Pulmonary Vascular Dysfunctions in Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the CFTR protein is a chloride channel expressed on a variety of cells throughout the human body, mutations in this gene impact several organs, particularly the lungs. For this very reason, research regarding CF disease and CFTR function has historically focused on the lung airway epithelium. Nevertheless, it was discovered more than two decades ago that CFTR is also expressed and functional on endothelial cells. Despite the great strides that have been made in understanding the role of CFTR in the airway epithelium, the role of CFTR in the endothelium remains unclear. Considering that the airway epithelium and endothelium work in tandem to allow gas exchange, it becomes very crucial to understand how a defective CFTR protein can impact the pulmonary vasculature and overall lung function. Fortunately, more recent research has been dedicated to elucidating the role of CFTR in the endothelium. As a result, several vascular dysfunctions associated with CF disease have come to light. Here, we summarize the current knowledge on pulmonary vascular dysfunctions in CF and discuss applicable therapies.

Predicting critical closing pressure in children with obstructive sleep apnea using fluid-structure interaction.

Surgical treatment of obstructive sleep apnea (OSA) in children requires knowledge of upper airway dynamics, including the closing pressure (Pcrit), a measure of airway collapsibility. We applied a flow-structure interaction (FSI) computational model to estimate Pcrit in patient-specific upper airway models obtained from magnetic resonance imaging (MRI) scans. We sought to examine the agreement between measured and estimated Pcrit from FSI models in children with Down syndrome. We hypothesized that the estimated Pcrit would accurately reflect measured Pcrit during sleep and therefore reflect the severity of OSA as measured by the obstructive apnea-hypopnea index (AHI). All participants (n = 41) underwent polysomnography and sedated sleep MRI scans. We used Bland-Altman plots to examine the agreement between measured and estimated Pcrit. We determined associations between estimated Pcrit and OSA severity, as measured by AHI, using regression models. The agreement between passive and estimated Pcrit showed a fixed bias of -1.31 [confidence interval (CI) = -2.78, 0.15] and a nonsignificant proportional bias. A weaker agreement with active Pcrit was observed. A model including AHI, gender, an interaction term for AHI, and gender and neck circumference explained the largest variation (R2 = 0.61) in the relationship between AHI and estimated Pcrit (P < 0.0001). Overlap between the areas of the airway with the lowest stiffness, and areas of collapse on dynamic MRI, was 77.4 ± 30% for the nasopharyngeal region and 78.6 ± 33% for the retroglossal region. The agreement between measured and estimated Pcrit and the significant association with AHI supports the validity of Pcrit estimates from the FSI model.NEW & NOTEWORTHY We present a noninvasive method for estimating critical closing pressure (Pcrit) using fluid-structure interaction (FSI) simulations and magnetic resonance imaging (MRI) scans in patients with obstructive sleep apnea (OSA). We used patient-specific stiffness measures in our FSI model to account for any individual variability in the elasticity of soft tissues surrounding the upper airway. We validated this model by measuring the degree of agreement between measured and estimated Pcrit.

Effects on the Upper Airway Morphology with Intravenous Addition of Ketamine after Dexmedetomidine Administration in Normal Children.

