Timothy E. Corcoran

HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction

Bronchiolitis obliterans syndrome (BOS) represents a major limitation in lung transplantation. While acute rejection is widely considered the most important risk factor for BOS, the impact of HLA‐specific antibodies is less understood. Of 51 lung recipients who were prospectively tested during a 4.2 ± 1.6‐year period, 14 patients developed HLA‐specific antibodies. A multi‐factorial analysis was performed to correlate the prevalence of BOS with HLA antibodies, persistent‐recurrent acute rejection (ACR‐PR), lymphocytic bronchiolitis, and HLA‐A, ‐B, and ‐DR mismatches. HLA‐specific antibodies were associated with ACR‐PR (10/14 vs. 11/37 with no antibodies, p < 0.05), lymphocytic bronchiolitis (8/14 vs. 10/37, p < 0.05), and BOS (10/14, vs. 9/37, p < 0.005). Other risk factors for BOS were: lymphocytic bronchiolitis (13/18 vs. 6/33 with no lymphocytic bronchiolitis, p < 0.0001), ACR‐PR (12/21 vs. 7/30 with no ACR‐PR, p < 0.05), and the number of HLA‐DR mismatches (1.7 ± 0.48 in BOS vs. 1.2 ± 0.63 without BOS, p < 0.05). The presence of antibodies exhibited a cumulative effect on BOS when it was associated with either lymphocytic bronchiolitis or ACR‐PR. The complex relationship between the development of HLA antibodies and acute and chronic lung allograft rejection determines the importance of post‐transplant screening for HLA‐specific antibodies as a prognostic element for lung allograft outcome.

Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial.

Background. Helium and oxygen mixtures (heliox) increase both pulmonary aerosol delivery and gas delivery relative to oxygen. We aimed to compare the effectiveness of a 70%:30% helium/oxygen (heliox)–driven continuous aerosol delivery versus 100% oxygen-driven delivery in the treatment of asthmatic children with moderate to severe exacerbations. Methods. We enrolled 30 children aged 2 to 18 years who presented to an urban, pediatric emergency department (ED) with moderate to severe asthma as defined by a pulmonary index (PI) score of ≥8. PI scores can range from 0 to 15. In this randomized, controlled, single-blind trial conducted in a convenience sample of children, all patients in the trial received an initial nebulized albuterol (5 mg) treatment driven by 100% oxygen and a dose of oral prednisone or prednisolone. Subsequently, patients were randomly assigned to receive continuously nebulized albuterol (15 mg/hour) delivered by either heliox or oxygen using a nonrebreathing face mask. The primary outcome measure was degree of improvement as assessed in blinded video-recorded PI scores over 240 minutes (at 30-minute intervals for the first 3 hours) or until ED discharge (if <240 minutes). Results. The mean change in PI score from baseline to 240 minutes or ED discharge was 6.67 for the heliox group compared with 3.33 for the oxygen group. Eleven (73%) patients in the heliox group were discharged from the hospital in <12 hours compared with 5 (33%) patients in the conventional group. Conclusion. Continuously nebulized albuterol delivered by heliox was associated with a greater degree of clinical improvement compared with that delivered by oxygen among children with moderate to severe asthma exacerbations.

Aerosol Delivery through Nasal Cannulas: An In Vitro Study

In most circumstances, a nasal route for the delivery of pulmonary aerosol medications is rarely considered; however, in specific instances, this route may be quite useful. Consider, for example, the delivery of aerosol treatments during humidified high-flow nasal cannula use in pediatric critical care, or continuous aerosol delivery via cannula for medications with short durations of action. The goal of this study was to evaluate the potential for delivering aerosols via nasal cannula through in vitro studies of aerosol output and size. The system utilized for testing included an Aerogen Solo nebulizer downstream of a heater/humidifier system, followed by a nasal cannula and an aerosol collection apparatus. Adult, pediatric, and infant cannulas were tested with and without an inhalation-only breathing simulator. The cannulas were driven by 3 lpm (50 psig) oxygen flows. Dose quantification was performed using radioisotope techniques. Total cannula output and system losses were measured. Aerosol size measurements were made from the nebulizer, from the heating tube, and from the prongs of the adult and pediatric cannulas, using laser-diffraction techniques. Total cannula output ranged from 8.4-25.1% and 18.6-26.9% of loaded dose, without and with the addition of inhalation flows. Volume median diameters were 2.2 +/- 0.2 microm from the adult cannula and 1.9 +/- 0.3 microm from the pediatric cannula. Ninety percent of the aerosol volume was in sizes smaller than 4.2 +/- 0.4 microm (adult) and 3.8 +/- 0.5 microm (pediatric). System losses were highest in the nebulizer-humidifier connectors, heated tube, and humidifier. Losses in the nebulizer were very low (2.2-3.5%). This study demonstrates that aerosols can be efficiently delivered through a humidified high-flow nasal cannula system. Further study is required to determine if this route is viable for pulmonary delivery.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2–3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients.

Lung transplant recipients exhibit a high incidence of invasive aspergillosis. The inhalation of lipid complex amphotericin‐B (Abelcet; ABLC) offers a possible prophylactic strategy. The goals of this study were to select the optimal nebulizer delivery system for ABLC and to measure deposited aerosol dose in 12 lung transplant recipients. In vitro testing was performed to select a nebulizer delivery system, and an empirical model was used to estimate lung deposition. Estimated pulmonary doses varied by as much as 2‐fold between different nebulizers. Aerosol deposition testing was performed in six single and six double lung recipients, each of whom received one 7 mL (35 mg) nebulized dose of Technetium‐labeled ABLC using the selected nebulizer. In single lung recipients, the average deposited doses were 3.9 ± 1.6 mg (mean ± S.D.) in the allograft versus 2.1 ± 1.1 mg in the native lung. Double lung recipients deposited on average 2.8 ± 0.8 mg (left lung) and 4.0 ± 1.3 mg (right lung). The drug was well distributed throughout the lungs, but delivery to the native lung was in some cases suboptimal. These studies provide an important precursor to studies of the efficacy of inhaled ABLC as a prophylaxis of invasive aspergillosis after lung transplant.

