapse were measured with electrical impedance tomography as well as ventilation/perfusion ratio (V/Q). After AOP detection, the effect of iNO (10ppm) was studied with PEEP set randomly above or below regional AOP. Respiratory mechanics, hemodynamics, and gas-exchange were recorded. RESULTS: All pigs presented airway closure (AOP > 0.5cmH2O) after injury. In bilateral injury, iNO was associated with an improved mean pulmonary pressure from 49 ± 8 to 42 ± 7mmHg; (p = 0.003), and ventilation/perfusion matching, caused by a reduction in pixels with low V/Q and shunt from 16%[IQR:13-19] to 9%[IQR:4-12] (p = 0.03) only at PEEP set above AOP. iNO had no effect on hemodynamics or gas exchange for PEEP below AOP (low V/Q 25%[IQR:16-30] to 23%[IQR:14-27]; p = 0.68). In asymmetrical injury, iNO improved pulmonary hemodynamics and ventilation/perfusion matching independently from the PEEP set. iNO was associated with improved oxygenation in all cases. CONCLUSIONS: In an animal model of bilateral lung injury, PEEP level relative to AOP markedly influences iNO efficacy on pulmonary hemodynamics and ventilation/perfusion match, independently of oxygenation.

Relationship between airway pathophysiology and airway inflammation in older asthmatics.

BACKGROUND AND OBJECTIVE: Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma, neutrophil airway inflammation increases airway closure during bronchoconstriction, while eosinophil airway inflammation increases airway hyperresponsiveness (AHR). METHODS: Asthmatic subjects (n = 26), aged ≥55 years (68% female), were studied, and AHR to 4.5% saline challenge was measured by the response-dose ratio (%fall in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). RESULTS: Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P < 0.001), but not with neutrophils or neutrophil mediators. The Closing Index correlated with total sputum neutrophils (r = 0.66, P = 0.005), neutrophil elastase, matrix metalloproteinase-9 and interleukin-8 (all P < 0.05). Further, FEV1 /FVC and residual volume/total lung capacity at rest correlated with neutrophil elastase (r = -0.46 and 0.66 respectively, P < 0.05) but not with eosinophils or eNO. CONCLUSIONS: In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during bronchoconstriction. The clinical implications of these findings remain to be determined.

Lung de-recruitment in the allergic asthma of obesity: evidence from an anatomically based inverse model.

The increase in asthma associated with the obesity epidemic cannot simply be due to airway hyperresponsiveness from chronic lung compression because chronic lung compression is a feature of obesity in general. We therefore sought to investigate what other factors might be at play in the impaired lung function seen in obese individuals with asthma. We measured respiratory system impedance in four groups-Lean Control, Lean Allergic Asthma, Obese Control, and Obese Allergic Asthma-before and after administration of albuterol. Impedance measurements were fit with an anatomically based computational model of lung mechanics that represents the airway tree as a branching structure with a uniform degree of asymmetry and a fixed radius scaling ratio, γ, between branches of sequential order. The two model parameters that define the airway tree, γ and tracheal radius, varied only modestly between the four study groups, indicating relatively minor differences in airway caliber. In contrast, respiratory system elastance was 57, 34, 143, and 271 cmH2O/L, respectively, for the four groups, suggesting that obesity induced significant lung de-recruitment that was exacerbated by allergic asthma. In addition, when the radii of the individual branches of the airway tree were varied randomly, we found that roughly half the terminal airways had to be closed to have the model fit the data well. We conclude that de-recruitment of small airways is a particular feature of Obese Allergic Asthma, and this can be inferred from respiratory system impedance fit with an anatomically based computational model.NEW & NOTEWORTHY Using a novel anatomically based computational model to interpret oscillometry measurements of impedance, we show that respiratory system elastance is increased in obesity and is increased dramatically in individuals with obese allergic asthma. A significant component of this increased elastance in obese allergic asthma appears to be due to closure of small airways rather than alveolar atelectasis, and this closure is partially mitigated by albuterol. These findings potentially point to nonpharmacological therapies in obese allergic asthma aimed at recruiting closed airways.