General anesthesia decreases the tone of upper airway muscles in a dose-dependent fashion, potentially narrowing the pharyngeal airway. We examined the effects of adding ketamine on the airway configuration after dexmedetomidine administration in spontaneously breathing children with normal airways. 25 children presenting for Magnetic Resonance Imaging (MRI) of the brain/spine under general anesthesia were prospectively recruited in the study. Patients were anesthetized with dexmedetomidine bolus (2 mcg over 10 min) followed by dexmedetomidine infusion (2 mcg·kg-1·h) and ketamine and permitted to breathe spontaneously via the native airway. MR-CINE images of the upper airway were obtained with dexmedetomidine infusion alone (baseline) and 5, 10, and 15 min after administering ketamine bolus (2 mg·kg-1) in two anatomical axial planes at the nasopharynx and the retroglossal upper airway. Airway lumen is segmented with a semi-automatic image processing approach using a region-growing algorithm. Outcome measures of cross-sectional area, transverse and anterior-posterior diameters of the airway in axial planes at the level of the epiglottis in the retroglossal airway, and in the superior nasopharynx were evaluated for changes in airway size with sedation. Airway dimensions corresponding to the maximum, mean, and minimum sizes during a respiratory cycle were obtained to compare the temporal changes in the airway size. The dose-response of adding ketamine to dexmedetomidine alone condition on airway dimensions were examined using mixed-effects of covariance models. 22/25 patients based on inclusion/exclusion criteria were included in the final analysis. The changes in airway measures with the addition of ketamine, when compared to the baseline of dexmedetomidine alone, were statistically insignificant. The modest changes in airway dimensions are clinically less impactful and within the accuracy of the semi-automatic airway segmentation approach. The effect sizes were small for most airway measures. The duration of ketamine seems to not affect the airway size. In conclusion, adding ketamine to dexmedetomidine did not significantly reduce upper airway configuration when compared to dexmedetomidine alone.

Effect of airflow and material models on tissue displacement for surgical planning of pharyngeal airways in pediatric down syndrome patients.

Pharyngeal narrowing in obstructive sleep apnea (OSA) results from flow-induced displacement of soft tissue. The objective of this study is to evaluate the effect of airflow parameters and material model on soft tissue displacement for planning surgical treatment in pediatric patients with OSA and Down syndrome (DS). Anatomically accurate, three-dimensional geometries of the pharynx and supporting tissue were reconstructed for one pediatric OSA patient with DS using magnetic resonance images. Six millimeters of adenoid tissue was virtually removed based on recommendations from the surgeon, to replicate the actual adenoidectomy. Computational simulations of flow-induced obstruction of the pharynx during inspiration were performed using patient-specific values of tissue elasticity for pre and post-operative airways. Sensitivity of tissue displacement to selection of turbulence model, variation in inspiratory airflow, nasal airway resistance and choice of non-linear material model was evaluated. The displacement was less sensitive to selection of turbulence model (10% difference) and more sensitive to airflow rate (20% difference) and nasal resistance (30% difference). The sensitivity analysis indicated that selection of Neo-Hookean, Yeoh, Mooney-Rivlin or Gent models would result in identical tissue displacements (less than 1% difference) for the same flow conditions. Change in pharyngeal airway resistance between the rigid and collapsible models was nearly twice for the pre-operative case as compared to the post-operative scenario. The tissue strain at the site of obstruction in the velopharyngeal airway was lowered by approximately 84% following surgery. Inclusion of tissue elasticity resulted in better agreement with the actual surgical outcome compared to a rigid wall assumption, thereby emphasizing the importance of pharyngeal compliance for guiding treatment in pediatric OSA patients.

Upper Airway Reflexes are Preserved During Dexmedetomidine Sedation in Children With Down Syndrome and Obstructive Sleep Apnea.

STUDY OBJECTIVES: The assessment of pharyngeal collapsibility is difficult to perform in children under normal sleep. An alternative is to perform the assessment under an anesthetic, such as dexmedetomidine (DEX), that induces non-rapid eye movement (NREM) sleep. The objectives of this study were to compare critical closing airway pressure (Pcrit) obtained during natural sleep to that obtained under DEX in patients with Down syndrome (DS) and persistent obstructive sleep apnea (OSA) and determine whether Pcrit measured under sedation predicts the severity of OSA. METHODS: The passive and active Pcrit, which represent airway passive mechanical properties and active dynamic responses to airway obstruction, respectively, were measured. Upper airway reflex activity was estimated by calculating the difference between active and passive Pcrit. Subjects underwent overnight polysomnography during which Pcrit was measured during normal sleep. Pcrit was also measured during DEX sedation at a dose of 2 µg/kg/h. RESULTS: The study included 50 patients with median age of 11.4 years (interquartile range: 7.0-13.9) and median body mass index of 23.0 kg/m2 (interquartile range: 18.4-29.1), 66% male and 80% Caucasian. Passive Pcrit was significantly higher than active Pcrit when measured during normal sleep and DEX-induced sleep. There was a positive association between apnea-hypopnea index and passive Pcrit (Spearman r = 0.53, P = .0001) and active Pcrit (r = 0.55, P = .0002) under DEX-induced sleep. There were no significant differences between the Pcrit measurements during natural sleep and during DEX sedation. CONCLUSION: Patients with OSA can compensate for airway obstruction under DEX-induced sleep. The close association between Pcrit and apnea-hypopnea index suggests that airway responses with DEX sedation parallel those seen during natural sleep. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01902407.