A Numerical and Experimental Study of Spray Dynamics in a Simple Throat Model

An inhalation airflow through a simple model of the human larynx and trachea, containing dispersed drug spray droplets, is studied numerically using the Computational Fluid Dynamics (CFD) code KIVA-3V (Amsden 1997) and experimentally using phase doppler interferometry. Flow conditions within the larynx and trachea affect the delivery of inhaled medications to the lungs. Deposition in these regions is considered undesirable and has been shown to be a particular problem for pediatric patients. The larynx geometry is represented by a constricted portion inside a straight tube. This constriction simulates the vocal folds within the larynx. The experimental model was 3.2 cm in diameter (approximately twice human scale) and 90 cm long. The constriction was 0.7 cm thick and was placed 30 cm from the inlet of the tube. The area of the constricted opening is approximately 40% of the tube area. Water droplets are introduced into the low-turbulence upstream airflow using a jet nebulizer. Measurements of axial velocity and axial turbulence intensity were made through an array of points between 2 diameters upstream and 4 diameters downstream of the constriction. Steady flows were used and the flow rates scaled to match in vivo tracheal Reynolds numbers simulating two different breathing conditions. The KIVA-3V code is specifically designed to analyze transient, two- and three-dimensional, chemically reactive fluid flows with sprays. The analysis considers spray dynamic effects such as coalescence, evaporation, deposition, and turbulent dispersion. The numeric simulation is carried out in a model consisting of a 21.7 cm long pipe simulating the measurement region. All other dimensions are identical to the experimental model. Several significant spray deposition mechanisms were notable in both the experimental and the numerical results.

Lung Deposition and Pharmacokinetics of Cyclosporine After Aerosolization in Lung Transplant Patients

AbstractPurpose. Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period. Methods. Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition. Results. Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t1/2 λz) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 ± 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 ± 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed. Conclusions. This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.

Computational Simulations of Airflow in an In Vitro Model of the Pediatric Upper Airways

In order to understand mechanisms of gas and aerosol transport in the human respiratory system airflow in the upper airways of a pediatric subject (male aged 5) was calculated using Computational Fluid Dynamic techniques. An in vitro reconstruction of the subjects anatomy was produced from MRI images. Flow fields were solved for steady inhalation at 6.4 and 8 LPM. For validation of the numerical solution, airflow in an adult cadaver based trachea was solved using identical numerical methods. Comparisons were made between experimental results and computational data of the adult model to determine solution validity. It was found that numerical simulations can provide an accurate representation of axial velocities and turbulence intensity. Data on flow resistance, axial velocities, secondary velocity vectors, and turbulent kinetic energy are presented for the pediatric case. Turbulent kinetic energy and axial velocities were heavily dependant on flow rate, whereas turbulence intensity varied less over the flow rates studied. The laryngeal jet from an adult model was compared to the laryngeal jet in the pediatric model based on Tracheal Reynolds number. The pediatric case indicated that children show axial velocities in the laryngeal jet comparable to adults, who have much higher tracheal Reynolds numbers than children due to larger characteristic dimensions. The intensity of turbulence follows a similar trend, with higher turbulent kinetic energy levels in the pediatric model than would be expected from measurements in adults at similar tracheal Reynolds numbers. There was reasonable agreement between the location of flow structures between adults and children, suggesting that an unknown length scale correlation factor could exist that would produce acceptable predictions of pediatric velocimetry based off of adult data sets. A combined scale for turbulent intensity as well may not exist due to the complex nature of turbulence production and dissipation.

Improving Drug Delivery from Medical Nebulizers: The Effects of Increased Nebulizer Flow Rates and Reservoirs

Drug delivery from jet nebulizers can be considered in terms of the dose inhaled and the respirability of that dose. It is proposed that dose respirability and dose per breath can be controlled through specification of the driving gas flowrate, and that the dose inhaled per breath can also be increased through the use of nebulizer reservoirs. When a Hudson Micromist nebulizer was used and assessments of respirability were made utilizing phase Doppler interferometry, it was noted that the portion of the spray mass in droplet sizes of <or=5 microm (general respirability) and in droplet sizes of <or=3 microm (deep lung respirability) increased linearly with gas flowrate for both tank air and helium-oxygen (70/30). Drug mass in the 2-6 microm range (tracheobronchial respirability) peaked at air flowrates of 8-10 LPM and decreased slightly for higher flowrates. Two portable compressors provided respirabilities similar to tank air at the same flowrates. Changing the nebulizer flowrate did not affect the ratio of the inhaled dose to the dose expelled by exhalation when a typical breathing pattern was simulated. A version of the Micromist with an attached reservoir (the Hudson AeroTee) provided a higher dose per breath to the patient and a higher total dose for the same treatment time by conserving the aerosol generated during exhalation. The inhaled dose increased approximately 28% when compared to a standard Micromist, despite significant deposition in the reservoir bag. Nebulizer reservoirs could be used to attain higher doses or to more efficiently utilize expensive medications.

Preservation of post-transplant lung function with aerosol cyclosporin

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2‐yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing ≥5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2–A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.