Continuous measurement of aortic dimensions in Turner syndrome: a cardiovascular magnetic resonance study.

BACKGROUND: Severity of thoracic aortic disease in Turner syndrome (TS) patients is currently described through measures of aorta size and geometry at discrete locations. The objective of this study is to develop an improved measurement tool that quantifies changes in size and geometry over time, continuously along the length of the thoracic aorta. METHODS: Cardiovascular magnetic resonance (CMR) scans for 15 TS patients [41 ± 9 years (mean age ± standard deviation (SD))] were acquired over a 10-year period and compared with ten healthy gender and age-matched controls. Three-dimensional aortic geometries were reconstructed, smoothed and clipped, which was followed by identification of centerlines and planes normal to the centerlines. Geometric variables, including maximum diameter and cross-sectional area, were evaluated continuously along the thoracic aorta. Distance maps were computed for TS and compared to the corresponding maps for controls, to highlight any asymmetry and dimensional differences between diseased and normal aortae. Furthermore, a registration scheme was proposed to estimate localized changes in aorta geometry between visits. The estimated maximum diameter from the continuous method was then compared with corresponding manual measurements at 7 discrete locations for each visit and for changes between visits. RESULTS: Manual measures at the seven positions and the corresponding continuous measurements of maximum diameter for all visits considered, correlated highly (R-value = 0.77, P < 0.01). There was good agreement between manual and continuous measurement methods for visit-to-visit changes in maximum diameter. The continuous method was less sensitive to inter-user variability [0.2 ± 2.3 mm (mean difference in diameters ± SD)] and choice of smoothing software [0.3 ± 1.3 mm]. Aortic diameters were larger in TS than controls in the ascending [TS: 13.4 ± 2.1 mm (mean distance ± SD), Controls: 12.6 ± 1 mm] and descending [TS: 10.2 ± 1.3 mm (mean distance ± SD), Controls: 9.5 ± 0.9 mm] thoracic aorta as observed from the distance maps. CONCLUSIONS: An automated methodology is presented that enables rapid and precise three-dimensional measurement of thoracic aortic geometry, which can serve as an improved tool to define disease severity and monitor disease progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier - NCT01678274 . Registered - 08.30.2012.

Dynamic Volume Computed Tomography Imaging of the Upper Airway in Obstructive Sleep Apnea.

STUDY OBJECTIVES: To describe a dynamic three-dimensional (3D) computed tomography (CT) technique for the upper airway and compare the required radiation dose to that used for common clinical studies of a similar anatomical area, such as for subjects undergoing routine clinical facial CT. METHODS: Dynamic upper-airway CT was performed on eight subjects with persistent obstructive sleep apnea, four of whom were undergoing magnetic resonance imaging and an additional four subjects who had a contraindication to magnetic resonance imaging. This Health Insurance Portability and Accountability Act-compliant study was approved by our institutional review board, and informed consent was obtained. The control subjects (n = 41) for comparison of radiation dose were obtained from a retrospective review of the clinical picture-archiving computer system to identify 10 age-matched patients per age-based control group undergoing facial CT. RESULTS: Dynamic 3D CT can be performed with an effective radiation dose of less than 0.38 mSv, a dose that is less than or comparable to that used for clinical facial CT. The resulting data- set is a uniquely complete, dynamic 3D volume of the upper airway through a full respiratory cycle that can be processed for clinical and modeling analyses. CONCLUSIONS: A dynamic 3D CT technique of the upper airway is described that can be performed with a clinically reasonable radiation dose and sets a benchmark for future use.

Computational Modeling of Airway Obstruction in Sleep Apnea in Down Syndrome: A Feasibility Study.

Current treatment options are successful in 40% to 60% of children with persistent obstructive sleep apnea after adenotonsillectomy. Residual obstruction assessments are largely subjective and do not clearly define multilevel obstruction. We endeavor to use computational fluid dynamics to perform virtual surgery and assess airflow changes in patients with Down syndrome and persistent obstructive sleep apnea. Three-dimensional airway models were reconstructed from respiratory-gated computed tomography and magnetic resonance imaging. Virtual surgeries were performed on 10 patients, mirroring actual surgeries. They demonstrated how surgical changes affect airflow resistance. Airflow and upper airway resistance was calculated from computational fluid dynamics. Virtual and actual surgery outcomes were compared with obstructive apnea-hypopnea index values. Actual surgery successfully treated 6 of 10 patients (postoperative obstructive apnea-hypopnea index <5). In 8 of 10 subjects, both apnea-hypopnea index and the calculated upper airway resistance after virtual surgery decreased as compared with baseline values. This is a feasibility and proof-of-concept study. Further studies are needed before using these techniques in surgical planning.

Upper Airway Elasticity Estimation in Pediatric Down Syndrome Sleep Apnea Patients Using Collapsible Tube Theory.

Elasticity of the soft tissues surrounding the upper airway lumen is one of the important factors contributing to upper airway disorders such as snoring and obstructive sleep apnea. The objective of this study is to calculate patient specific elasticity of the pharynx from magnetic resonance (MR) images using a 'tube law', i.e., the relationship between airway cross-sectional area and transmural pressure difference. MR imaging was performed under anesthesia in children with Down syndrome (DS) and obstructive sleep apnea (OSA). An airway segmentation algorithm was employed to evaluate changes in airway cross-sectional area dilated by continuous positive airway pressure (CPAP). A pressure-area relation was used to make localized estimates of airway wall stiffness for each patient. Optimized values of patient specific Young's modulus for tissue in the velopharynx and oropharynx, were estimated from finite element simulations of airway collapse. Patient specific deformation of the airway wall under CPAP was found to exhibit either a non-linear 'hardening' or 'softening' behavior. The localized airway and tissue elasticity were found to increase with increasing severity of OSA. Elasticity based patient phenotyping can potentially assist clinicians in decision making on CPAP and airway or tissue elasticity can supplement well-known clinical measures of OSA severity.

Compliance Measurements of the Upper Airway in Pediatric Down Syndrome Sleep Apnea Patients.

Compliance of soft tissue and muscle supporting the upper airway are two of several factors contributing to pharyngeal airway collapse. We present a novel, minimally invasive method of estimating regional variations in pharyngeal elasticity. Magnetic resonance images for pediatric sleep apnea patients with Down syndrome [9.5 ± 4.3 years (mean age ± standard deviation)] were analyzed to segment airways corresponding to baseline (no mask pressure) and two positive pressures. A three dimensional map was created to evaluate axial and circumferential variation in radial displacements of the airway, dilated by the positive pressures. The displacements were then normalized with respect to the appropriate transmural pressure and radius of an equivalent circle to obtain a measure of airway compliance. The resulting elasticity maps indicated the least and most compliant regions of the pharynx. Airway stiffness of the most compliant region [403 ± 204 (mean ± standard deviation) Pa] decreased with severity of obstructive sleep apnea. The non-linear response of the airway wall to continuous positive airway pressure was patient specific and varied between anatomical locations. We identified two distinct elasticity phenotypes. Patient phenotyping based on airway elasticity can potentially assist clinical practitioners in decision making on the treatments needed to improve airway patency.

Numerical investigation of mass transport through patient-specific deformed aortae.

Blood flow in human arteries has been investigated using computational fluid dynamics tools. This paper considers flow modeling through three aorta models reconstructed from cross-sectional magnetic resonance scans of female patients. One has the normal control configuration, the second has elongation of the transverse aorta, and the third has tortuosity of the aorta with stenosis. The objective of this study is to determine the impact of aortic abnormal geometries on the wall shear stress (WSS), luminal surface low-density lipoproteins (LDLs) concentration, and oxygen flux along the arterial wall. The results show that the curvature of the aortic arch and the stenosis have significant effects on the blood flow, and in turn, the mass transport. The location of hypoxia areas can be predicted well by ignoring the effect of hemoglobin on the oxygen transport. However, this simplification indeed alters the absolute value of Sherwood number on the wall.

Planning human upper airway surgery using computational fluid dynamics.

The study advances the idea of using computational fluid dynamics in the process of planning surgical treatment modalities for patients with obstructive airway disorders. It is hypothesized that the a priori knowledge of the functional outcome of surgical intervention on the flow and airway resistance can guide the surgeon in choosing an effective surgical strategy. Computed tomography images spanning the respiratory tract of an adult patient with a combined glottic and subglottic stenosis are used to reconstruct three-dimensional geometrical models of the airway. Computational fluid dynamics is used to obtain airway flow patterns during inspiration and expiration in these models. Numerical predictions about flow velocity, pressure distribution on the airway lumen, wall shear stress, and airway resistance are obtained so that the relevance of each individual stenotic level is quantified. Four different virtual surgeries in different combinations are assessed in order to remedy the constricted airway. The virtual surgery based airway models are evaluated by comparisons with the pre-treatment flow modeling results. The predicted numerical data revealed that the removal of the constriction at the level of the vocal folds will have the most significant effect on the airway resistance. The flow simulations offer a quantitative method of evaluating the airway resistance in patients with combined glottic and subglottic stenoses. Predictions of airway resistances and other numerical calculations from different virtual surgeries give additional inputs for the surgeon, in deciding the most appropriate surgery on a case-by-case basis.

Patterns in pharyngeal airflow associated with sleep-disordered breathing.

OBJECTIVE: To establish the feasibility of a noninvasive method to identify pharyngeal airflow characteristics in sleep-disordered breathing. METHODS: Four patients with sleep-disordered breathing who underwent surgery or used positive airway pressure devices and four normal healthy controls were studied. Three-dimensional CT imaging and computational fluid dynamics modeling with standard steady-state numerical formulation were used to characterize pharyngeal airflow behavior in normals and pre-and post-treatment in patients. Dynamic flow simulations using an unsteady approach were performed in one patient. RESULTS: The pre-treatment pharyngeal airway below the minimum cross-sectional area obstruction site showed airflow separation. This generated recirculation airflow regions and enhanced turbulence zones where vortices developed. This interaction induced large fluctuations in airflow variables and increased aerodynamic forces acting on the pharyngeal wall. At post-treatment, for the same volumetric flow rate, airflow field instabilities vanished and airflow characteristics improved. Mean maximum airflow velocity during inspiration reduced from 18.3±5.7 m/s pre-treatment to 6.3±4.5 m/s post-treatment (P=0.002), leading to a reduction in maximum wall shear stress from 4.8±1.7 Pa pre-treatment to 0.9±1.0 Pa post-treatment (P=0.01). The airway resistance improved from 4.3±1.4 Pa/L/min at pre-treatment to 0.7±0.7 Pa/L/min at post-treatment (P=0.004). Post-treatment airflow characteristics were not different from normal controls (all P ≥ 0.39). CONCLUSION: This study demonstrates that pharyngeal airflow variables may be derived from CT imaging and computational fluid dynamics modeling, resulting in high quality visualizations of airflow characteristics of axial velocity, static pressure, and wall shear stress in sleep-disordered breathing.

Large eddy simulation of the pharyngeal airflow associated with obstructive sleep apnea syndrome at pre and post-surgical treatment.

Obstructive Sleep Apnea Syndrome (OSAS) is the most common sleep-disordered breathing medical condition and a potentially life-threatening affliction. Not all the surgical or non-surgical OSAS therapies are successful for each patient, also in part because the primary factors involved in the etiology of this disorder are not completely understood. Thus, there is a need for improving both diagnostic and treatment modalities associated with OSAS. A verified and validated (in terms of mean velocity and pressure fields) Large Eddy Simulation approach is used to characterize the abnormal pharyngeal airflow associated with severe OSAS and its interaction with the airway wall in a subject who underwent surgical treatment. The analysis of the unsteady flow at pre- and post-treatment is used to illustrate the airflow dynamics in the airway associated with OSAS and to reveal as well, the changes in the flow variables after the treatment. At pre-treatment, large airflow velocity and wall shear stress values were found at the obstruction site in all cases. Downstream of obstruction, flow separation generated flow recirculation regions and enhanced the turbulence production in the jet-like shear layers. The interaction between the generated vortical structures and the pharyngeal airway wall induced large fluctuations in the pressure forces acting on the pharyngeal wall. After the surgery, the flow field instabilities vanished and both airway resistance and wall shear stress values were significantly reduced.

Influence of gender on pharyngeal airway length in obese adolescents.

OBJECTIVES: Although pharyngeal airway length has been implicated in an increased male predisposition for obstructive sleep apnea (OSA) in adults, data in obese children and adolescents are lacking. Our objective was to determine the influence of gender on pharyngeal airway length in obese adolescents, and to apply computational simulations to better understand the effect of pharyngeal airway length on the airway's predisposition to collapse in this select group. METHODS: Obese subjects without OSA were recruited from our Sleep Center. Their pharyngeal airway length was measured on midline sagittal magnetic resonance images as the distance between the hard palate and the base of the epiglottis. Computational fluid dynamics analysis was used to study the effect of pharyngeal airway length on airflow characteristics. The gender groups were compared for anthropometric measurements and pharyngeal airway length by an unpaired Student's t-test. RESULTS: Our study group included 18 female and 16 male obese adolescents with a mean (+/-SD) age of 14.7 +/- 2.3 years and a mean body mass index of 38.9 +/- 6.9 kg/m2. The groups did not differ in age, body weight, or normalized pharyngeal airway length (0.44 +/- 0.08 mm/cm in girls versus 0.44 +/- 0.11 mm/cm in boys; p = 0.9). The computational fluid dynamics simulation indicated that the 3-dimensional flow field and airway wall pressures were not significantly affected by pharyngeal airway lengthening of up to 10 mm. CONCLUSIONS: Our results indicate that in obese adolescents, there is no influence of gender on pharyngeal airway length, and pharyngeal airway length alone does not significantly affect the airway's predisposition to collapse. These findings suggest that pharyngeal airway length may not explain the increased male gender predisposition for OSA in this select group.

Validation of computational fluid dynamics methodology used for human upper airway flow simulations.

An anatomically accurate human upper airway model was constructed from multiple magnetic resonance imaging axial scans. This model was used to conduct detailed Computational Fluid Dynamics (CFD) simulations during expiration, to investigate the fluid flow in the airway regions where obstruction could occur. An identical physical model of the same airway was built using stereo lithography. Pressure and velocity measurements were conducted in the physical model. Both simulations and experiments were performed at a peak expiratory flow rate of 200 L/min. Several different numerical approaches within the FLUENT commercial software framework were used in the simulations; unsteady Large Eddy Simulation (LES), steady Reynolds-Averaged Navier-Stokes (RANS) with two-equation turbulence models (i.e. k-epsilon, standard k-omega, and k-omega Shear Stress Transport (SST)) and with one-equation Spalart-Allmaras model. The CFD predictions of the average wall static pressures at different locations along the airway wall were favorably compared with the experimental data. Among all the approaches, standard k-omega turbulence model resulted in the best agreement with the static pressure measurements, with an average error of approximately 20% over all ports. The highest positive pressures were observed in the retroglossal regions below the epiglottis, while the lowest negative pressures were recorded in the retropalatal region. The latter is a result of the airflow acceleration in the narrow retropalatal region. The largest pressure drop was observed at the tip of the soft palate. This location has the smallest cross section of the airway. The good agreement between the computations and the experimental results suggest that CFD simulations can be used to accurately compute aerodynamic flow characteristics of the upper airway.